Ted Reichborn-Kjennerud

• Hoyos, Lucía de; Schlag, Fenja; Jahagirdar, Sanjeevan; Corfield, Elizabeth Claire; Allegrini, Andrea G. & Admiraal, Danielle [Vis alle 95 forfattere av denne artikkelen] (2026). Genome-wide analysis of social behaviour across social domains, reporters and developmental stages: a meta-regression approach. Nature Human Behaviour. doi: 10.1038/s41562-026-02551-z. Fulltekst i vitenarkiv Vis sammendrag

  Social behaviour is a heritable trait linked to well-being and mental health, yet it varies across social context, including social domains, informants and development, which may shape its underlying genomic architecture. Here, we conducted a genome-wide meta-regression meta-analysis of social behaviour from infancy to early adulthood, studying ~500,000 repeated measures in European-ancestry cohorts ( N  = 73,321). We modelled heterogeneity in single-variant associations across social domains (low prosocial behaviour and peer/social difficulties), multiple informants (parents, teachers and self-reports) and ages (2–29 years), identifying 6 associated loci, including variation within CADM2 ( P  = 2.51 × 10 −9 ). Single nucleotide polymorphism-based heritability ranged from 2% to 7%, and the genetic architecture comprised 4 factors reflecting differences in either social domains or informants. Polygenic scores ( N  = 16,305) accurately predicted contextual variation in independent cohorts, with some cross-ancestry transferability. Context-specific patterns of genetic correlations, particularly when estimating the developmental onset of associations, offer opportunities to disentangle shared trajectories linking social behaviour with later-life and mental health outcomes.

• Termorshuizen, Jet D.; Davies, Helena L.; Lee, Sang-Hyuck; Dennis, Jessica K.; Hübel, Christopher & Johnson, Jessica S. [Vis alle 186 forfattere av denne artikkelen] (2026). Genomic meta-analyses of binge-eating behavior and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes. Nature Mental Health. 4, s. 1361–1377. doi: 10.1038/s44220-026-00698-2. Fulltekst i vitenarkiv Vis sammendrag

  Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

• Corfield, Elizabeth Claire; Shadrin, Alexey; Frei, Oleksandr; Rahman, Mohammad Zillur; Akdeniz, Bayram Cevdet & Filiz, Tahir Tekin [Vis alle 29 forfattere av denne artikkelen] (2026). Family genetic designs in MoBa provide insights into health and functioning. Nature. ISSN 0028-0836. doi: 10.1038/s41586-026-10926-5. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies using large, population-based samples of unrelated individuals have discovered thousands of genetic associations with health and disease1. These studies can help explain genetic and environmental risks. However, increasing evidence suggests that population-based estimates, while precise, can also reflect confounding that affects their use and interpretation. This confounding can be overcome using data from genotyped family members, such as nuclear mother–father–child trios2,3. However, samples of genotyped families are rare4,5,6,7,8,9,10,11. Here we illustrate some of the advantages of familial data using the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based cohort of parents and offspring with extensive genotype data (n ≈ 230,000) (ref. 3), along with broad and longitudinal phenotyping of health and functioning. We provide an overview of MoBa and describe the quality control of genotype data tailored to this extensively related sample. We then use trio data to illustrate how family-based genomic designs can identify distinct direct and indirect sources of genetic influence and structural confounding. As examples, we analyse children’s height, educational achievement, depressive symptoms and sleep duration. These demonstrations highlight MoBa as a broadly valuable resource for advancing understanding of health and functioning across the lifecourse and generations.

• Streit, Fabian; Awasthi, Swapnil; Hall, Alisha S.M.; Braun, Alice; Niarchou, Maria & Marouli, Eirini [Vis alle 152 forfattere av denne artikkelen] (2026). Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders. Nature Genetics. ISSN 1061-4036. 58, s. 1831–1844. doi: 10.1038/s41588-026-02654-3. Fulltekst i vitenarkiv Vis sammendrag

  Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

• Bjørndal, Ludvig Daae; Hegemann, Laura Elizabeth; Pettersen, Johanne Hagen; Corfield, Elizabeth Claire; Hannigan, Laurie & Yilmaz, Zeynep [Vis alle 14 forfattere av denne artikkelen] (2026). Investigating Relationships Between Genetic Risk, Childhood Maltreatment, and Eating Disorders in Women. Biological Psychiatry: Global Open Science. 6(5). doi: 10.1016/j.bpsgos.2026.100761. Fulltekst i vitenarkiv Vis sammendrag

  Background Genetic and environmental factors contribute to eating disorder risk, yet their interplay is poorly understood. We examined whether childhood maltreatment and polygenic scores for anorexia nervosa (PGS-AN) and binge-eating broad (PGS-BEB) are associated with eating disorders. We also examined the interactions between childhood maltreatment and PGSs in predicting eating disorders. Methods This nested case-control study used data from up to 63,989 mothers in the MoBa (Norwegian Mother, Father and Child Cohort Study). Mothers reported on their own experiences of 4 childhood maltreatment types: long-term humiliation or degradation, threats to self or someone close, physical abuse, and sexual abuse. Diagnoses of AN, bulimia nervosa (BN), binge-eating disorder (BED), purging disorder (PD), and binge-eating spectrum disorders (BESP) were obtained using self-report data from 5 time points and population health registers. Results The prevalence of AN, BN, BED, PD, and BESP was 2.19%, 4.15%, 10.39%, 0.60%, and 12.96%, respectively. All childhood maltreatment types were strongly associated with elevated eating disorder likelihood (with odds ratios [ORs] ranging from 1.71 to 3.29) as were eating disorder PGSs (with ORs ranging from 1.05 to 1.31). There were no multiplicative interaction effects between childhood maltreatment and PGSs. Small additive interactions were observed between PGS-AN and PGS-BEB and degradation/humiliation for BN and BESP in exploratory analyses. Conclusions Eating disorder PGSs and childhood maltreatment are associated with higher odds of eating disorders. Furthermore, we found tentative evidence of small additive interaction effects between polygenic liability and childhood maltreatment, suggesting that their combined influence further elevates the risk of some eating disorders.

• Strom, Nora I.; Verhulst, Brad; Bacanu, Silviu Alin; Cheesman, Rosa Catherine Gillespie; Purves, Kirstin L. & Gedik, Hüseyin [Vis alle 135 forfattere av denne artikkelen] (2026). Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling. Nature Genetics. ISSN 1061-4036. 58(2), s. 275–288. doi: 10.1038/s41588-025-02485-8. Fulltekst i vitenarkiv Vis sammendrag

  The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat–response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

• Valstad, Mathias; Eftedal, Nikolai Haahjem; Yang, Tianfang; Kvarstein, Elfrida Hartveit; Reichborn-Kjennerud, Ted & Ystrom, Eivind [Vis alle 7 forfattere av denne artikkelen] (2026). The epidemiology of personality disorders in Norway: a nationwide patient registry study. Social Psychiatry and Psychiatric Epidemiology. ISSN 0933-7954. doi: 10.1007/s00127-026-03083-7. Fulltekst i vitenarkiv
• Wotton, Robyn E.; Crowley, James J.; Pol‐Fuster, Josep; Holmberg, Anna; Rück, Christian & Mataix‐Cols, David [Vis alle 10 forfattere av denne artikkelen] (2026). Are There Causal Associations Between Obsessive‐Compulsive Disorder and Cardiometabolic Phenotypes? A Genetic Correlation and Bi‐Directional Mendelian Randomization Study. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 201(5), s. 321–330. doi: 10.1002/ajmgb.70003. Fulltekst i vitenarkiv Vis sammendrag

  In epidemiological studies, obsessive‐compulsive disorder (OCD) is robustly associated with increased risk of cardiometabolic disorders, including cardiovascular diseases, type 2 diabetes, and obesity. However, the mechanisms behind these associations are unclear. We conducted genetic correlation analyses to explore shared genetic etiology and bi‐directional summary‐level Mendelian randomization (MR) to explore potential causal effects between genetic liability to OCD and 14 cardiometabolic phenotypes (e.g., coronary artery disease, blood pressure, body mass index [BMI]). If causal effects were observed, we planned to conduct multivariable MR to explore indirect effects via health behaviors. We found no evidence for genetic correlations between OCD and any of the cardiometabolic phenotypes under study, except for a negative correlation with BMI (rG = −0.123, SE = 0.029, p  < 0.001). Summary‐level MR showed no evidence for causal effects. Therefore, multivariable MR was not conducted. We found limited evidence for shared genetic etiology or causal effects using the largest OCD GWAS to date. However, we were predominantly only powered to detect medium to large effects in the direction of OCD to cardiometabolic traits, leaving the possibility of smaller causal effects existing. Future studies with larger, more representative samples will help to further interpret findings.

• Lu, Zheng An; Ploner, Alexander; Birgegård, Andreas; Consortium, Eating Disorders Working Group of the Psychiatric Genomics; Landén, Mikael & Bulik, Cynthia M. [Vis alle 222 forfattere av denne artikkelen] (2025). Leveraging transdiagnostic genetic liability to psychiatric disorders to dissect clinical outcomes of anorexia nervosa. Molecular Psychiatry. ISSN 1359-4184. 31, s. 1475–1484. doi: 10.1038/s41380-025-03264-x. Fulltekst i vitenarkiv Vis sammendrag

  Anorexia nervosa (AN) has extensive genetic correlations with other psychiatric disorders, and genetic risk for different psychiatric disorders was associated with distinct clinical courses in AN. Uncovering associations between transdiagnostic psychiatric genetic liability and AN outcomes can facilitate its personalized treatment. In this study, we investigated the associations between transdiagnostic psychiatric genetic liability and outcomes of AN. Genomic structural equation models were fitted to genome-wide association data for AN and psychiatric disorders with high genetic correlations with AN (obsessive-compulsive symptoms [OCS], major depressive disorder [MDD], schizophrenia, and anxiety disorders) to extract one shared and five trait-specific genetic components. Next, we calculated the polygenic risk scores (PRS) for these components, including PRSshared, PRSAN-specific, PRSOCS-specific, PRSMDD-specific, PRSSCZ-specific and PRSANX-specific, which index the shared genetic liability to all five psychiatric traits, and genetic liability specific to AN, OCS, MDD, SCZ and ANX, respectively. We then tested associations between these PRSs and clinical outcomes reported between 1997 and 2018 among AN cases from the Anorexia Nervosa Genetics Initiative (ANGI), linked to Swedish National Registers. The clinical outcomes included cumulative disease burden (i.e., number of diagnoses, medication prescriptions, and inpatient days), risks of psychiatric comorbidities, and AN symptomatology. Among 4028 included AN cases, the mean (SD) birth year was 1985 (9), and 3947 (98.0%) were female. Within AN, +1 SD increase of PRSshared was associated with 9–39% excess risk of disease burden and psychiatric comorbidity, whereas the associations between PRSAN-specific and most clinical outcomes were statistically non-significant. +1 SD increase of PRSMDD-specific was associated with 3–29% increased risk of AN disease burden. Our findings show that shared psychiatric liability is associated with more adverse AN outcomes, whereas AN-specific liability is not a good indicator for its clinical course. This study provides a novel perspective on factors influencing heterogeneity in AN clinical course.

• Laan, Camiel M. van der; Ip, Hill F.; Schipper, Marijn; Hottenga, Jouke-Jan; Pourcain, Beate St & Zayats, Tetyana [Vis alle 129 forfattere av denne artikkelen] (2025). Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes. Nature Genetics. ISSN 1061-4036. 57, s. 2427–2435. doi: 10.1038/s41588-025-02295-y. Fulltekst i vitenarkiv Vis sammendrag

  We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < −0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

• Bauer, Anna E.; Jaholkowski, Piotr Pawel; Lu, Yi; Guintivano, Jerry; Hannigan, Laurie John & Corfield, Elizabeth Claire [Vis alle 14 forfattere av denne artikkelen] (2025). Identification and validation of postpartum depression subtypes: a population-based cohort study. EClinicalMedicine. 89, s. 103540–103540. doi: 10.1016/j.eclinm.2025.103540. Fulltekst i vitenarkiv Vis sammendrag

  Background Postpartum depression (PPD) affects 18% of postpartum women globally. PPD is a heterogeneous condition with diverse presentations, which may differ in underlying etiology, potential outcomes, and optimal treatment. This study aimed to identify and validate PPD subtypes using comprehensive phenotypic and genetic data from a large, nationwide cohort. Methods In this population-based cohort study, we used data from the Norwegian Mother, Father, and Child Cohort Study and Medical Birth Registry of Norway (MoBa), and applied unsupervised clustering (Uniform Manifold Approximation and Projection [UMAP] + Density-Based Spatial Clustering of Applications with Noise [DBSCAN]) to identify PPD subtypes among 7859 women with PPD (training set n = 5239). All pregnant women in Norway were eligible to enroll in MoBa between Jun 1, 1999 and Dec 31, 2008. Among women with their first recorded pregnancies in MoBa, they were considered to have clinically significant PPD if they scored ≥8 on the 6-item version of the Edinburgh Postnatal Depression Scale (EPDS) (equivalent to ≥11 on the full EPDS) administered at six months after birth. Input variables included psychiatric symptom severity, psychiatric history, trauma history, pain, and substance use. We then characterized clusters and tested associations with perinatal-relevant auxiliary variables and polygenic scores (PGS) for eight psychiatric and neurodevelopmental conditions. Findings were validated in a reserved test set (n = 2620). Findings Nine clusters were identified in the training set (n = 5239), with seven replicating in the independent test set (n = 2620). Clusters were differentiated by symptom severity, onset timing, trauma history, and pain during pregnancy. In the training set, the cluster with the most severe symptoms was characterized by depression + trauma and comprised 28% [1483/5239] of training sample. This cluster showed marked socioeconomic adversity and elevated genetic risk for psychiatric conditions compared to other clusters (ADHD PGS OR 1.19, 95% CI 1.12–1.28; major depression PGS OR 1.15, 95% CI 1.07–1.23; PTSD PGS OR 1.09, 95% CI 1.02–1.17). In the test set, this cluster also comprised 28% [729/2620] and showed consistent associations with ADHD (OR 1.23, 95% CI 1.12–1.35), major depression (OR 1.09, 95% CI 0.99–1.20), and PTSD (OR 1.17, 95% CI 1.06–1.29). Conversely, the mild PPD cluster (10% [498/5239] of training sample) showed a protective profile (ADHD PGS OR 0.81, 95% CI 0.73–0.90; major depression PGS OR 0.85, 95% CI 0.77–0.94). In the test set, it represented 10% (263/2620), with consistent protective associations for ADHD (OR 0.84, 95% CI 0.72–0.96) and major depression (OR 0.77, 95% CI 0.67–0.89). Two early-onset clusters demonstrated distinct profiles despite similar symptom severity. The cluster characterized as early-onset PPD + pain (6% of training set [310/5239] and 7% of test set [178/2620]) had the highest prevalence of somatic conditions, including migraines (19% [58/310] training; 15% [26/178] test), nausea (47% [144/310] training; 53% [94/178] test), prenatal hospitalization (41% [128/310] training; 35% [62/178] test), and birth by caesarean section (10% [31/310] training; 8% [14/178] test), whereas the cluster characterized as early-onset PPD + anger (6% [307/5239] of training sample; 6% [158/2620] of test sample) showed many fewer physical health burdens. The clusters in the training and testing set had moderate to high concordance (ARI = 0.76 [95% CI 0.74, 0.77], FMI = 0.79 [95% CI 0.77, 0.81]).

• Dypås, Lene Brattsti; Olsen, Ann-Karin Hardie; Gützkow, Kristine Bjerve; Andreassen, Ole; Brunborg, Gunnar & Magnus, Per Minor [Vis alle 9 forfattere av denne artikkelen] (2025). Circulating MicroRNAs in Cord Blood to Predict Attention-Deficit/Hyperactivity Disorder Diagnosis. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2025.10.010. Fulltekst i vitenarkiv Vis sammendrag

  Background There are large knowledge gaps in the etiology of attention-deficit/hyperactivity disorder (ADHD), and although it is a prevalent and highly heritable neurodevelopmental disorder, diagnosis can be challenging. We aimed to assess the association of circulating blood plasma microRNAs (miRNAs) at birth with ADHD for use as biomarker candidates and build an miRNA-based prediction model. Methods Our study population consisted of 206 children with ADHD (33.0% female), 207 control children (33.8% female), and their parents from the MoBa (Norwegian Mother, Father, and Child Cohort Study). Expression levels of 51 selected miRNAs in plasma from children’s cord blood at birth and from both parents during early pregnancy were quantified by quantitative polymerase chain reaction and tested for association with children’s ADHD diagnosis and ADHD symptom scores based on ratings by parents. Results Seven miRNAs were differentially expressed at birth in children with ADHD and control children (false discovery rate < .05), and 31 had a statistically significant linear relationship with parent-rated ADHD symptom score at 8 years. A 19-miRNA ADHD prediction model achieved good discrimination in the test population (area under the receiver operating curve = 0.959, accuracy = 0.893). Functional analysis for the 19-miRNA prediction set revealed involvement in several highly relevant pathways, e.g., dopaminergic synapse, circadian rhythm, and axon guidance. We also found that parental miRNA expression levels significantly associated with children’s ADHD diagnoses and/or ADHD symptoms scores. Conclusions We showed that expression levels of circulating miRNAs at birth may be used to predict increased risk of ADHD diagnosis, and our 19-miRNA set should be included in future efforts to develop a biomarker panel.

• Shorter, John R.; Pasman, Joëlle A.; Kurvits, Siim; Jangmo, Andreas; Naamanka, Joonas & Harder, Arvid [Vis alle 31 forfattere av denne artikkelen] (2025). Genome-wide association analyses identify distinct genetic architectures for early-onset and late-onset depression. Nature Genetics. ISSN 1061-4036. 57, s. 2972–2979. doi: 10.1038/s41588-025-02396-8. Fulltekst i vitenarkiv Vis sammendrag

  Major depressive disorder (MDD) is a common and heterogeneous disorder of complex etiology. Studying more homogeneous groups stratified according to clinical characteristics, such as age of onset, can improve the identification of the underlying genetic causes and lead to more targeted treatment strategies. We leveraged Nordic biobanks with longitudinal health registries to investigate differences in the genetic architectures of early-onset (eoMDD; n  = 46,708 cases) and late-onset (loMDD; n  = 37,168 cases) MDD. We identified 12 genomic loci for eoMDD and two for loMDD. Overall, the two MDD subtypes correlated moderately (genetic correlation, r g  = 0.58) and differed in their genetic correlations with related traits. These findings suggest that eoMDD and loMDD have partially distinct genetic signatures, with a specific developmental brain signature for eoMDD. Importantly, we demonstrate that polygenic risk scores (PRS) for eoMDD predict suicide attempts within the first 10 years after the initial diagnosis: the absolute risk for suicide attempt was 26% in the top PRS decile, compared to 12% and 20% in the bottom decile and the intermediate group, respectively. Taken together, our findings can inform precision psychiatry approaches for MDD.

• Haram, Marit; Jangmo, Andreas; Jaholkowski, Piotr Pawel; Pasman, Joëlle; Meijsen, Joeri & Shorter, John R. [Vis alle 15 forfattere av denne artikkelen] (2025). Associations of polygenic risk scores for major depression and depression severity: an investigation of 105 623 individuals with 16 years follow-up. Molecular Psychiatry. ISSN 1359-4184. s. 1–8. doi: 10.1038/s41380-025-03243-2. Fulltekst i vitenarkiv Vis sammendrag

  Genetic risk could be informative for identifying individuals at risk of depression with severe outcomes. With the novel approach of combined health care registries and self-report measures related to depression, the authors aimed to identify the impact of polygenic risk scores (PRS) for major depression on self report measures and a diagnosis of depression across diagnostic thresholds. The study sample comprised participants from the Norwegian Mother, Father and Child Cohort Study with linked information of depression diagnoses during 2006–2022 from health registries. Linear and logistic models were used to estimate the associations between PRS for major depression and self-reported measures related to depression (Symptom Checklist- 5, Satisfaction With Life Scale, Rosenberg Self-Esteem Scale), and a diagnosis of depression. Analyses were performed in groups stratified by level of depression severity defined by registrations in primary and specialist health care. Among the 105 623 individuals included in the study, mean (SD) age was 33.9 (5.3) and 58.5% were female. The associations between PRS for major depression and Rosenberg Self-Esteem Scale were more prominent in individuals with a history of inpatient status compared to outpatient status (β = 0.095, cluster robust 95% CI 0.029–0.162; P  = 0.005) and status of primary care (β = 0.098, cluster robust 95% CI 0.035–0.160; P  = 0.002). PRS for major depression were associated with a diagnosis of depression in all groups of depression severity, with highest effect sizes for more severe types (history of inpatient status: OR = 1.85, cluster robust 95% CI 1.75–1.94; P  < 0.01). The results provide new knowledge of how PRS for major depression vary with depression severity.

• Adams, Mark J.; Streit, Fabian; Meng, Xiangrui; Awasthi, Swapnil; Adey, Brett N. & Choi, Karmel W. [Vis alle 51 forfattere av denne artikkelen] (2025). Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. Cell. ISSN 0092-8674. 188(3), s. 640–652.e9. doi: 10.1016/j.cell.2024.12.002. Fulltekst i vitenarkiv Vis sammendrag

  In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.

• Strom, Nora I.; Gerring, Zachary F.; Galimberti, Marco; Yu, Dongmei; Halvorsen, Matthew W. & Abdellaoui, Abdel [Vis alle 214 forfattere av denne artikkelen] (2025). Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder. Nature Genetics. ISSN 1061-4036. 57, s. 1389–1401. doi: 10.1038/s41588-025-02189-z. Fulltekst i vitenarkiv Vis sammendrag

  Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

• Walle, Kjersti Mæhlum; Gustavson, Kristin; Mjaaland, Siri; Askeland, Ragna Bugge; Magnus, Per Minor & Susser, Ezra [Vis alle 12 forfattere av denne artikkelen] (2025). Maternal immune-mediated conditions and ADHD risk in offspring. BMC Medicine. 23, s. 1–15. doi: 10.1186/s12916-025-04227-3. Fulltekst i vitenarkiv Vis sammendrag

  Background Maternal immune-mediated conditions during pregnancy have been linked with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. The relative contributions of maternal inflammatory/immune responses versus shared genetic predispositions remain unclear. This study uses paternal immune-mediated conditions as a negative control to explore these factors, as we investigate associations between maternal immune-mediated conditions during pregnancy and offspring ADHD. Methods Prospective data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) was linked with the Medical Birth Registry of Norway (MBRN) and the Norwegian Patient Registry (NPR) to assess associations between prenatal exposure to maternal immune-mediated conditions and offspring ADHD risk up to age 18. Nationwide recruitment from 1999 to 2008 yielded 104,270 eligible mother–child pairs, with 21,340 children exposed to maternal allergic conditions (asthma, allergies, atopic conditions) and 7478 to other immune conditions (autoimmune, inflammatory). Paternal self-reported immune conditions served as negative controls. Children’s ADHD diagnoses were obtained from NPR, and Cox proportional hazard models estimated hazard ratios for ADHD. Results Both overall categories were associated with increased offspring ADHD risk (allergic conditions HR 1.23, 95% CI, 1.14–1.34; other immune conditions HR 1.36, 95% CI, 1.21–1.53). Specific associations included maternal asthma (HR 1.47, 95% CI, 1.30–1.67), allergies (HR 1.20, 95% CI, 1.10–1.31), rheumatologic/musculoskeletal conditions (HR 1.64, 95% CI, 1.28–2.10), Crohn’s disease/ulcerative colitis (adjusted HR 1.95, 95% CI, 1.23–3.09), and endocrine conditions (HR 1.42, 95% CI, 1.15–1.77), specifically, type 1 diabetes (adjusted HR 2.50, 95% CI, 1.66–3.75). Although some paternal immune-mediated conditions (psoriasis, ulcerative colitis, Crohn’s disease) showed similar trends in ADHD risk, only paternal asthma was significantly associated (adjusted HR 1.26, 95% CI, 1.10–1.45). Conclusions Several maternal immune-mediated conditions were associated with increased offspring ADHD risk. The higher, more consistent ADHD risk estimates with maternal conditions compared to paternal ones indicate that unmeasured genetic confounding does not fully explain these associations. These results suggest direct effects on fetal development through events at the maternal–fetal interface which may alter fetal immune responses and lead to greater ADHD risk in offspring. Asthma may be an exception to this mechanism, as paternal asthma was also linked with offspring ADHD risk.

• Verhoef, Ellen; Allegrini, Andrea G.; Jansen, Philip R.; Lange, Katherine; Wang, Carol A. & Morgan, Angela T. [Vis alle 64 forfattere av denne artikkelen] (2024). Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits. Biological Psychiatry. ISSN 0006-3223. 95(9), s. 859–869. doi: 10.1016/j.biopsych.2023.11.025. Fulltekst i vitenarkiv
• Askelund, Adrian Dahl; Wootton, Robyn E.; Torvik, Fartein A.; Lawn, Rebecca B.; Ask, Helga & Corfield, Elizabeth C. [Vis alle 15 forfattere av denne artikkelen] (2024). Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study. BMC Medicine. 22(1). doi: 10.1186/s12916-024-03361-8. Fulltekst i vitenarkiv Vis sammendrag

  Background: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. Methods: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. Results: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β =  − 0.11, 95% CI [− 0.12, − 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (β =  − 0.07, 95% CI [− 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. Conclusions: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

• Che, Xiaoyu; Roy, Ayan; Bresnahan, Michaeline; Mjaaland, Siri; Reichborn-Kjennerud, Ted & Magnus, Per Minor [Vis alle 12 forfattere av denne artikkelen] (2023). Metabolomic analysis of maternal mid-gestation plasma and cord blood in autism spectrum disorders. Molecular Psychiatry. ISSN 1359-4184. 28, s. 2355–2369. doi: 10.1038/s41380-023-02051-w. Fulltekst i vitenarkiv
• Hall, Amber M.; Keil, Alexander P.; Choi, Giehae; Ramos, Amanda M.; Richardson, David B. & Olshan, Andrew F. [Vis alle 15 forfattere av denne artikkelen] (2023). Prenatal organophosphate ester exposure and executive function in Norwegian preschoolers. Environmental Epidemiology. 7(3), s. 1–9. doi: 10.1097/EE9.0000000000000251. Fulltekst i vitenarkiv Vis sammendrag

  Background: Organophosphate esters (OPEs) are ubiquitous chemicals, used as flame retardants and plasticizers. OPE usage has increased over time as a substitute for other controlled compounds. This study investigates the impact of prenatal OPE exposure on executive function (EF) in preschoolers. Methods: We selected 340 preschoolers from the Norwegian Mother, Father, and Child Cohort Study. Diphenyl-phosphate (DPhP), di-n-butyl-phosphate (DnBP), bis(2-butoxyethyl) phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in maternal urine. EF was measured using the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P) and the Stanford-Binet fifth edition (SB-5). EF scores were scaled so a higher score indicated worse performance. We estimated exposure-outcome associations and evaluated modification by child sex using linear regression. Results: Higher DnBP was associated with lower EF scores across multiple rater-based domains. Higher DPhP and BDCIPP were associated with lower SB-5 verbal working memory (β = 0.49, 95% CI = 0.12, 0.87; β = 0.53, 95% CI = 0.08, 1.02), and higher BBOEP was associated with lower teacher-rated inhibition (β = 0.34, 95% CI = 0.01, 0.63). DPhP was associated with lower parent-reported BRIEF-P measures in boys but not girls [inhibition: boys: 0.37 (95% CI = 0.03, 0.93); girls: –0.48 (95% CI = –1.27, 0.19); emotional control: boys: 0.44 (95% CI = –0.13, 1.26); girls: –0.83 (95% CI = –1.73, –0.00); working memory: boys: 0.49 (95% CI = 0.03, 1.08); girls: –0.40 (95% CI = –1.11, 0.36)]. Fewer sex interactions were observed for DnBP, BBOEP, and BDCIPP, with irregular patterns observed across EF domains. Conclusions: We found some evidence prenatal OPE exposure may impact EF in preschoolers and variation in associations by sex.

• Askeland, Ragna Bugge; Hannigan, Laurie John; O'Connell, Kevin Sean; Corfield, Elizabeth Claire; Frei, Oleksandr & Thapar, Anita [Vis alle 11 forfattere av denne artikkelen] (2023). Developmental manifestations of polygenic risk for bipolar disorder from infancy to middle childhood. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02522-2. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Knowledge on how genetic risk for bipolar disorder manifests in developmental, emotional or behavioral traits during childhood is lacking. This issue is important to address to inform early detection and intervention efforts. We investigated whether polygenic risk for bipolar disorder is associated with developmental outcomes during early to middle childhood in the general population, and if associations differ between boys and girls. Our sample consisted of 28 001 children from the Norwegian Mother, Father and Child Cohort study, a prospective pregnancy cohort with available genotype and developmental data. Mothers reported on a range of developmental outcomes in their children at 6 and 18 months, 3, 5 and 8 years. Polygenic risk scores reflecting common variant liability to bipolar disorder were calculated. Linear regression models were used in a multi-group framework to investigate associations between polygenic risk score and developmental outcomes, using sex as a grouping variable. We found robust evidence for an association between polygenic risk scores for bipolar disorder and conduct difficulties (β = 0.041, CI = 0.020–0.062) and oppositional defiant difficulties (β = 0.032, CI = 0.014–0.051) at 8 years. Associations with most other outcomes were estimated within the region of practical equivalence to zero (equivalence range D  = −0.1 to 0.1), with the exceptions of negative association for activity levels (β = −0.028, CI = −0.047– −0.010) at age 5 and benevolence (β = −0.025, CI = –0.043 to –0.008) at age 8, and positive association for motor difficulties (β = 0.025, CI = 0.008–0.043) at age 3, inattention (β = 0.021, CI = 0.003–0.041) and hyperactivity (β = 0.025, CI = 0.006–0.044) at age 8. Our results suggest that genetic risk for bipolar disorder manifests as disruptive behaviors like oppositional defiant and conduct difficulties in childhood in the general population.

• Guintivano, Jerry; Byrne, Enda M.; Kiewa, Jacqueline; Yao, Shuyang; Bauer, Anna E. & Aberg, Karolina A. [Vis alle 78 forfattere av denne artikkelen] (2023). Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression. American Journal of Psychiatry. ISSN 0002-953X. 180(12), s. 884–895. doi: 10.1176/appi.ajp.20230053. Fulltekst i vitenarkiv
• Havdahl, Alexandra; Farmer, Cristan; Suren, Pål; Øyen, Anne-Siri; Magnus, Per Minor & Susser, Ezra [Vis alle 11 forfattere av denne artikkelen] (2023). Attainment and loss of early social-communication skills across neurodevelopmental conditions in the Norwegian Mother, Father and Child Cohort Study. Journal of Child Psychology and Psychiatry. ISSN 0021-9630. doi: 10.1111/jcpp.13792. Fulltekst i vitenarkiv Vis sammendrag

  Background Delays and loss of early-emerging social-communication skills are often discussed as unique to autism. However, most studies of regression have relied on retrospective recall and clinical samples. Here, we examine attainment and loss of social-communication skills in the population-based Norwegian Mother, Father and Child Cohort Study (MoBa). Methods Mothers rated their child's attainment of 10 early-emerging social-communication skills at ages 18 and 36 months (N = 40,613, 50.9% male). Prospectively reported loss was defined as skill presence at 18 months but absence at 36 months. At 36 months, mothers also recalled whether the child had lost social-communication skills. The Norwegian Patient Registry was used to capture diagnoses of Autism Spectrum Disorder (autism) and other neurodevelopmental disabilities (NDDs). Results Delay in at least one skill was observed in 14% of the sample and loss in 5.4%. Recalled loss of social-communication skills was rare (0.86%) and showed low convergence with prospectively reported loss. Delay and especially loss were associated with elevated odds of an autism diagnosis (n = 383) versus no autism diagnosis (n = 40,230; ≥3 skills delayed: OR = 7.09[4.15,12.11]; ≥3 skills lost: OR = 30.66[17.30,54.33]). They were also associated with an increased likelihood of autism compared to some other NDDs. Delay (relative risk [RR] = 4.16[2.08, 8.33]) and loss (RR = 10.00[3.70, 25.00]) associated with increased likelihood of autism versus ADHD, and loss (RR = 4.35[1.28,14.29]), but not delay (RR = 2.00[0.78,5.26]), associated with increased likelihood of autism compared to language disability. Conversely, delay conferred decreased likelihood of autism versus intellectual disability (RR = 0.11[0.06,0.21]), and loss was not reliably associated with likelihood of autism versus intellectual disability (RR = 1.89[0.44,8.33]). Conclusions This population-based study suggests that loss of early social communication skills is more common than studies using retrospective reports have indicated and is observed across several NDD diagnoses (not just autism). Nevertheless, most children with NDD diagnoses showed no reported delay or loss in these prospectively measured skills.

• Pasman, Joëlle A.; Meijsen, Joeri J.; Haram, Marit; Kowalec, Kaarina; Harder, Arvid & Xiong, Ying [Vis alle 23 forfattere av denne artikkelen] (2023). Epidemiological overview of major depressive disorder in Scandinavia using nationwide registers. The Lancet Regional Health - Europe. 29. doi: 10.1016/j.lanepe.2023.100621. Fulltekst i vitenarkiv Vis sammendrag

  Background Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries. Methods This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975–2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable. Findings MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35–48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations. Interpretation The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies.

• Wootton, Robyn E; Lawn, Rebecca B.; Magnus, Maria C.; Treur, Jorien L.; Corfield, Elizabeth C. & Njølstad, Pål Rasmus [Vis alle 14 forfattere av denne artikkelen] (2023). Associations between health behaviours, fertility and reproductive outcomes: triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa). BMC Medicine. 21. doi: 10.1186/s12916-023-02831-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. Methods This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462–1,232,091) and controlled for education and ADHD liability using multivariable MR. Results In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. Conclusions Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.

• Demontis, Ditte; Walters, G. Bragi; Athanasiadis, Georgios; Walters, Raymond; Therrien, Karen & Nielsen, Trine Tollerup [Vis alle 88 forfattere av denne artikkelen] (2023). Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics. ISSN 1061-4036. 55, s. 198–208. doi: 10.1038/s41588-022-01285-8. Fulltekst i vitenarkiv
• Tesli, Martin Steen; Nesvåg, Ragnar; Haukvik, Unn Kristin Hansen; Gustavson, Kristin; Tesli, Natalia & Friestad, Christine [Vis alle 12 forfattere av denne artikkelen] (2023). Common genetic and environmental risk for personality disorders and psychotic-like experiences in young adult twins. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 148(6), s. 561–569. doi: 10.1111/acps.13596. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Psychotic‐like experiences (PLE) have been associated with the subsequent emergence of psychotic disorders as well as several other domains of psychopathology. In this twin study, we estimated the genetic and environmental correlations between PLE and 10 personality disorders (PD). Methods Diagnoses of 10 PDs according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) and PLE from the Composite International Diagnostic Interview (CIDI) were retrieved for 2793 young adult twins from the Norwegian Twin Registry. Risk for having a PD and PLEs was modeled using item response theory. Biometric twin models were fitted to estimate the genetic and environmental correlations between PDs and PLEs. Co‐twin control analysis was performed to estimate additional within‐family risk for PLEs when having a PD. Results Phenotypic overlap between PDs and PLEs ranged from 14% to 44% in males and from 11% to 39% in females, with the highest overlap for borderline PD in both sexes. In general, we found higher genetic correlations ( r  = 0.14–0.72) than environmental correlations ( r  = 0.06–0.28) between PDs and PLEs. The highest genetic correlations between PLE and PDs were found for borderline ( r  = 0.72), paranoid ( r  = 0.56), schizotypal ( r  = 0.56) and antisocial PD (r = 0.49). Conclusion We found that the co‐occurrence between PDs and PLE is the best explained by shared genetic determinants, with minor contributions from environmental factors. Interestingly, borderline PD was highly genetically correlated with PLE, warranting molecular genetic studies of this association.

• Thistle, Jake E.; Ramos, Amanda; Roell, Kyle R.; Choi, Giehae; Manley, Cherrel K. & Hall, Amber M. [Vis alle 16 forfattere av denne artikkelen] (2022). Prenatal organophosphorus pesticide exposure and executive function in preschool-aged children in the Norwegian Mother, Father and Child Cohort Study (MoBa). Environmental Research. ISSN 0013-9351. 212(Part D). doi: 10.1016/j.envres.2022.113555. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Prenatal exposure to organophosphorus pesticides (OPPs) has been associated with neurodevelopmental deficits in children, however evidence linking OPPs with specific cognitive mechanisms, such as executive function (EF), is limited. Objective: This study aims to evaluate the association between prenatal exposure to OPPs with multiple measures of EF in preschool-aged children, while considering the role of variant alleles in OPP metabolism genes. Methods: We included 262 children with preschool attention-deficit/hyperactivity disorder (ADHD), and 78 typically developing children, from the Preschool ADHD substudy of the Norwegian, Mother, Father, and Child Cohort Study. Participants who gave birth between 2004 and 2008 were invited to participate in an on-site clinical assessment when the child was approximately 3.5 years; measurements of EF included parent and teacher rating on Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P), and three performance-based assessments. We measured OPP metabolites in maternal urines collected at ∼17 weeks' gestation to calculate total dimethyl- (ΣDMP) and diethyl phosphate (ΣDEP) metabolite concentrations. We estimated multivariable adjusted β's and 95% confidence intervals (CIs) corresponding to a change in z-score per unit increase in log-ΣDMP/DEP. We further characterized gene-OPP interactions for maternal variants in PON1 (Q192R, M55L), CYP1A2 (1548T > C), CYP1A1 (IntG > A) and CYP2A6 (-47A > C). Results: Prenatal OPP metabolite concentrations were associated with worse parent and teacher ratings of emotional control, inhibition, and working memory. A one log-∑DMP increase was associated with poorer teacher ratings of EF on the BRIEF-P (e.g. emotional control domain: β = 0.55, 95% CI: 0.35, 0.74), when weighted to account for sampling procedures. We found less consistent associations with performance-based EF assessments. We found some evidence of modification for PON1 Q192R and CYP2A6 -47A > C. Association with other variants were inconsistent. Conclusions: Biomarkers of prenatal OPP exposure were associated with more adverse teacher and parent ratings of EF in preschool-aged children.

• Havdahl, Alexandra; Wootton, Robyn E; Leppert, Beate; Riglin, Lucy; Ask, Helga & Tesli, Martin Steen [Vis alle 16 forfattere av denne artikkelen] (2022). Associations between Pregnancy-Related Predisposing Factors for Offspring Neurodevelopmental Conditions and Parental Genetic Liability to Attention-Deficit/Hyperactivity Disorder, Autism, and Schizophrenia: The Norwegian Mother, Father and Child Cohort Study (MoBa). JAMA psychiatry. ISSN 2168-6238. 79(8), s. 799–810. doi: 10.1001/jamapsychiatry.2022.1728. Fulltekst i vitenarkiv Vis sammendrag

  Importance Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal genetic liability. Objective To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures. Design, Setting, and Participants The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother’s pregnancy. Analysis took place between March 2021 and March 2022. Exposures PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies. Main Outcomes and Measures Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use. Results Data were available for up to 14 539 mothers (mean [SD] age, 30.00 [4.45] years) and 14 897 fathers (mean [SD] age, 32.46 [5.13] years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio [OR], 1.15 [95% CI, 1.06-1.25]), smoking (OR, 1.26 [95% CI, 1.19-1.33]), prepregnancy body mass index (β, 0.25 [95% CI, 0.18-0.31]), pregnancy weight gain (β, 0.20 [95% CI, 0.10-0.30]), taking folate (OR, 0.92 [95% CI, 0.88-0.96]), and not taking supplements (OR, 1.09 [95% CI, 1.04-1.14]). Schizophrenia PGS was associated with coffee consumption (OR, 1.09 [95% CI, 1.05-1.12]), smoking (OR, 1.12 [95% CI, 1.06-1.19]), prepregnancy body mass index (β, −0.18 [95% CI, −0.25 to −0.11]), and pregnancy weight gain (β, 0.17 [95% CI, 0.07-0.27]). All 3 PGSs associated with symptoms of depression/anxiety (ADHD: OR, 1.15 [95% CI, 1.09-1.22]; autism: OR, 1.13 [95% CI, 1.06-1.19]; schizophrenia: OR, 1.13 [95% CI, 1.07-1.20]). Associations were largely consistent for maternal and paternal PGS, except ADHD PGS and smoking (fathers: OR, 1.13 [95% CI, 1.09-1.17]). Conclusions and Relevance In this study, genetic liability to neurodevelopmental conditions that is passed from mothers to children was associated with several pregnancy-related factors and may therefore confound associations between these pregnancy-related factors and offspring neurodevelopment that have previously been thought to be causal. It is crucial that future study designs account for genetic confounding to obtain valid causal inferences so that accurate advice can be given to pregnant individuals.

• Weiner, Daniel J.; Ling, Emi; Erdin, Serkan; Tai, Derek J. C.; Yadav, Rachita & Grove, Jakob [Vis alle 110 forfattere av denne artikkelen] (2022). Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p. Nature Genetics. ISSN 1061-4036. 54(11), s. 1630–1639. doi: 10.1038/s41588-022-01203-y. Fulltekst i vitenarkiv Vis sammendrag

  The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

• Hall, Amber M.; Ramos, Amanda M.; Drover, Samantha S. M.; Choi, Giehae; Keil, Alexander P. & Richardson, David B. [Vis alle 16 forfattere av denne artikkelen] (2022). Gestational organophosphate ester exposure and preschool attention-deficit/hyperactivity disorder in the Norwegian Mother, Father, and Child cohort study. International Journal of Hygiene and Environmental Health. ISSN 1438-4639. 248. doi: 10.1016/j.ijheh.2022.114078. Fulltekst i vitenarkiv
• Bjørndal, Ludvig Daae; Kendler, Kenneth S.; Reichborn-Kjennerud, Ted & Ystrøm, Eivind (2022). Stressful life events increase the risk of major depressive episodes: A population-based twin study. Psychological Medicine. ISSN 0033-2917. 53(11), s. 5194–5202. doi: 10.1017/S0033291722002227. Fulltekst i vitenarkiv Vis sammendrag

  Background Previous studies have found that stressful life events (SLEs) are associated with an increased risk of adult depression. However, many studies are observational in nature and limited by methodological issues, such as potential confounding by genetic factors. Genetically informative research, such as the co-twin control design, can strengthen causal inference in observational studies. Discrete-time survival analysis has several benefits and multilevel survival analysis can incorporate frailty terms (random effects) to estimate the components of the biometric model. In the current study, we investigated associations between SLEs and depression risk in a population-based twin sample (N = 2299). Methods A co-twin control design was used to investigate the influence of the occurrence of SLEs on depression risk. The co-twin control design involves comparing patterns of associations in the full sample and within dizygotic (DZ) and monozygotic twins (MZ). Associations were modelled using discrete-time survival analysis with biometric frailty terms. Data from two time points were used in the analyses. Mean age at Wave 1 was 28 years and mean age at Wave 2 was 38 years. Results SLE occurrence was associated with increased depression risk. Co-twin control analyses indicated that this association was at least in part due to the causal influence of SLE exposure on depression risk for event occurrence across all SLEs and for violent SLEs. A minor proportion of the total genetic risk of depression reflected genetic effects related to SLEs. Conclusions The results support previous research in implicating SLEs as important risk factors with probable causal influence on depression risk.

• Ystrøm, Eivind; Degerud, Eirik Magnus Meek; Tesli, Martin Steen; Høye, Anne; Reichborn-Kjennerud, Ted & Næss, Øyvind Erik (2022). Alcohol consumption and lower risk of cardiovascular and all-cause mortality: The impact of accounting for familial factors in twins. Psychological Medicine. ISSN 0033-2917. doi: 10.1017/S0033291722000812. Fulltekst i vitenarkiv Vis sammendrag

  Background. A moderate to high alcohol consumption is associated with a lower risk of cardiovascular disease (CVD) mortality in comparison with low consumption. The mechanisms underlying this association are not clear and have been suggested to be caused by residual confounding. The main objective of this study was to separate the familial and individual risk for CVD mortality and all-cause mortality related to alcohol consumption. This will be done by estimating the risk for CVD mortality and all-cause mortality in twin pairs discordant for alcohol consumption.<p> <p>Methods. Alcohol consumption was assessed at two time points using self-report questionnaires in the Norwegian Twin Registry. Data on CVD mortality was obtained from the Norwegian Cause of Death Registry. Exposure–outcome associations for all-cause mortality and mortality due to other causes than CVD were estimated for comparison. <p>Results. Coming from a family with moderate to high alcohol consumption was protective against cardiovascular death (HR = 0.54, 95% CI 0.65–0.83). Moderate and high alcohol consumption levels were associated with a slightly increased risk of CVD mortality at the individual level (HR = 1.33, 95% CI 1.02–1.73). There was no association between alcohol consumption and all-cause mortality both at the familial nor at the individual level. <p>Conclusions. The protective association of moderate to high alcohol consumption with a lower risk of CVD mortality was accounted for by familial factors in this study of twins. Early life genetic and environmental familial factors may mask an absence of health effect of moderate to high alcohol consumption on cardiovascular mortality.

• Engel, Stephanie M.; Villanger, Gro Dehli; Herring, Amy; Nethery, Rachel C.; Drover, Samantha S. M. & Zoeller, R. Thomas [Vis alle 12 forfattere av denne artikkelen] (2022). Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study. Paediatric and Perinatal Epidemiology. ISSN 0269-5022. doi: 10.1111/ppe.12941. Fulltekst i vitenarkiv
• Helgeland, Øyvind; Vaudel, Marc; Sole-Navais, Pol; Flatley, Christopher; Juodakis, Julius & Bacelis, Jonas [Vis alle 18 forfattere av denne artikkelen] (2022). Characterization of the genetic architecture of infant and early childhood body mass index. Nature Metabolism. 4, s. 344–358. doi: 10.1038/s42255-022-00549-1. Fulltekst i vitenarkiv Vis sammendrag

  Early childhood obesity is a growing global concern; however, the role of common genetic variation on infant and child weight development is unclear. Here, we identify 46 loci associated with early childhood body mass index at specific ages, matching different child growth phases, and representing four major trajectory patterns. We perform genome-wide association studies across 12 time points from birth to 8 years in 28,681 children and their parents (27,088 mothers and 26,239 fathers) in the Norwegian Mother, Father and Child Cohort Study. Monogenic obesity genes are overrepresented near identified loci, and several complex association signals near LEPR, GLP1R, PCSK1 and KLF14 point towards a major influence for common variation affecting the leptin–melanocortin system in early life, providing a link to putative treatment strategies. We also demonstrate how different polygenic risk scores transition from birth to adult profiles through early child growth. In conclusion, our results offer a fine-grained characterization of a changing genetic landscape sustaining early childhood growth.

• Tesli, Martin Steen; Degerud, Eirik Magnus Meek; Plana-Ripoll, Oleguer; Gustavson, Kristin; Torvik, Fartein Ask & Ystrøm, Eivind [Vis alle 13 forfattere av denne artikkelen] (2022). Educational attainment and mortality in schizophrenia. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 145(5), s. 481–493. doi: 10.1111/acps.13407. Fulltekst i vitenarkiv Vis sammendrag

  Background Individuals suffering from schizophrenia have a reduced life expectancy with cardiovascular disease (CVD) as a major contributor. Low educational attainment is associated with schizophrenia, as well as with all-cause and CVD mortality. However, it is unknown to what extent low educational attainment can explain the increased mortality in individuals with schizophrenia. Aim Here, we quantify associations between educational attainment and all-cause and CVD mortality in individuals with schizophrenia, and compare them with the corresponding associations in the general population. Method All Norwegian citizens born between January 1, 1925, and December 31, 1959, were followed up from January 1, 1990, to December 31, 2014. The total sample included 1,852,113 individuals, of which 6548 were registered with schizophrenia. We estimated hazard ratios (HR) for all-cause and CVD mortality with Cox models, in addition to life years lost. Educational attainment for index persons and their parents were included in the models. Results In the general population individuals with low educational attainment had higher risk of all-cause (HR: 1.48 [95% CI: 1.47–1.49]) and CVD (HR: 1.59 [95% CI: 1.57–1.61]) mortality. In individuals with schizophrenia these estimates were substantially lower (all-cause: HR: 1.13 [95% CI: 1.05–1.21] and CVD: HR: 1.12 [95% CI: 0.98–1.27]). Low educational attainment accounted for 3.28 (3.21–3.35) life years lost in males and 2.48 (2.42–2.55) years in females in the general population, but was not significantly associated with life years lost in individuals with schizophrenia. Results were similar for parental educational attainment. Conclusions Our results indicate that while individuals with schizophrenia in general have lower educational attainment and higher mortality rates compared with the general population, the association between educational attainment and mortality is smaller in schizophrenia subjects than in the general population.

• Jami, Eshim S.; Hammerschlag, Anke R.; Ip, Hill F.; Allegrini, Andrea G.; Benyamin, Beben & Border, Richard [Vis alle 94 forfattere av denne artikkelen] (2022). Genome-wide association meta-analysis of childhood and adolescent internalizing symptoms. Journal of the American Academy of Child and Adolescent Psychiatry. ISSN 0890-8567. 61(7), s. 934–945. doi: 10.1016/j.jaac.2021.11.035. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

• Pingault, Jean-Baptiste; Barkhuizen, Wikus; Wang, Biyao; Hannigan, Laurie John; Eilertsen, Espen Moen & Corfield, Elizabeth Claire [Vis alle 16 forfattere av denne artikkelen] (2022). Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-022-01863-6. Fulltekst i vitenarkiv Vis sammendrag

  Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of parents in shaping their children’s outcomes. We investigated whether genetic transmission and genetic nurture (environmentally mediated effects) underlie associations between polygenic scores indexing parental risk and protective factors and their offspring’s ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children’s ADHD traits (n = 9,454 children) using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders. We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score (pΔβ = 9.95 × 10−17 for maternal and pΔβ = 1.48 × 10−14 for paternal estimates), suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children’s ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects.

• Kendler, Kenneth S.; Czajkowski, Nikolai Olavi & Reichborn-Kjennerud, Ted (2022). Ludvig Dahl's psychiatric genetic studies in his 1859 monograph: “Contribution to the knowledge of insanity in Norway”. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 189(6), s. 177–184. doi: 10.1002/ajmg.b.32914. Fulltekst i vitenarkiv
• Che, Xiaoyu; Hornig, Mady; Bresnahan, Michaeline; Stoltenberg, Camilla; Magnus, Per Minor & Suren, Pål [Vis alle 10 forfattere av denne artikkelen] (2022). Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD. Molecular Psychiatry. ISSN 1359-4184. 27, s. 1527–1541. doi: 10.1038/s41380-021-01415-4. Fulltekst i vitenarkiv
• Hughes, Amanda M.; Sanderson, Eleanor; Morris, Tim; Ayorech, Ziada; Tesli, Martin Steen & Ask, Helga [Vis alle 16 forfattere av denne artikkelen] (2022). Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study. eLIFE. 11. doi: 10.7554/eLife.74320. Fulltekst i vitenarkiv Vis sammendrag

  Background: Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment. Methods: This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype. Results: Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child’s own BMI increased their depressive symptoms (per 5 kg/m2 increase in BMI, beta = 0.26 S.D., CI = −0.01,0.52, p=0.06) and ADHD symptoms (beta = 0.38 S.D., CI = 0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child’s depressive symptoms (per 5 kg/m2 increase in maternal BMI, beta = 0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents’ BMI affected the child’s ADHD symptoms, or that the child’s or parents’ BMI affected the child’s anxiety symptoms. Conclusions: We found inconsistent evidence that a child’s BMI affected their depressive and ADHD symptoms, and little evidence that a child’s BMI affected their anxiety symptoms. There was limited evidence of an influence of parents’ BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child’s own BMI. Funding: This research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

• Walle, Kjersti Mæhlum; Askeland, Ragna Bugge; Gustavson, Kristin; Mjaaland, Siri; Ystrøm, Eivind & Lipkin, W. Ian [Vis alle 13 forfattere av denne artikkelen] (2022). Risk of attention-deficit hyperactivity disorder in offspring of mothers with infections during pregnancy. JCPP Advances. 2(2), s. 1–11. doi: 10.1002/jcv2.12070. Fulltekst i vitenarkiv Vis sammendrag

  Background Maternal infections during pregnancy are common events that have been suggested to be risk factors for Attention-deficit hyperactivity disorder (ADHD) in offspring. Only a few studies have been conducted to date and results are conflicting. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, considering timing of exposure and the role of fever. Methods We used data from the prospective Norwegian Mother, Father and Child Cohort Study (MoBa), including more than 112,000 pregnancies, linked with data from the Medical Birth Registry of Norway and the Norwegian Patient Registry to estimate odds ratios for the likelihood that children develop ADHD after being exposed to maternal infections during gestation. Results Children exposed to any maternal infection during pregnancy showed increased risk of receiving an ADHD diagnosis (OR = 1.15, CI = 1.03–1.27). Specifically, increased ADHD risk was observed after exposure to genitourinary infections in second (OR = 1.42, CI = 1.06–1.90) or third trimester (OR = 2.04, CI = 1.19–3.49), and to respiratory infections in second trimester (OR = 1.31, CI = 1.12–1.54), provided these infections were accompanied by episodes of fever. Increased ADHD risk was also observed after exposure to diarrhea without fever in the third trimester (OR = 1.25, CI = 1.07–1.46). Conclusions Overall, our results suggest that prenatal exposure to maternal infections, particularly with co-occurring episodes of fever, are risk factors for ADHD. Fever (or severity of the infection) appears to be more important in mid-pregnancy associations. Our results indicate that type of infection and timing of exposure might influence the associations, but small effect sizes require careful interpretations. The association between infection and ADHD should be estimated using discordant siblings or other negative control designs that give better adjustment for unmeasured familial confounding.

• Manley, Cherrel K.; Villanger, Gro Dehli; Thomsen, Cathrine; Mancineiras, Enrique Cequier; Sakhi, Amrit Kaur & Reichborn-Kjennerud, Ted [Vis alle 16 forfattere av denne artikkelen] (2022). Prenatal Exposure to Organophosphorus Pesticides and Preschool ADHD in the Norwegian Mother, Father and Child Cohort Study. International Journal of Environmental Research and Public Health (IJERPH). ISSN 1661-7827. 19(13), s. 1–16. doi: 10.3390/ijerph19138148. Fulltekst i vitenarkiv Vis sammendrag

  Prenatal organophosphorus pesticide (OPP) exposure has been associated with child attention-deficit/hyperactivity disorder (ADHD) in agricultural communities and those that are exposed to residentially applied insecticides. To examine this association in populations that are exposed primarily through diet, we estimate the associations between prenatal OPP exposure and preschool ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa), and describe modification by paraoxonase 1 (PON1) gene variants. We used participants from the MoBa Preschool ADHD Sub-study (n = 259 cases) and a random sample of MoBa sub-cohort participants (n = 547) with birth years from 2004 to 2008. Prenatal urinary dialkylphosphate (DAP) metabolites (total diethylphosphate [∑DEP] and total dimethylphosphate [∑DMP]) were measured by an ultra-performance liquid chromatography-time-of-flight system and summed by molar concentration. Maternal DNA was genotyped for coding variants of PON1 (Q192R and L55M). We used a multivariable logistic regression to calculate the odds ratios (OR) and 95% confidence intervals, adjusted for maternal education, parity, income dependency, age, marital status, ADHD-like symptoms, pesticide use, produce consumption, and season. We found no associations between DAP metabolite concentrations and preschool ADHD. The adjusted ORs for exposure quartiles 2–4 relative to 1 were slightly inverse. No monotonic trends were observed, and the estimates lacked precision, likely due to the small sample size and variation in the population. We found no evidence of modification by PON1 SNP variation or child sex. Maternal urinary DAP concentrations were not associated with preschool ADHD.

• Torvik, Fartein Ask; Eilertsen, Espen Moen; Hannigan, Laurie John; Cheesman, Rosa Catherine Gillespie; Howe, Laurence J. & Magnus, Per Minor [Vis alle 11 forfattere av denne artikkelen] (2022). Modeling assortative mating and genetic similarities between partners, siblings, and in-laws. Nature Communications. 13(1). doi: 10.1038/s41467-022-28774-y. Fulltekst i vitenarkiv Vis sammendrag

  Assortative mating on heritable traits can have implications for the genetic resemblance between siblings and in-laws in succeeding generations. We studied polygenic scores and phenotypic data from pairs of partners (n = 26,681), siblings (n = 2,170), siblings-in-law (n = 3,905), and co-siblings-in-law (n = 1,763) in the Norwegian Mother, Father and Child Cohort Study. Using structural equation models, we estimated associations between measurement error-free latent genetic and phenotypic variables. We found evidence of genetic similarity between partners for educational attainment (rg = 0.37), height (rg = 0.13), and depression (rg = 0.08). Common genetic variants associated with educational attainment correlated between siblings above 0.50 (rg = 0.68) and between siblings-in-law (rg = 0.25) and co-siblings-in-law (rg = 0.09). Indirect assortment on secondary traits accounted for partner similarity in education and depression, but not in height. Comparisons between the genetic similarities of partners and siblings indicated that genetic variances were in intergenerational equilibrium. This study shows genetic similarities between extended family members and that assortative mating has taken place for several generations.

• Bakken, Nora Refsum; Hannigan, Laurie John; Shadrin, Alexey; Hindley, Guy Frederick Lanyon; Ask, Helga & Reichborn-Kjennerud, Ted [Vis alle 9 forfattere av denne artikkelen] (2022). Childhood temperamental, emotional, and behavioral characteristics associated with mood and anxiety disorders in adolescence: A prospective study. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 147(2), s. 217–228. doi: 10.1111/acps.13522. Fulltekst i vitenarkiv Vis sammendrag

  Background Mood and anxiety disorders account for a large share of the global burden of disability. Some studies suggest that early signs may emerge already in childhood. However, there is a lack of well-powered, prospective studies investigating how and when childhood mental traits and trajectories relate to adolescent mood and anxiety disorders. Methods We here examine cross-sectional and longitudinal association between maternally reported temperamental traits, emotional and behavioral problems in childhood (0.5–8 years) and clinical diagnosis of mood or anxiety (“emotional”) disorders in adolescence (10–18 years), using the prospective Norwegian Mother, Father and Child Cohort Study (MoBa) of 110,367 children. Results Logistic regression analyses showed consistent and increasing associations between childhood negative emotionality, behavioral and emotional problems and adolescent diagnosis of emotional disorders, present from 6 months of age (negative emotionality). Latent profile analysis incorporating latent growth models identified five developmental profiles of emotional and behavioral problems. A profile of early increasing behavioral and emotional problems with combined symptoms at 8 years (1.3% of sample) was the profile most strongly associated with emotional disorders in adolescence (OR vs. reference: 5.00, 95% CI: 3.70–6.30). Conclusions We found a consistent and increasing association between negative emotionality, behavioral and emotional problems in early to middle childhood and mood and anxiety disorders in adolescence. A developmental profile coherent with early and increasing disruptive mood dysregulation across childhood was the profile strongest associated with adolescent emotional disorders. Our results highlight the importance of early emotional dysregulation and childhood as a formative period in the development of adolescent mood and anxiety disorders, supporting potential for prevention and early intervention initiatives.

• Hall, Amber M.; Thistle, Jake E.; Manley, Cherrel K.; Roell, Kyle R.; Ramos, Amanda M. & Villanger, Gro Dehli [Vis alle 13 forfattere av denne artikkelen] (2022). Organophosphorus Pesticide Exposure at 17 Weeks’ Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study. International Journal of Environmental Research and Public Health (IJERPH). ISSN 1661-7827. 19(24). doi: 10.3390/ijerph192416851. Fulltekst i vitenarkiv Vis sammendrag

  Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks’ gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks’ gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

• Høye, Anne; Jacobsen, Bjarne K.; Bramness, Jørgen Gustav; Nesvåg, Ragnar; Reichborn-Kjennerud, Ted & Heiberg, Ina Heidi (2021). Total and cause‑specific mortality in patients with personality disorders: the association between comorbid severe mental illness and substance use disorders. Social Psychiatry and Psychiatric Epidemiology. ISSN 0933-7954. 56, s. 1809–1819. doi: 10.1007/s00127-021-02055-3. Fulltekst i vitenarkiv Vis sammendrag

  PurposeTo investigate the mortality in both in- and outpatients with personality disorders (PD), and to explore the associa-tion between mortality and comorbid substance use disorder (SUD) or severe mental illness (SMI).MethodsAll residents admitted to Norwegian in- and outpatient specialist health care services during 2009–2015 with a PD diagnosis were included. Standardized mortality ratios (SMRs) with 95% confidence intervals (CI) were estimated in patients with PD only and in patients with PD and comorbid SMI or SUD. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs in patients with PD and comorbid SMI or SUD compared to patients with PD only.ResultsMortality was increased in both in- and outpatients with PD. The overall SMR was 3.8 (95% CI 3.6–4.0). The highest SMR was estimated for unnatural causes of death (11.0, 95% CI 10.0–12.0), but increased also for natural causes of death (2.2, 95% CI 2.0–2.5). Comorbidity was associated with higher SMRs, particularly due to poisoning and suicide. Patients with comorbid PD & SUD had almost four times higher all-cause mortality HR than patients with PD only; young women had the highest HR.ConclusionThe SMR was high in both in- and outpatients with PD, and particularly high in patients with comorbid PD & SUD. Young female patients with PD & SUD were at highest risk. The higher mortality in patients with PD cannot, however, fully be accounted for by comorbidity.

• Skogheim, Thea Steen; Weyde, Kjell Vegard Fjeldheim; Engel, Stephanie M.; Aase, Heidi; Suren, Pål & Øie, Merete Glenne [Vis alle 12 forfattere av denne artikkelen] (2021). Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children. Environment International. ISSN 0160-4120. 152, s. 1–14. doi: 10.1016/j.envint.2021.106468. Fulltekst i vitenarkiv Vis sammendrag

  Background Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring. Objectives We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD. Methods This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach. Results For ASD, we identified positive associations (increased risks) in the second quartile of arsenic [OR = 1.77 (CI: 1.26, 2.49)] and the fourth quartiles of cadmium and manganese [OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59)], respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium [OR = 1.59 (CI: 1.15, 2.18); [OR = 1.42 (CI: 1.06, 1.91)]. There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses. Conclusion Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals’ and elements’ impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.

• Ip, Hill F.; Laan, Camiel M. van der; Krapohl, Eva M. L.; Brikell, Isabell; Sánchez-Mora, Cristina & Nolte, Ilja M. [Vis alle 50 forfattere av denne artikkelen] (2021). Genetic association study of childhood aggression across raters, instruments, and age. Translational Psychiatry. 11, s. 1–9. doi: 10.1038/s41398-021-01480-x. Fulltekst i vitenarkiv Vis sammendrag

  Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg|: 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

• Lupattelli, Angela; Mahic, Milada; Handal, Marte; Ystrøm, Eivind; Reichborn-Kjennerud, Ted & Nordeng, Hedvig Marie Egeland (2021). Attention-Deficit/Hyperactivity Disorder in Children Following Prenatal Exposure to Antidepressants: results from the Norwegian Mother, Father and Child Cohort Study. BJOG: An International Journal of Obstetrics and Gynaecology. ISSN 1470-0328. 128(21), s. 1917–1927. doi: 10.1111/1471-0528.16743. Fulltekst i vitenarkiv Vis sammendrag

  Objective To determine the association between child attention-deficit/hyperactivity disorder (ADHD) and prenatal exposure to selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor antidepressants, by timing and duration, with quantification of bias due to exposure misclassification. Design Norwegian Mother, Father and Child Cohort Study and national health registries. Setting Nationwide, Norway. Population A total of 6395 children born to women who reported depression/anxiety in pregnancy and were either medicated with SSRI/SNRI in pregnancy (n = 818) or non-medicated (n = 5228), or did not report depression/anxiety but used antidepressants 6 months before pregnancy (discontinuers, n = 349). Main outcome measure Diagnosis of ADHD or filled prescription for ADHD medication in children, and mother-reported symptoms of ADHD by child age 5 years. Results When the hazard was averaged over the duration of the study follow up, there was no difference in ADHD risk between ever in utero SSRI/SNRI-exposed children and comparators (weighted hazard ratio [wHR] 1.07, 95% CI 0.76–1.51 versus non-medicated; wHR 1.53, 95% CI 0.77–3.07 versus discontinuers). Underestimation of effects due to exposure misclassification was modest. In early childhood, the risk for ADHD was lower with prenatal SSRI/SNRI exposure compared with no exposure, and so were ADHD symptoms (weighted β −0.23, 95% CI −0.39 to −0.08); this risk became elevated at child age 7–9 years (wHR 1.93, 95% CI 1.22–3.05). Maternal depression/anxiety before pregnancy was independently associated with child ADHD. Conclusion Prenatal SSRI/SNRI exposure is unlikely to considerably increase the risk of child ADHD beyond that posed by maternal depression/anxiety. The elevated risk at child age 7–9 years needs to be elucidated.

• Gustavson, Kristin; Torvik, Fartein Ask; Eilertsen, Espen Moen; Ask, Helga; McAdams, Tom A. & Hannigan, Laurie John [Vis alle 9 forfattere av denne artikkelen] (2021). Genetic and environmental contributions to co-occurring ADHD and emotional problems in school-aged children. Developmental Psychology. ISSN 0012-1649. 57(8), s. 1359–1371. doi: 10.1037/dev0001229. Fulltekst i vitenarkiv
• Skogheim, Thea Steen; Weyde, Kjell Vegard Fjeldheim; Aase, Heidi; Engel, Stephanie M.; Suren, Pål & Øie, Merete Glenne [Vis alle 13 forfattere av denne artikkelen] (2021). Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with attention-deficit/hyperactivity disorder and autism spectrum disorder in children. Environmental Research. ISSN 0013-9351. 202(111692). doi: 10.1016/j.envres.2021.111692. Fulltekst i vitenarkiv Vis sammendrag

  Background Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent. Objectives We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Methods This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach. Results Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]. Conclusion Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.

• Choi, Giehae; Keil, Alexander P.; Richardson, David B.; Daniels, Julie L; Hoffman, Kate & Villanger, Gro Dehli [Vis alle 11 forfattere av denne artikkelen] (2021). Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study. Environment International. ISSN 0160-4120. 154. doi: 10.1016/j.envint.2021.106549. Fulltekst i vitenarkiv Vis sammendrag

  Background: Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD. Objective: To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa). Methods: We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (ΣDEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation. Results: DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 μg/L) as compared to the sub-cohort (0.52 μg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural indirect effect: 1.04 [1.00, 1.10]; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 [0.98, 2.28]). We did not observe notable differences in ADHD by DNBP (0.88 [0.62, 1.26]) or BBOEP (1.03 [0.73, 1.46]) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 [0.64, 0.72]. Conclusion: Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.

• Gustavson, Kristin; Ystrøm, Eivind; Ask, Helga; Torvik, Fartein Ask; Hornig, Mady & Susser, Ezra [Vis alle 16 forfattere av denne artikkelen] (2021). Acetaminophen use during pregnancy and offspring attention deficit hyperactivity disorder - a longitudinal sibling control study. JCPP Advances. 1(2). doi: 10.1002/jcv2.12020. Fulltekst i vitenarkiv Vis sammendrag

  Background: Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association. Methods: We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis. Results: Children exposed to acetaminophen up to 28 days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I. = 0.70-1.08) for exposure 1 to 7 days, and 1.13 (95% C.I. = 0.82–1.49) for 8–28 days. Long-term exposure (29 days or more) was associated with a two-fold increase in risk of ADHD diagnosis (aHR = 2.02, 95% C.I = 1.17–3.25). In the sibling control model, the association between long-term acetaminophen use and ADHD in the child was aHR = 2.77 (95% C.I. = 1.48–5.05) at the between-family level, and aHR = 1.06 (95% C.I. = 0.51–2.05) at the within-family level. Conclusions: Both the exposed and the unexposed children of mothers with long-term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long-term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors.

• Haan, Elis; Sallis, Hannah M.; Zuccolo, Luisa; Labrecque, Jeremy; Ystrøm, Eivind & Reichborn-Kjennerud, Ted [Vis alle 9 forfattere av denne artikkelen] (2021). Prenatal smoking, alcohol and caffeine exposure and maternal-reported attention deficit hyperactivity disorder symptoms in childhood: triangulation of evidence using negative control and polygenic risk score analyses. Addiction. ISSN 0965-2140. 117(5), s. 1458–1471. doi: 10.1111/add.15746. Fulltekst i vitenarkiv Vis sammendrag

  Background and aims Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors. Design First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner's substance use). The results were meta-analysed across the cohorts. Secondly, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. Setting We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. Participants Phenotype data available for children were: NALSPAC = 5455–7751; NGENR = 1537–3119; NMOBA = 28 053–42 206. Genotype data available for mothers was: NALSPAC = 7074; NMOBA = 14 583. Measurements A measure of offspring ADHD symptoms at age 7–8 years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. Findings The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms [odds ratio (OR)SMOKING = 1.11, 95% confidence interval (CI) = 1.00–1.23; ORALCOHOL = 1.27, 95% CI = 1.08–1.49; ORCAFFEINE = 1.05, 95% CI = 1.00–1.11], while not for fathers (ORSMOKING = 1.03, 95% CI = 0.95–1.13; ORALCOHOL = 0.83, 95% CI = 0.47–1.48; ORCAFFEINE = 1.02, 95% CI = 0.97–1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa. Conclusions There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms.

• Askeland, Ragna Bugge; Hannigan, Laurie J.; Ask, Helga; Ayorech, Ziada; Tesli, Martin Steen & Corfield, Elizabeth [Vis alle 12 forfattere av denne artikkelen] (2021). Early manifestations of genetic risk for neurodevelopmental disorders. Journal of Child Psychology and Psychiatry. ISSN 0021-9630. s. 1–10. doi: 10.1111/jcpp.13528. Fulltekst i vitenarkiv Vis sammendrag

  Background: Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism) and schizophrenia are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. It is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls. Methods: Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a subsample of 15 205 children from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mother-reported traits of repetitive behavior, social communication, language and motor difficulties, hyperactivity and inattention were measured in children at 6 and 18 months, 3, 5 and 8 years. Linear regression models in a multigroup framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, using sex as a grouping variable. Results: Before the age of 2, the ADHD PRS was robustly associated with hyperactivity and inattention, with increasing strength up to 8 years, and with language difficulties at age 5 and 8. The autism PRS was robustly associated with language difficulties at 18 months, motor difficulties at 36 months, and hyperactivity and inattention at 8 years. We did not identify robust associations for the schizophrenia PRS. In general, the PRS associations were similar in boys and girls. The association between ADHD PRS and hyperactivity at 18 months was, however, stronger in boys. Conclusions: Polygenic risk for autism and ADHD in the general population manifests early in childhood and broadly across behavioral measures of neurodevelopmental traits.

• Choi, Giehae; Villanger, Gro Dehli; Drover, Samantha S.M.; Sakhi, Amrit Kaur; Thomsen, Cathrine & Nethery, Rachel C. [Vis alle 15 forfattere av denne artikkelen] (2021). Prenatal phthalate exposures and executive function in preschool children. Environment International. ISSN 0160-4120. 149. doi: 10.1016/j.envint.2021.106403. Fulltekst i vitenarkiv Vis sammendrag

  Background Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF. Methods Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks’ gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding. Results Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: −0.63 [−2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: −0.15 [−1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT. Conclusion and relevance Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures.

• Haan, E; Sallis, H; Ystrøm, Eivind; Njølstad, Pål Rasmus; Andreassen, Ole & Reichborn-Kjennerud, Ted [Vis alle 9 forfattere av denne artikkelen] (2021). Maternal and offspring genetic risk score analyses of fetal alcohol exposure and attention-deficit hyperactivity disorder risk in offspring. Alcoholism: Clinical and Experimental Research. ISSN 0145-6008. 45(10), s. 2090–2102. doi: 10.1111/acer.14692. Fulltekst i vitenarkiv Vis sammendrag

  Background: Studies investigating the effects of prenatal alcohol exposure on childhood attention-deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7–8 years. Methods: We used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (NALSPAC = 8196; NMOBA = 13,614), fathers (NMOBA = 13,935), and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status. Results: The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97–1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING = 0.98, 95% CI 0.94–1.02; ORNO DRINKING = 0.99, 95% CI 0.97–1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa. Conclusions: We did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.

• Kamai, Elizabeth M.; Villanger, Gro Dehli; Nethery, Rachel C.; Thomsen, Cathrine; Sakhi, Amrit Kaur & Drover, Samantha S.M. [Vis alle 14 forfattere av denne artikkelen] (2021). Gestational Phthalate Exposure and Preschool Attention Deficit Hyperactivity Disorder in Norway. Environmental Epidemiology. 5(4). doi: 10.1097/EE9.0000000000000161. Fulltekst i vitenarkiv Vis sammendrag

  Prenatal phthalate exposure has been linked to altered neurobehavioral development in both animal models and epidemiologic studies, but whether or not these associations translate to increased risk of neurodevelopmental disorders is unclear. We used a nested case-cohort study design to assess whether maternal urinary concentrations of 12 phthalate metabolites at 17 weeks gestation were associated with criteria for Attention Deficit Hyperactivity Disorder (ADHD) classified among 3-year-old children in the Norwegian Mother, Father and Child Cohort Study (MoBa). Between 2007 and 2011, 260 children in this substudy were classified with ADHD using a standardized, on-site clinical assessment; they were compared with 549 population-based controls. We modeled phthalate levels both linearly and by quintiles in logistic regression models adjusted for relevant covariates and tested for interaction by child sex. Children of mothers in the highest quintile of di-iso-nonyl phthalate (∑DiNP) metabolite levels had 1.70 times the odds of being classified with ADHD compared with those in the lowest quintile (95% confidence interval [CI] = 1.03 to 2.82). In linear models, there was a trend with the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP); each natural log-unit increase in concentration was associated with 1.22 times the odds of ADHD (95% CI = 0.99 to 1.52). In boys, but not girls, mono-n-butyl phthalate exposure was associated with increased odds of ADHD (odds ratio [OR] 1.42; 95% CI = 1.07 to 1.88). Additional adjustment for correlated phthalate metabolites attenuated estimates. These results suggest gestational phthalate exposure may impact the behavior of children as young as 3 years.

• Unnarsdóttir, Anna Bára; Lovik, Anikó; Fawns-Ritchie, Chloe; Ask, Helga; Kõiv, Kadri & Hagen, Kristen [Vis alle 52 forfattere av denne artikkelen] (2021). Cohort Profile: COVIDMENT: COVID-19 cohorts on mental health across six nations. International Journal of Epidemiology. ISSN 0300-5771. 51(3), s. 1–15. doi: 10.1093/ije/dyab234. Fulltekst i vitenarkiv Vis sammendrag

  Key features • COVIDMENT [www.covidment.is] is a NordForsk-funded research collaboration across six nations, with the overarching aim to significantly advance current knowledge on mental morbidity trajectories associated with the coronavirus disease 2019 (COVID-19) in the general population and in specific risk groups. • From March 2020 through August 2021, 392 817 individuals have been recruited to the seven COVIDMENT cohorts: the Danish Blood Donor Study (N ¼ 71 562), the Estonian Biobank COVID-19 and Mental Health Data Collection cohorts (N ¼ 13 329 and N ¼ 86 116, respectively), the Icelandic COVID-19 National Resilience Cohort (N ¼ 22 849), the Norwegian BRY.DEG2020 (N ¼ 19 343), the Norwegian Mother, Father and Child Cohort Study (N ¼ 132 486), the Scottish Generation Scotland/CovidLife (N ¼ 18 518) and the Swedish Omtanke2020 (N ¼ 28 614). Semi-harmonized questionnaire data have been collected across all COVIDMENT cohorts with longitudinal data available, e.g. through linkage to the national registers. • The average age of participants ranged from 31.8 to 58.5 years across cohorts. The prevalence of depressive symptoms above cut-off point varied considerably across cohorts (4.2–20.8%). The prevalence of depressive symptoms was highest at COVID-19 incidence of 30 cases per week per 100 000 persons, i.e. 14.3% [95% confidence interval (CI): 9.4–21.8%], which was 61.0% (95% CI: 34.0–94.1%) higher than the prevalence at COVID-19 incidence of 0 cases per week per 100 000 persons (P ¼ 1.1 x 10 ^( 6)). •

• Hannigan, Laurie John; Askeland, Ragna Bugge; Ask, Helga; Tesli, Martin; Corfield, Elizabeth & Ayorech, Ziada [Vis alle 15 forfattere av denne artikkelen] (2021). Genetic Liability for Schizophrenia and Childhood Psychopathology in the General Population. Schizophrenia Bulletin. ISSN 0586-7614. 47(4), s. 1179–1189. doi: 10.1093/schbul/sbaa193. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Genetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time dependent during childhood, nor if they are specific across different forms of psychopathology. Using genotype and questionnaire data on children (N = 15 105) from the Norwegian Mother, Father and Child Cohort Study, we used schizophrenia polygenic risk scores to test developmental stability in associations with measures of emotional and behavioral problems between 18 months and 5 years, and domain specificity in associations with symptoms of depression, anxiety, conduct problems, oppositionality, inattention, and hyperactivity at 8 years. We then sought to identify symptom profiles—across development and domains—associated with schizophrenia polygenic liability. We found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioral problems, with the latter being mediated specifically via the rate of change in symptoms (β slope = 0.032; 95% CI: 0.007–0.057). At age 8, associations were better explained by a model of symptom-specific polygenic effects rather than effects mediated via a general psychopathology factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR = 1.310 [95% CIs: 1.122–1.528]) to have a profile of increasing behavioral and emotional symptoms in early childhood, followed by elevated symptoms of conduct disorder, oppositionality, hyperactivity, and inattention by age 8. Schizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia.

• Ask, Helga; Eilertsen, Espen Moen; Gjerde, Line Cecilie; Hannigan, Laurie John; Gustavson, Kristin & Havdahl, Alexandra [Vis alle 12 forfattere av denne artikkelen] (2021). Intergenerational transmission of parental neuroticism to emotional problems in 8-year-old children: Genetic and environmental influences. JCPP Advances. 1(4). doi: 10.1002/jcv2.12054. Fulltekst i vitenarkiv Vis sammendrag

  Background Children of parents with high levels of neuroticism tend to have high neuroticism themselves as well as increased risk of experiencing symptoms of anxiety and depression. It is not yet clear how much of this link is attributable to a potential effect of parent on child (e.g., via a socializing effect) versus to shared genetic risk. We aimed to determine whether there is an intergenerational association after accounting for genetic transmission and assortative mating. Methods We used data from the Norwegian Mother, Father and Child Cohort Study including 11,088 sibling pairs in the parental generation, their partners (N = 22,176) and their offspring (N = 26,091). Exposures were maternal and paternal neuroticism (self-reported), and the outcomes were neuroticism, symptoms of depression, and symptoms of anxiety in 8-year-old children (mother-reported). Results After accounting for assortative mating in parents (phenotypic r = 0.26) and genetic transmission (explaining 0%–18% of the mother-offspring correlations), potential maternal effects explained 80% (95% CI = 47–95) of the association with offspring neuroticism (mother-child r = 0.31), 78% (95% CI = 66–89) of the association with offspring depressive symptoms (r = 0.31), and 98% (95% CI = 45–112) of the association with offspring anxiety symptoms (r = 0.16). Intergenerational transmission of genetic variants associated with paternal neuroticism accounted for ∼40% (CI = 22%–58%) of the father-offspring correlations with neuroticism and symptoms of depression (r = 0.13 and 0.13, respectively) but none with offspring symptoms of anxiety (r = 0.05). The remaining father-offspring correlations were explained by maternal influences through assortative mating. Conclusions These results are consistent with direct effects between maternal and offspring neuroticism and between maternal neuroticism and offspring symptoms of anxiety and depression. Further understanding of these intergenerational processes will require an adequate model of how these constructs (neuroticism, anxiety and depression) relate to each other within generations.

• Martin, Joanna; Agha, Sharifah Shameem; Eyre, Olga; Riglin, Lucy; Langley, Kate & Hubbard, Leon [Vis alle 57 forfattere av denne artikkelen] (2021). Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 186(7), s. 412–422. doi: 10.1002/ajmg.b.32842. Fulltekst i vitenarkiv
• Ørbeck, Beate; Furu, Kari; Zeiner, Pål; Aase, Heidi; Reichborn-Kjennerud, Ted & Pripp, Are Hugo [Vis alle 7 forfattere av denne artikkelen] (2020). Child and Parental Characteristics of Medication Use for Attention-Deficit/Hyperactivity Disorder. Journal of child and adolescent psychopharmacology. ISSN 1044-5463. 30(7), s. 456–464. doi: 10.1089/cap.2019.0019. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To investigate child and parental characteristics of medication use for attention-deficit/hyperactivity disorder (ADHD). Methods: Participants were part of the prospective population-based Norwegian Mother, Father and Child Cohort study (MoBa) (n = 114,500 children, 95,000 mothers, and 75,000 fathers). This cohort was linked to the Norwegian Prescription Database (NorPD) and the Norwegian Patient Registry (NPR) to compare child and parental characteristics in children medicated and not medicated for ADHD during years 2008–2013. Results: One thousand seven hundred and sixty-four children (74% boys) with ADHD (International Classification of Diseases [ICD-10]: F90 and F98.8) were identified. One thousand three hundred and sixty-two (77%) used medication. Boys and girls did not differ in the use of ADHD medication (both 77%). Mean age at first prescription was 9 years in both boys and girls, and age at ADHD diagnosis was 8 years in medicated and unmedicated children. Significantly more hyperkinetic conduct disorders (F90.1), and significantly fewer with attention-deficit disorder (F98.8) were found among the medicated children compared to the unmedicated children. The medicated children also had a significantly lower global functioning (Child Global Assessment Scale). Child disruptive symptoms reported in the MoBa child age 3 year questionnaire were significantly higher in children who used medication compared to the nonusers (t = 2.2, p = 0.03), and group differences in ADHD symptoms at age 3 years were close to significant (t = 1.8, p = 0.07). Other preschool child and parental characteristics were not significantly different in the two groups. Conclusion: In this large birth cohort study, where a great majority of children with ADHD used medication, only child characteristics were significantly associated with the use of medication. We could not replicate previous findings suggesting that “environmental factors,” such as parental education and psychopathology, drive medication use. The small differences between medicated and unmedicated children in this cohort study, where a majority used medication, might be due to strong established clinical practices where medication is offered as a treatment option, particularly for hyperkinetic conduct disorder in an egalitarian high-income society.

• Villanger, Gro Dehli; Drover, Samantha S.M.; Nethery, Rachel C.; Thomsen, Cathrine; Sakhi, Amrit Kaur & Øvergaard, Kristin Romvig [Vis alle 11 forfattere av denne artikkelen] (2020). Associations between urine phthalate metabolites and thyroid function in pregnant women and the influence of iodine status. Environment International. ISSN 0160-4120. 137. doi: 10.1016/j.envint.2020.105509. Fulltekst i vitenarkiv Vis sammendrag

  Background Human populations, including susceptible subpopulations such as pregnant women and their fetuses, are continuously exposed to phthalates. Phthalates may affect the thyroid hormone system, causing concern for pregnancy health, birth outcomes and child development. Few studies have investigated the joint effect of phthalates on thyroid function in pregnant women, although they are present as a mixture with highly inter-correlated compounds. Additionally, no studies have investigated if the key nutrient for thyroid health, iodine, modifies these relationships. Methods In this study, we examined the cross-sectional relationships between concentrations of 12 urinary phthalate metabolites and 6 plasma thyroid function biomarkers measured mid-pregnancy (~17 week gestation) in pregnant women (N = 1072), that were selected from a population-based prospective birth cohort, The Norwegian Mother, Father and Child Cohort study (MoBa). We investigated if the phthalate metabolite-thyroid function biomarker associations differed by iodine status by using a validated estimate of habitual dietary iodine intake based on a food frequency questionnaire from the 22nd gestation week. We accounted for the phthalate metabolite mixture by factor analyses, ultimately reducing the exposure into two uncorrelated factors. These factors were used as predictors in multivariable adjusted linear regression models with thyroid function biomarkers as the outcomes. Results Factor 1, which included high loadings for mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and monobenzyl phthalate (MBzP), was associated with increased total triiodothyronine (TT3) and free T3 index (fT3i). These associations appeared to be driven primarily by women with low iodine intake (<150 µg/day, ~70% of our sample). Iodine intake significantly modified (p-interaction < 0.05) the association of factor 1 with thyroid stimulating hormone (TSH), total thyroxine (TT4) and free T4 index (fT4i), such that only among women in the high iodine intake category (≥150 µg/day, i.e. sufficient) was this factor associated with increased TSH and decreased TT4 and FT4i, respectively. In contrast, factor 2, which included high loadings for di-2-ethylhexyl phthalate metabolites (∑DEHP) and di-iso-nonyl phthalate metabolites (∑DiNP), was associated with a decrease in TT3 and fT3i, which appeared fairly uniform across iodine intake categories. Conclusion We find that phthalate exposure is associated with thyroid function in mid-pregnancy among Norwegian women, and that iodine intake, which is essential for thyroid health, could influence some of these relationships.

• Villanger, Gro Dehli; Ystrøm, Eivind; Engel, Stephanie M.; Longnecker, Matthew P.; Pettersen, Rolf Dagfinn & Rowe, Alexander D. [Vis alle 8 forfattere av denne artikkelen] (2020). Neonatal thyroid‐stimulating hormone and association with attention‐deficit/hyperactivity disorder. Paediatric and Perinatal Epidemiology. ISSN 0269-5022. 34(5), s. 590–596. doi: 10.1111/ppe.12643. Fulltekst i vitenarkiv
• Bryois, Julien; Skene, Nathan G.; Hansen, Thomas Folkmann; Kogelman, Lisette J.A.; Watson, Hunna J. & Liu, Zijing [Vis alle 50 forfattere av denne artikkelen] (2020). Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease. Nature Genetics. ISSN 1061-4036. 52, s. 482–493. doi: 10.1038/s41588-020-0610-9. Fulltekst i vitenarkiv
• Ask, Helga; Handal, Marte; Hauge, Lars Johan; Reichborn-Kjennerud, Ted & Skurtveit, Svetlana (2020). Incidence of diagnosed pediatric anxiety disorders and use of prescription drugs: a nation-wide registry study. European Child and Adolescent Psychiatry. ISSN 1018-8827. doi: 10.1007/s00787-019-01419-0. Fulltekst i vitenarkiv
• Lund, Ingunn Olea; Eilertsen, Espen Moen; Gjerde, Line C.; Torvik, Fartein Ask; Røysamb, Espen & Reichborn-Kjennerud, Ted [Vis alle 7 forfattere av denne artikkelen] (2020). Maternal Drinking and Child Emotional and Behavior Problems. Pediatrics. ISSN 0031-4005. 145(3). doi: 10.1542/peds.2019-2007. Fulltekst i vitenarkiv
• Czajkowski, Nikolai Olavi; Kendler, Kenneth S; Torvik, Fartein Ask; Ystrøm, Eivind; Rosenström, Tom Henrik & Gillespie, Nathan [Vis alle 7 forfattere av denne artikkelen] (2020). Caffeine consumption, toxicity, tolerance and withdrawal; shared genetic influences with normative personality and personality disorder traits. Experimental and clinical psychopharmacology. ISSN 1064-1297. doi: 10.1037/pha0000429. Fulltekst i vitenarkiv
• Munn-Chernoff, Melissa A.; Johnson, Emma C.; Chou, Yi-Ling; Coleman, Jonathan R.I.; Thornton, Laura M. & Walters, Raymond K. [Vis alle 104 forfattere av denne artikkelen] (2020). Shared genetic risk between eating disorder‐ and substance‐use‐related phenotypes: Evidence from genome‐wide association studies. Addiction Biology. ISSN 1355-6215. doi: 10.1111/adb.12880. Fulltekst i vitenarkiv
• Kiselev, Yury; Handal, Marte; Hjellvik, Vidar; Reichborn-Kjennerud, Ted; Stoltenberg, Camilla & Suren, Pål [Vis alle 8 forfattere av denne artikkelen] (2020). Nationwide study of neuropsychiatric comorbidity and medicines use in children with autism spectrum disorder in Norway. Frontiers in Psychiatry. 11, s. 1–8. doi: 10.3389/fpsyt.2020.596032. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Autism spectrum disorder (ASD) has a high rate of comorbidity. While many children with ASD are exposed to psychotropic medicines, their efficacy and safety in these patients are unclear. There is a need for more detailed knowledge on which medicines are most commonly used and for which disorders. We aimed to investigate (a) prevalence and incidence rate of ASD among Norwegian children, and further, among newly diagnosed ASD children in 2014, study the (b) co-occurrence of neuropsychiatric disorders, (c) use of psychotropic drugs, and (d) the relationship between co-occurring diagnoses and use of psychotropic drugs. Method: Nationwide registry-based study of children 2–17 years old in Norway. Results: The ASD prevalence was 0.76% and the incidence rate was 0.12% in 2014. Of the children who received an initial ASD diagnosis in 2014 (n = 1,234), 64.8% had one or more co-occurring neuropsychiatric diagnosis. Psychotropic medication use was moderate (∼20% used stimulants or hypnotics) in general, and low in children without comorbidity (nearly only hypnotics). There was a good accordance between co-occurring diagnoses and indication for the prescribed medications. Conclusions: Children with newly diagnosed ASD mainly received psychotropic drugs to treat co-occurring neuropsychiatric conditions.

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• Yang, Tianfang; Eftedal, Nikolai Haahjem; Valstad, Mathias; Reichborn-Kjennerud, Ted; Ystrom, Eivind & Czajkowski, Nikolai Olavi (2025). The lifespan impact of personality disorder on marital outcome: a Norwegian population study. Fulltekst i vitenarkiv
• Valstad, Mathias; Eftedal, Nikolai Haahjem; Yang, Tianfang; Reichborn-Kjennerud, Ted; Ystrom, Eivind & Czajkowski, Nikolai Olavi (2025). Epidemiology of personality disorders in Norway, 2010 to 2022. Fulltekst i vitenarkiv
• Yang, Tianfang; Ystrøm, Eivind; Valstad, Mathias; Eftedal, Nikolai Haahjem; Reichborn-Kjennerud, Ted & Czajkowski, Nikolai Olavi (2025). Marital Consequence of Personality Disorder: Evidence from Norwegian Registry. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Hannigan, Laurie John; Reichborn-Kjennerud, Ted; Ask, Helga & Havdahl, Alexandra (2024). Investigating the relationship between sleep phenotypes and neurodevelopmental conditions in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Fulltekst i vitenarkiv
• Yang, Tianfang; Ystrøm, Eivind; Valstad, Mathias; Eftedal, Nikolai Haahjem; Reichborn-Kjennerud, Ted & Krueger, Robert F [Vis alle 7 forfattere av denne artikkelen] (2024). The Intergenerational Impact of Borderline and Avoidant Personality Disorders on Child Academic Achievement: A Registry Study in Norway. Fulltekst i vitenarkiv
• Czajkowski, Nikolai Olavi; Eftedal, Nikolai Haahjem; Yang, Tianfang; Valstad, Mathias; Reichborn-Kjennerud, Ted & Ystrøm, Eivind (2024). The Role of Parental Personality Disorders in High School Dropout: Insights from a Nationwide Cohort Study. Fulltekst i vitenarkiv
• Valstad, Mathias; Eilertsen, Espen Moen; Timpe, Clara Marie Fides; Yang, Tianfang; Eftedal, Nikolai Haahjem & Reichborn-Kjennerud, Ted [Vis alle 8 forfattere av denne artikkelen] (2024). Genetic and environmental effects on diagnosed Borderline Personality Disorder (BPD) without clinic bias. Fulltekst i vitenarkiv
• Helgeland, Øyvind; Vaudel, Marc; Sole-Navais, Pol; Flatley, Christopher; Juodakis, Julius & Bacelis, Jonas [Vis alle 18 forfattere av denne artikkelen] (2024). Correction to: Characterization of the genetic architecture of infant and early childhood body mass index (Nature Metabolism, (2022), 4, 3, (344-358), 10.1038/s42255-022-00549-1). Nature Metabolism. 6(2), s. 378–378. doi: 10.1038/s42255-024-01004-z. Fulltekst i vitenarkiv
• Yang, Tianfang; Ystrøm, Eivind; Valstad, Mathias; Eftedal, Nikolai Haahjem; Reichborn-Kjennerud, Ted & Czajkowski, Nikolai Olavi (2024). Parental Personality Disorder, Substance Abuse and Child Academic Performance: a Norwegian Registry Study. Fulltekst i vitenarkiv
• Askelund, Adrian Dahl; Wootton, Robyn E; Torvik, Fartein Ask; Lawn, Rebecca B.; Ask, Helga & Corfield, Elizabeth Claire [Vis alle 15 forfattere av denne artikkelen] (2024). Assessing causal links between age at menarche and adolescent mental health: triangulation of evidence from a Registered Report. Fulltekst i vitenarkiv Vis sammendrag

  The timing of puberty may influence adolescent mental health. Earlier age at menarche has been associated with depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. In this Registered Report, we used a new wave of data (N=13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess causal links between age at menarche and adolescent mental health. As hypothesised, earlier age at menarche was associated with elevated depressive symptoms in early adolescence based on multiple regression (β = -0.11, 95% CI [-0.12, -0.09], p one-tailed = 0.01). One-sample MR analyses suggested that this relationship may be causal (β = -0.07, 95% CI [-0.13, 0.00], p one- tailed = 0.03). There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], p one-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Meanwhile, we found little evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. Age at menarche affected adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

• Corfield, Elizabeth Claire; Hannigan, Laurie John; Reichborn-Kjennerud, Ted; Ask, Helga & Havdahl, Alexandra (2023). Investigating the Relationship between Sleep Phenotypes and Neurodevelopmental Conditions in Children and Adolescents from the Norwegian Mother, Father, and Child Cohort Study (MoBa). Fulltekst i vitenarkiv
• Demontis, Ditte; Walters, G. Bragi; Athanasiadis, Georgios; Walters, Raymond; Therrien, Karen & Nielsen, Trine Tollerup [Vis alle 86 forfattere av denne artikkelen] (2023). Author Correction: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains (Nature Genetics, (2023), 55, 2, (198-208), 10.1038/s41588-022-01285-8). Nature Genetics. ISSN 1061-4036. doi: 10.1038/s41588-023-01350-w. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Frei, Oleksandr; Shadrin, Alexey; Rahman, Zillur; Lin, Aihua & Athanasiu, Lavinia [Vis alle 26 forfattere av denne artikkelen] (2022). The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: the MoBaPsychGen_v1 pipeline. Fulltekst i vitenarkiv
• Ystrøm, Eivind & Reichborn-Kjennerud, Ted (2022). Genomics of borderline personality disorder: Common Genetic Factors for Personality Disorders, Common Mental Disorders, Substance Abuse, and Stressful Life Events: A population based longitudinal twin study. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To evaluate the contribution of genetic and environmental factors for stability in, comorbidity with, and life events related to personality disorders. Methods: DSM-IV criteria for 10 personality disorders were assessed using structured interviews in 2801 Norwegian twins in early adulthood (age 28; range 19-36) and again in 2282 twins 10 years later. Biometric models were used on criteria counts to analyze the genetic and environmental factors for PDs and: 10-year stability, comorbidity with common mental disorders and psychotic-like experiences, substance abuse, and stressful life events. Results: Heritability of PDs were estimated to be 40% to 20% heritable. The 10-year stability estimated as tetrachoric correlation of PDs ranged from .35 to .58. Genetic variants influencing PDs were estimated to be the same over 10 years, the environmental factors were estimated to change 74-84% over the same period. Genetic and environmental factors for comorbidity between PDs and common mental disorders have different dimensionality and structure. The link between PDs and substance use are dependent on the specific criteria endorsed rather than at the disorder level. Stressful life events are important for the development of PDs and substance use over and beyond what can be explained by life-course selection due to genetic risk. Conclusion: Although PDs at specific assessments are mostly influenced by environmental factors, genetic factors are more important in explaining stability and comorbidity. The unequal structure of genetic and environmental factors leads to a mismatch between the observed comorbidity between PDs and mental disorders and the expected commonality in genetic factors. Aggregation of symptoms and disorders according to the estimated genetic structure could improve the precision of molecular genetic studies. This longitudinal twin study has also shown that PDs are related to stressful life events, mental disorders, and substance abuse over and beyond what can be explained by genetic risk.

• Askeland, Ragna Bugge; Hannigan, Laurie John; O'Connell, Kevin Sean; Corfield, Elizabeth Claire; Frei, Oleksandr & Thapar, Anita [Vis alle 11 forfattere av denne artikkelen] (2022). Developmental manifestations of polygenic risk for bipolar disorder from infancy to middle childhood. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Shadrin, Alexey; Frei, Oleksandr; Rahman, Zillur; Lin, Aihua & Athanasiu, Lavinia [Vis alle 15 forfattere av denne artikkelen] (2022). Genetic profile of the Norwegian Mother, Father, and Child Cohort Study (MoBa): Results from the MoBaPsychGen pipeline. Fulltekst i vitenarkiv
• Barkhuizen, Wikus; Pingault, Jean-Baptiste; Wang, Biyao; Hannigan, Laurie John; Eilertsen, Espen Moen & Andreassen, Ole [Vis alle 14 forfattere av denne artikkelen] (2021). Direct and indirect genetic influences involved in the intergenerational transmission of risk for ADHD in the Norwegian Mother, Father and Child Cohort. Fulltekst i vitenarkiv
• Skogheim, Thea Steen; Weyde, Kjell Vegard Fjeldheim; Engel, Stephanie M.; Aase, Heidi; Suren, Pål & Øie, Merete Glenne [Vis alle 12 forfattere av denne artikkelen] (2021). Risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in children associated with gestational levels of toxic metals and essential elements. Fulltekst i vitenarkiv
• Hannigan, Laurie John; Corfield, Elizabeth; Biele, Guido; Tilling, Kate; McAdams, Tom A. & Badini, Isabella [Vis alle 19 forfattere av denne artikkelen] (2021). The genomic basis of participation in the Norwegian Mother, Father and Child Cohort Study. Fulltekst i vitenarkiv
• Høye, Anne; Jacobsen, Bjarne K.; Bramness, Jørgen Gustav; Nesvåg, Ragnar; Reichborn-Kjennerud, Ted & Heiberg, Ina Heidi (2021). Correction to: Total and cause-specific mortality in patients with personality disorders: the association between comorbid severe mental illness and substance use disorders. Social Psychiatry and Psychiatric Epidemiology. ISSN 0933-7954. doi: 10.1007/s00127-021-02124-7. Fulltekst i vitenarkiv
• Barkhuizen, Wikus; Pingault, Jean-Baptiste; Wang, Biyao; Hannigan, Laurie John; Eilertsen, Espen Moen & Andreassen, Ole [Vis alle 14 forfattere av denne artikkelen] (2021). Direct and indirect genetic influences involved in the intergenerational transmission of risk for ADHD in the Norwegian Mother, Father and Child Cohort. Behavior Genetics. ISSN 0001-8244. 51(6), s. 692–691. Fulltekst i vitenarkiv
• Wootton, Robyn; Dack, Kyle; Borges, Carolina; Pagoni, Panagiota; Riglin, Lucy & Andreassen, Ole [Vis alle 12 forfattere av denne artikkelen] (2021). Nutritional biomarkers in pregnancy and neurodevelopmental outcomes in offspring: A Mendelian Randomization study in the Norwegian Mother, Father and Child Cohort Study (MoBa). Fulltekst i vitenarkiv
• Hughes, Amanda; Morris, Tim; Ayorech, Ziada; Tesli, Martin Steen; Ask, Helga & Askeland, Ragna Bugge [Vis alle 16 forfattere av denne artikkelen] (2021). The causal effect of BMI on neurodevelopment: a within family Mendelian randomization study using MoBa. International Journal of Epidemiology. ISSN 0300-5771. 50(Suppl 1). doi: 10.1093/ije/dyab168.296. Fulltekst i vitenarkiv
• Askeland, Ragna Bugge; Hannigan, Laurie John; Ask, Helga; Lennox, Ziada Ayorech; Tesli, Martin Steen & Corfield, Elizabeth [Vis alle 9 forfattere av denne artikkelen] (2020). Genetic risk factors for neurodevelopmental disorders. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Frei, Oleksandr; Shadrin, Alexey; Rahman, Zillur; Lin, Aihua & Athanasiu, Lavinia [Vis alle 26 forfattere av denne artikkelen] (2022). The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: MoBaPsychGen pipeline v.1. Cold Spring Harbor Laboratory Press (CSHL). doi: 10.1101/2022.06.23.496289. Fulltekst i vitenarkiv Vis sammendrag

  Background: The Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers. Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness. Methods: The MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation). Results: In total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 SNPs passed the MoBaPsychGen pipeline. The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs. Discussion: MoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

• Wootton, Robyn E; Lawn, Rebecca B.; Magnus, Maria Christine; Treur, Jorien L; Corfield, Elizabeth Claire & Njølstad, Pål Rasmus [Vis alle 14 forfattere av denne artikkelen] (2022). Health behaviours prior to pregnancy and fertility outcomes: Triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa). Cold Spring Harbor Laboratory Press (CSHL). doi: 10.1101/2022.03.22.22272772. Fulltekst i vitenarkiv
• Askeland, Ragna Bugge; Hannigan, Laurie John; Ask, Helga; Ayorech, Ziada; Tesli, Martin Steen & Corfield, Elizabeth [Vis alle 12 forfattere av denne artikkelen] (2020). Early manifestations of genetic risk for neurodevelopmental disorders. PsyArXiv (Preprint artikkel). doi: 10.31234/osf.io/qbvw8. Fulltekst i vitenarkiv

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