Aree Widya Witoelar

• Garvert, Anna Christina; Bieler, Malte; Witoelar, Aree Widya & Vervaeke, Koen Gerard Alois (2025). Area-specific encoding of temporal information in the neocortex. Cell reports. 44(3). doi: 10.1016/j.celrep.2025.115363. Full text in Research Archive Show summary

  Episodic memory requires remembering the temporal sequence of events, a process attributed to hippocampal “time cells.” However, the distributed nature of brain areas supporting episodic memory suggests that temporal representations may extend beyond the hippocampus. To investigate this possibility, we trained mice to remember the identity of an odor for a specific duration. Using mesoscale two-photon imaging of neuronal activity across the neocortex, we reveal a striking area-specific temporal representation. The retrosplenial cortex (RSC), a hippocampal target area, exhibits time-dependent sequential neuronal firing that encodes both odor identity and elapsed time, with decreasing accuracy over time. By contrast, temporal coding is far less prominent in areas surrounding the RSC, including the posterior parietal cortex and visual, somatosensory, and motor areas, highlighting functional specialization. Our results establish the RSC as a key temporal processing hub for episodic memory, supporting conjunctive “what” and “when” coding models.

• Hennestad, Eivind; Witoelar, Aree Widya; Chambers, Anna Ruth & Vervaeke, Koen Gerard Alois (2021). Mapping vestibular and visual contributions to angular head velocity tuning in the cortex. Cell reports. 37(12). doi: 10.1016/j.celrep.2021.110134. Full text in Research Archive Show summary

  Neurons that signal the angular velocity of head movements (AHV cells) are important for processing visual and spatial information. However, it has been challenging to isolate the sensory modality that drives them and to map their cortical distribution. To address this, we develop a method that enables rotating awake, head-fixed mice under a two-photon microscope in a visual environment. Starting in layer 2/3 of the retrosplenial cortex, a key area for vision and navigation, we find that 10% of neurons report angular head velocity (AHV). Their tuning properties depend on vestibular input with a smaller contribution of vision at lower speeds. Mapping the spatial extent, we find AHV cells in all cortical areas that we explored, including motor, somatosensory, visual, and posterior parietal cortex. Notably, the vestibular and visual contributions to AHV are area dependent. Thus, many cortical circuits have access to AHV, enabling a diverse integration with sensorimotor and cognitive information.

• Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific Reports. 9(7013). doi: 10.1038/s41598-019-43458-2. Full text in Research Archive Show summary

  Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

• Drange, Ole Kristian; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Finseth, Per Ivar; Witoelar, Aree & Frei, Oleksandr [Show all 52 contributors for this article] (2019). Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes. Frontiers in Neuroscience. ISSN 1662-4548. 13. doi: 10.3389/fnins.2019.00220. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect). Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

• Jansen, Iris E.; Savage, Jeanne E.; Watanabe, Kyoko; Bryois, Julien; Williams, Dylan M. & Steinberg, Stacy [Show all 53 contributors for this article] (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nature Genetics. ISSN 1061-4036. 51(3), p. 404–413. doi: 10.1038/s41588-018-0311-9. Full text in Research Archive Show summary

  Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

• Bettella, Francesco; Brown, AA; Smeland, Olav Bjerkehagen; Wang, Yunpeng; Witoelar, Aree & Demur, AA Buil [Show all 11 contributors for this article] (2018). Cross-tissue eQTL enrichment of associations in schizophrenia. PLOS ONE. 13(9). doi: 10.1371/journal.pone.0202812. Full text in Research Archive Show summary

  The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

• Srinivasan, Saurabh; Bettella, Francesco; Frei, Oleksandr; Hill, W. David; Wang, Yunpeng & Witoelar, Aree [Show all 17 contributors for this article] (2018). Enrichment of genetic markers of recent human evolution in educational and cognitive traits. Scientific Reports. 8:12585, p. 1–9. doi: 10.1038/s41598-018-30387-9. Full text in Research Archive Show summary

  Higher cognitive functions are regarded as one of the main distinctive traits of humans. Evidence for the cognitive evolution of human beings is mainly based on fossil records of an expanding cranium and an increasing complexity of material culture artefacts. However, the molecular genetic factors involved in the evolution are still relatively unexplored. Here, we investigated whether genomic regions that underwent positive selection in humans after divergence from Neanderthals are enriched for genetic association with phenotypes related to cognitive functions. We used genome wide association data from a study of college completion (N = 111,114), one of educational attainment (N = 293,623) and two different studies of general cognitive ability (N = 269,867 and 53,949). We found nominally significant polygenic enrichment of associations with college completion (p = 0.025), educational attainment (p = 0.043) and general cognitive ability (p = 0.015 and 0.025, respectively), suggesting that variants influencing these phenotypes are more prevalent in evolutionarily salient regions. The enrichment remained significant after controlling for other known genetic enrichment factors, and for affiliation to genes highly expressed in the brain. These findings support the notion that phenotypes related to higher order cognitive skills typical of humans have a recent genetic component that originated after the separation of the human and Neanderthal lineages.

• Broce, Iris J.; Tan, Chin Hong; Fan, CC; Jansen, Iris E.; Savage, Jeanne E. & Witoelar, Aree [Show all 34 contributors for this article] (2018). Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica. ISSN 0001-6322. doi: 10.1007/s00401-018-1928-6. Full text in Research Archive
• Witoelar, Aree; Rongve, Arvid; Almdahl, Ina Selseth; Ulstein, Ingun; Engvig, Andreas & White, Linda Rosemary [Show all 33 contributors for this article] (2018). Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci. Scientific Reports. 8(1). doi: 10.1038/s41598-018-36429-6. Full text in Research Archive Show summary

  A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.

• Zuber, Verena; Jönsson, Erik Gunnar; Frei, Oleksandr; Witoelar, Aree; Thompson, Wesley Kurt & Schork, Andrew J. [Show all 18 contributors for this article] (2018). Identification of shared genetic variants between schizophrenia and lung cancer. Scientific Reports. 674(8), p. 1–8. doi: 10.1038/s41598-017-16481-4. Full text in Research Archive Show summary

  Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.

• Hellard, Stephanie Le; Wang, Yunpeng; Witoelar, Aree; Zuber, Verena; Bettella, Francesco & Hugdahl, Kenneth [Show all 15 contributors for this article] (2017). Identification of gene loci that overlap between schizophrenia and educational attainment. Schizophrenia Bulletin. ISSN 0586-7614. 43(3), p. 654–664. doi: 10.1093/schbul/sbw085. Full text in Research Archive
• Srinivasan, Saurabh; Bettella, Francesco; Hassani, Sahar; Wang, Yunpeng; Witoelar, Aree & Schork, Andrew J. [Show all 13 contributors for this article] (2017). Probing the association between early evolutionary markers and schizophrenia. PLOS ONE. 12:e0169227(1), p. 1–15. doi: 10.1371/journal.pone.0169227. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Kauppi, Karolina; Hill, W. David; Li, Wen & Wang, Yunpeng [Show all 22 contributors for this article] (2017). Identification of genetic loci jointly influencing schizophrenia risk and the cognitive traits of verbal-numerical reasoning, reaction time, and general cognitive function. JAMA psychiatry. ISSN 2168-6238. 74(10), p. 1065–1075. doi: 10.1001/jamapsychiatry.2017.1986. Full text in Research Archive Show summary

  Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10−7), general cognitive function (z score, –4.43; P = 9.42 × 10−6), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 10−8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

• Smeland, Olav Bjerkehagen; Wang, Yunpeng; Lo, Min-Tzu; Li, Wen; Frei, Oleksandr & Witoelar, Aree [Show all 13 contributors for this article] (2017). Identification of genetic loci shared between schizophrenia and the Big Five personality traits. Scientific Reports. 7:2222(1), p. 1–9. doi: 10.1038/s41598-017-02346-3. Full text in Research Archive Show summary

  Schizophrenia is associated with differences in personality traits, and recent studies suggest that personality traits and schizophrenia share a genetic basis. Here we aimed to identify specific genetic loci shared between schizophrenia and the Big Five personality traits using a Bayesian statistical framework. Using summary statistics from genome-wide association studies (GWAS) on personality traits in the 23andMe cohort (n = 59,225) and schizophrenia in the Psychiatric Genomics Consortium cohort (n = 82,315), we evaluated overlap in common genetic variants. The Big Five personality traits neuroticism, extraversion, openness, agreeableness and conscientiousness were measured using a web implementation of the Big Five Inventory. Applying the conditional false discovery rate approach, we increased discovery of genetic loci and identified two loci shared between neuroticism and schizophrenia and six loci shared between openness and schizophrenia. The study provides new insights into the relationship between personality traits and schizophrenia by highlighting genetic loci involved in their common genetic etiology.

• Witoelar, Aree; Jansen, Iris E.; Wang, Yunpeng; Desikan, Rahul S.; Gibbs, J. Raphael & Thompson, Wesley Kurt [Show all 26 contributors for this article] (2017). Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurology. ISSN 2168-6149. 74(7), p. 780–792. doi: 10.1001/jamaneurol.2017.0469. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Wang, Yunpeng; Frei, Oleksandr; Li, Wen; Hibar, Derrek P & Franke, Barbara [Show all 13 contributors for this article] (2017). Genetic overlap between schizophrenia and volumes of hippocampus, putamen, and intracranial volume indicates shared molecular genetic mechanisms. Schizophrenia Bulletin. ISSN 0586-7614. 44(4), p. 854–864. doi: 10.1093/schbul/sbx148. Full text in Research Archive
• Zuber, Verena; Bettella, Francesco; Witoelar, Aree; Andreassen, Ole Andreas; Mills, Ian Geoffrey & Urbanucci, Alfonso (2017). Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genomics. 18:270, p. 1–11. doi: 10.1186/s12864-017-3620-y. Full text in Research Archive Show summary

  Background Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Results Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. Conclusions This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.

• Winsvold, Bendik K S; Bettella, Francesco; Witoelar, Aree; Anttila, Verneri; Gormley, Padhraig & Kurth, Tobias [Show all 18 contributors for this article] (2017). Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants. PLOS ONE. 12(9), p. 1–15. doi: 10.1371/journal.pone.0185663. Full text in Research Archive Show summary

  Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10−5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

• Devor, Anna; Andreassen, Ole Andreas; Wang, Yunpeng; Mäki-Marttunen, Tuomo; Smeland, Olav Bjerkehagen & Fan, Chun Chieh [Show all 18 contributors for this article] (2017). Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia. Molecular Psychiatry. ISSN 1359-4184. 22(6), p. 792–801. doi: 10.1038/mp.2017.33. Full text in Research Archive Show summary

  The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.

• Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana; Guelfi, Sebastian; Witoelar, Aree & Karch, Celeste M. [Show all 22 contributors for this article] (2017). Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. 88(2), p. 152–164. doi: 10.1136/jnnp-2016-314411. Full text in Research Archive
• Desikan, Rahul S.; Fan, Chun Chieh; Wang, Yunpeng; Schork, Andrew J; Cabral, Howard J & Cupples, L. Adrienne [Show all 34 contributors for this article] (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. Nature Methods. ISSN 1548-7091. 14(3:e1002258), p. 1–17. doi: 10.1371/journal.pmed.1002258. Full text in Research Archive
• Shadrin, Alexey A.; Smeland, Olav Bjerkehagen; Zayats, Tetyana; Schork, Andrew J; Frei, Oleksandr & Bettella, Francesco [Show all 19 contributors for this article] (2017). Novel loci associated with attention-deficit/hyperactivity disorder are revealed by leveraging polygenic overlap with educational attainment. Journal of the American Academy of Child and Adolescent Psychiatry. ISSN 0890-8567. 57(2), p. 86–95. doi: 10.1016/j.jaac.2017.11.013. Full text in Research Archive Show summary

  Objective Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes. Method A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. Results At levels of condFDR<0.01 and conjFDR<0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1),whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (rg=−0.403, p=7.90×10−8) and >10-fold mutual enrichment of SNPs associated with both traits. Conclusion We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.

• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2016). Functional effects of schizophrenia-linked genetic variants on intrinsic single-neuron excitability: a modeling study. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 1(1), p. 49–59. doi: 10.1016/j.bpsc.2015.09.002. Full text in Research Archive Show summary

  BACKGROUND: Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. METHODS: We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. RESULTS: We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. CONCLUSIONS: Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior. Keywords: Biophysical modeling, Functional genomics, Genome-wide association studies, Layer V pyramidal cell, Neuron excitability, Schizophrenia

• Holland, Dominic; Wang, Yunpeng; Thompson, Wesley K.; Schork, Andrew J.; Chen, Chi-Hua & Lo, Min-Tzu [Show all 11 contributors for this article] (2016). Estimating effect sizes and expected replication probabilities from GWAS summary statistics. Frontiers in Genetics. 7(15). doi: 10.3389/fgene.2016.00015. Full text in Research Archive
• Yokoyama, Jennifer S.; Wang, Yunpeng; Schork, Andrew J.; Thompson, Wesley K.; Karch, Celeste M. & Cruchaga, Carlos [Show all 28 contributors for this article] (2016). Association between genetic traits for immune-mediated diseases and Alzheimer disease. JAMA Neurology. ISSN 2168-6149. 73(6), p. 691–697. doi: 10.1001/jamaneurol.2016.0150. Full text in Research Archive
• Wang, Yunpeng; Bos, Steffan Daniel; Harbo, Hanne Flinstad; Thompson, Wesley K.; Schork, Andrew J. & Bettella, Francesco [Show all 14 contributors for this article] (2016). Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors. Multiple Sclerosis. ISSN 1352-4585. 22(14), p. 1783–1793. doi: 10.1177/1352458516635873. Full text in Research Archive
• Zuber, Verena; Marconett, Crystal; Shi, Jianxin; Hua, Xing; Wheeler, William & Yang, Chenchen [Show all 41 contributors for this article] (2016). Pleiotropic analysis of lung cancer and blood triglycerides. Journal of the National Cancer Institute. ISSN 0027-8874. 108:djv167(12), p. 1–4. doi: 10.1093/jnci/djw167. Full text in Research Archive
• Vijayaraghavan, Swetha; Darreh-Shori, Taher; Rongve, Arvid; Berge, Guro; Sando, Sigrid Botne & White, Linda [Show all 11 contributors for this article] (2016). Association of Butyrylcholinesterase-K allele and Apolipoprotein E ε 4 allele with cognitive decline in dementia with lewy bodies and Alzheimer's disease. Journal of Alzheimer's Disease. ISSN 1387-2877. 50(2), p. 567–576. doi: 10.3233/JAD-150750. Full text in Research Archive
• Wang, Yunpeng; Thompson, Wesley K.; Schork, Andrew J.; Holland, Dominic; Chen, Chi-Hua & Bettella, Francesco [Show all 22 contributors for this article] (2016). Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS. PLoS Genetics. ISSN 1553-7390. doi: 10.1371/journal.pgen.1005803. Full text in Research Archive Show summary

  Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic (“z-score”) of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a “relative enrichment score” for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3.

• Thompson, WK; Wang, Yunpeng; Schork, AJ; Witoelar, Aree; Zuber, Verena & Xu, S [Show all 10 contributors for this article] (2015). An Empirical Bayes Mixture Model for Effect Size Distributions in Genome-Wide Association Studies. PLoS Genetics. ISSN 1553-7390. 11(12). doi: 10.1371/journal.pgen.1005717. Full text in Research Archive
• Srinivasan, Saurabh; Bettella, Francesco; Mattingsdal, Morten; Wang, Yunpeng; Witoelar, Aree & Schork, AJ [Show all 17 contributors for this article] (2015). Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2015.10.009. Full text in Research Archive
• LeBlanc, Marissa; Zuber, Verena; Kulle, Bettina; Witoelar, Aree; Zeng, Limin & Bettella, Francesco [Show all 26 contributors for this article] (2015). Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes with Several Cardiovascular Risk Factors. Circulation Research. ISSN 0009-7330. 1, p. 83–94. doi: 10.1161/CIRCRESAHA.115.306629. Full text in Research Archive
• Desikan, Rahul S.; Schork, Andrew J.; Wang, Yunpeng; Thompson, Wesley K.; Dehghan, Abbas & Ridker, Paul M. [Show all 47 contributors for this article] (2015). Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease. Circulation. ISSN 0009-7322. 131(23), p. 2061–2069. doi: 10.1161/CIRCULATIONAHA.115.015489. Full text in Research Archive Show summary

  Background—Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results—Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05–1.11; P=2.86×10−8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04–1.11; P=3.38×10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions—We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

• Desikan, RS; Schork, AJ; Wang, Yunpeng; Witoelar, Aree; Sharma, M & McEvoy, LK [Show all 45 contributors for this article] (2015). Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Molecular Psychiatry. ISSN 1359-4184. 20(12), p. 1588–1595. doi: 10.1038/mp.2015.6. Full text in Research Archive
• Couey, Jonathan Jay; Witoelar, Aree Widya; Zhang, Sheng Jia; Zheng, Kang; Ye, Jing & Dunn, Benjamin Adric [Show all 11 contributors for this article] (2013). Recurrent inhibitory circuitry as a mechanism for grid formation. Nature Neuroscience. ISSN 1097-6256. 16(3), p. 318–324. doi: 10.1038/nn.3310. Full text in Research Archive

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• Rongve, Arvid; Witoelar, Aree Widya; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla & Clarimon, Jordi [Show all 40 contributors for this article] (2019). Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study (Scientific Reports, (2019), 9, 1, (7013), 10.1038/s41598-019-43458-2). Scientific Reports. 9(1). doi: 10.1038/s41598-019-51827-0. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Wang, Yunpeng; Fan, Chun Chieh; Shadrin, Alexey A. & Li, Wen [Show all 13 contributors for this article] (2017). C-Reactive Protein Levels and Schizophrenia Share Genetic Influences. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Wang, Yunpeng; Fan, Chun Chieh; Alexey, Shadrin & Li, Wen [Show all 13 contributors for this article] (2017). Increased discovery of risk loci for bipolar disorder by leveraging prior probabilities of true associations using the covariate modulated mixture model (CM3). Full text in Research Archive
• Smeland, Olav Bjerkehagen; Wang, Yunpeng; Frei, Oleksandr; Li, Wen; Hibar, Derrek & Franke, Barbara [Show all 13 contributors for this article] (2017). Conditional false discovery rate analysis of genome-wide association studies uncovers genetic loci shared between schizophrenia and volumes of hippocampus, putamen and intracranial volume. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Witoelar, Aree; Lo, Min-Tzu; Tesli, Martin Steen; Wang, Yunpeng & Hinds, David A. [Show all 11 contributors for this article] (2016). Genetic overlap between schizophrenia and the Big Five personality traits. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Kauppi, Karolina; Wang, Yunpeng; Frei, Oleksandr; Li, Wen & Hill, David W [Show all 17 contributors for this article] (2016). Schizophrenia and general cognitive function share genetic influences. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Witoelar, Aree; Wang, Yunpeng; Chen, Chi-Hua; Djurovic, Srdjan & Dale, Anders [Show all 7 contributors for this article] (2016). Genetic overlap between schizophrenia and brain structural volumes indicates shared molecular genetic mechanisms with potential relevance for antipsychotics. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2015). Towards biophysical psychiatry: A modeling approach for studying effects of schizophrenia-linked gens on single-neuron excitability. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2015). Towards biophysical psychiatry: A modeling approach for studying effects of schizophrenia-linked genes on single-neuron excitability. Full text in Research Archive
• Smeland, Olav Bjerkehagen; Lo, Min-Tzu; Witoelar, Aree; Tesli, Martin; Hinds, David & Hu, Youna [Show all 12 contributors for this article] (2015). Genetic overlap between Schizophrenia and the Big Five personality traits. Full text in Research Archive
• Couey, Jonathan Jay; Witoelar, Aree Widya; Zhang, Sheng Jia; Czajkowski, Rafal; Dunn, Benjamin Adric & Ye, Jing [Show all 10 contributors for this article] (2012). 702.06/DDD22 - Medial entorhinal cortex layer ii stellate cells are embedded within a recurrent inhibitory network. SFN Abstract Viewer/Itinerary Planner. Full text in Research Archive
• Dunn, Benjamin Adric; Witoelar, Aree Widya; Couey, Jonathan Jay; Bonnevie, Tora; Moser, May-Britt & Moser, Edvard Ingjald [Show all 8 contributors for this article] (2012). 702.08/DDD24 - An inhibitory network of grid cells. SFN Abstract Viewer/Itinerary Planner. Full text in Research Archive
• Dunn, Benjamin Adric; Witoelar, Aree Widya; Couey, Jonathan Jay; Moser, May-Britt; Moser, Edvard Ingjald & Witter, Menno [Show all 7 contributors for this article] (2012). 3899. Grid Cells Emerge From A Competitive Network. FENS. Full text in Research Archive
• Witoelar, Aree Widya & Roudi, Yasser (2011). Neural network reconstruction using kinetic Ising models with memory. BMC Neuroscience. Full text in Research Archive

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