Shahram Bahrami

• Bahrami, Shahram; Shadrin, Alexey A.; Frei, Oleksandr; O`Connell, Kevin; Bettella, Francesco; Krull, Florian; Fan, Chun Chieh; Røssberg, Jan Ivar; Hindley, Guy Frederick Lanyon; Ueland, Torill; Dale, Anders; Djurovic, Srdjan; Steen, Nils Eiel; Smeland, Olav Bjerkehagen & Andreassen, Ole Andreas (2021). Genetic loci shared between major depression and intelligence with mixed directions of effect. Nature Human Behaviour.  ISSN 2397-3374.  s 1- 9 . doi: 10.1038/s41562-020-01031-2
• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Lin, Aihua; Gani, Osman; Shadrin, Alexey A.; Smeland, Olav Bjerkehagen; O'Connell, Kevin; Elvsåshagen, Torbjørn; Winterton, Adriano; Quintana, Daniel; Hindley, Guy Frederick Lanyon; Werner, Maren Caroline Frogner; Djurovic, Srdjan; Dale, Anders Martin; Lagerberg, Trine Vik; Steen, Nils Eiel & Andreassen, Ole Andreas (2021). Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms. Translational Psychiatry.  ISSN 2158-3188.  11(1) . doi: 10.1038/s41398-020-01142-4 Full text in Research Archive. Show summary

  Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

• Bahrami, Shahram; Steen, Nils Eiel; Shadrin, Alexey A.; O`Connell, Kevin; Frei, Oleksandr; Bettella, Francesco; Wirgenes, Katrine Verena; Krull, Florian; Fan, Chun C.; Dale, Anders; Smeland, Olav Bjerkehagen; Djurovic, Srdjan & Andreassen, Ole Andreas (2020). Shared genetic loci between body mass index and major psychiatric disorders: A genome-wide association study. JAMA psychiatry.  ISSN 2168-6238.  77(5), s 503- 512 . doi: 10.1001/jamapsychiatry.2019.4188 Show summary

  IMPORTANCE People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. OBJECTIVE To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. DESIGN, SETTING, AND PARTICIPANTS Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. MAIN OUTCOMES AND MEASURES The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. RESULTS Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = −0.11, P = 2.1 × 10−10; BIP: r for genetic = −0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10−10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. CONCLUSIONS AND RELEVANCE In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones

• Elvsåshagen, Torbjørn; Bahrami, Shahram; van der Meer, Dennis; Agartz, Ingrid; Alnæs, Dag; Barch, Deanna M.; Baur-Streubel, Ramona; Bertolino, Alessandro; Beyer, Mona K.; Blasi, Giuseppe; Borgwardt, Stefan; Boye, Birgitte; Buitelaar, Jan; Bøen, Erlend; Celius, Elisabeth Gulowsen; Cervenka, Simon; Conzelmann, Annette; Coynel, David; di Carlo, Pasquale; Djurovic, Srdjan; Eisenacher, Sarah; Espeseth, Thomas; Fatouros-Bergman, Helena; Flyckt, Lena; Franke, Barbara; Frei, Oleksandr; Gelao, Barbara; Harbo, Hanne Flinstad; Hartman, Catharina A.; Håberg, Asta; Heslenfeld, Dirk; Hoekstra, Pieter J.; Høgestøl, Einar August; Jonassen, Rune; Jönsson, Erik Gunnar; Kirsch, Peter; Kloszewska, Iwona; Lagerberg, Trine Vik; Landrø, Nils Inge; Le Hellard, Stephanie; Lesch, Klaus-Peter; Maglanoc, Luigi Angelo; Malt, Ulrik Fredrik; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Moberget, Torgeir; Nordvik, Jan Egil; Nyberg, Lars; O`Connell, Kevin; Oosterlaan, Jaap; Papalino, Marco; Papassotiropoulos, Andreas; Pauli, Paul; Pergola, Giulio; Persson, Karin Ester Torun; de Quervain, Dominique; Reif, Andreas; Rokicki, Jaroslav; Van Rooij, Daan; Shadrin, Alexey A.; Schmidt, André; Schwarz, Emanuel; Selbæk, Geir; Sowa, Piotr; Soininen, Hilkka; Steen, Vidar Martin; Vellas, Bruno; Tsolaki, Magda; Wang, Lei; Westman, Eric; Ziegler, Georg C.; Zink, Mathias; Andreassen, Ole Andreas; Westlye, Lars Tjelta & Kaufmann, Tobias (2020). The genetic architecture of human brainstem structures and their involvement in common brain disorders. Nature Communications.  ISSN 2041-1723.  11 . doi: 10.1038/s41467-020-17376-1 Full text in Research Archive. Show summary

  Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

• Shadrin, Alexey A.; Frei, Oleksandr; Smeland, Olav Bjerkehagen; Bettella, Francesco; O`Connell, Kevin; Gani, Osman; Bahrami, Shahram; Uggen, Tea Kristiane Espeland; Djurovic, Srdjan; Holland, Dominic; Andreassen, Ole Andreas & Dale, Anders (2020). Phenotype-specific differences in polygenicity and effect size distribution across functional annotation categories revealed by AI-MiXeR. Bioinformatics.  ISSN 1367-4803. . doi: 10.1093/bioinformatics/btaa568 Full text in Research Archive.
• Shadrin, Alexey A.; Mucha, Sören; Ellinghaus, David; Makarious, Mary B; Blauwendraat, Cornelis; Sreelatha, Ashwin; Heras-Garvin, Antonio; Ding, Jinhui; Hammer, Monia B.; Foubert-Samier, Alexandra; Meissner, Wassilios G.; Rascol, Olivier; Traon, Anne Pavy-Le; Frei, Oleksandr; O`Connell, Kevin; Bahrami, Shahram; Schreiber, Stefan; Lieb, Wolfgang; Müller-Nurasyid, Martina; Schminke, Ulf; Homuth, Georg; Schmidt, Carsten O.; Nöthen, Markus M.; Hoffman, Per; Gieger, Christian; Wenning, Gregor; Gibbs, J. Raphael; Franke, Andre; Hardy, John; Stefanova, Nadia; Gasser, Thomas; Singleton, Andrew; Houlden, Henry; Scholz, Sonja W.; Andreassen, Ole Andreas & Sharma, Manu (2020). Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease. Movement Disorders.  ISSN 0885-3185. . doi: 10.1002/mds.28338 Full text in Research Archive.
• Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Bahrami, Shahram; Broce, Iris J.; Tesli, Martin Steen; Frei, Oleksandr; Wirgenes, Katrine Verena; O`Connell, Kevin; Krull, Florian; Bettella, Francesco; Steen, Nils Eiel; Sugrue, Leo P.; Wang, Yunpeng; Svenningsson, Per; Sharma, Manu; Pihlstrøm, Lasse; Toft, H. Mathias S.; O’Donovan, Michael; Djurovic, Srdjan; Desikan, Rahul S; Dale, Anders M. & Andreassen, Ole Andreas (2020). Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci. Biological Psychiatry.  ISSN 0006-3223.  89(3), s 227- 235 . doi: 10.1016/j.biopsych.2020.01.026 Full text in Research Archive. Show summary

  BACKGROUND:Parkinson’s disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involvedysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between thedisorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs.Despite this, little is known about shared genetic etiology between the disorders.METHODS:We analyzed recent large genome-wide association studies on patients with SCZ (N= 77,096) and PD(N= 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap incommon genetic variants and improve statistical power for genetic discovery. Using a variety of biologicalresources, we functionally characterized the identified genomic loci.RESULTS:We observed genetic enrichment in PD conditional onassociations with SCZ and vice versa, indicatingpolygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PDrisk loci and 1 novel SCZ locus at conditional FDR,.01. Furthermore, we identified 9 genomic loci jointly associated withPD and SCZ at conjunctional FDR,.05. There was an even distribution of antagonistic and agonistic effect directionsamong the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to theshared loci, 65 are expressed in the human brain and show cell type–specific expression profiles.CONCLUSIONS:Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD,indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinicalfeatures between the disorders.

• Akkouh, Ibrahim; Skrede, Silje; Holmgren, Asbjørn; Ersland, Kari Merete; Hansson, Lars Johan Axel; Bahrami, Shahram; Andreassen, Ole Andreas; Steen, Vidar Martin; Djurovic, Srdjan & Hughes, Timothy (2019). Exploring lithium's transcriptional mechanisms of action in bipolar disorder: a multi-step study. Neuropsychopharmacology.  ISSN 0893-133X.  s 1- 9 . doi: 10.1038/s41386-019-0556-8 Full text in Research Archive.
• O`Connell, Kevin; Shadrin, Alexey A.; Bahrami, Shahram; Smeland, Olav Bjerkehagen; Bettella, Francesco; Frei, Oleksandr; Krull, Florian; Askeland, Ragna Bugge; Walters, Bragi; Davíðsdóttir, Katrín; Haraldsdóttir, Gyða; Guðmundsson, Ólafur; Stefánsson, Hreinn; Fan, Chun C.; Steen, Nils Eiel; Reichborn-Kjennerud, Ted; Dale, Anders M.; Stefánsson, Kári; Djurovic, Srdjan & Andreassen, Ole Andreas (2019). Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder. Molecular Psychiatry.  ISSN 1359-4184.  s 1- 11 . doi: 10.1038/s41380-019-0613-z Full text in Research Archive. Show summary

  Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.

• O`Connell, Kevin; Shadrin, Alexey A.; Smeland, Olav Bjerkehagen; Bahrami, Shahram; Frei, Oleksandr; Bettella, Francesco; Krull, Florian; Fan, Chun C.; Askeland, Ragna Bugge; Knudsen, Gun Peggy Strømstad; Halmøy, Anne; Steen, Nils Eiel; Ueland, Torill; Walters, G. Bragi; Davíðsdóttir, Katrín; Haraldsdóttir, Gyda S.; Guðmundsson, Ólafur; Stefansson, Hreinn; Reichborn-Kjennerud, Ted; Haavik, Jan; Dale, Anders M.; Stefánsson, Kári; Djurovic, Srdjan & Andreassen, Ole Andreas (2019). Identification of genetic loci shared between ADHD, intelligence and educational attainment. Biological Psychiatry.  ISSN 0006-3223.  87(12), s 1052- 1062 . doi: 10.1016/j.biopsych.2019.11.015 Full text in Research Archive.
• Smeland, Olav Bjerkehagen; Bahrami, Shahram; Frei, Oleksandr; Shadrin, Alexey A.; O`Connell, Kevin; Savage, Jeanne E.; Watanabe, Kyoko; Krull, Florian; Bettella, Francesco; Steen, Nils Eiel; Ueland, Torill; Posthuma, Danielle; Djurovic, Srdjan; Dale, Anders & Andreassen, Ole Andreas (2019). Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Molecular Psychiatry.  ISSN 1359-4184.  s 1- 10 . doi: 10.1038/s41380-018-0332-x Full text in Research Archive.
• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Shadrin, Alexey A.; O`Connell, Kevin; Fan, Chun Chieh; Bahrami, Shahram; Holland, Dominic; Djurovic, Srdjan; Thompson, Wesley Kurt; Dale, Anders & Andreassen, Ole Andreas (2019). Discovery of shared genomic loci using the conditional false discovery rate approach. Human Genetics.  ISSN 0340-6717.  s 1- 10 . doi: 10.1007/s00439-019-02060-2 Full text in Research Archive.
• Witoelar, Aree; Rongve, Arvid; Almdahl, Ina Selseth; Ulstein, Ingun; Engvig, Andreas; White, Linda Rosemary; Selbæk, Geir; Stordal, Eystein; Andersen, Fred; Brækhus, Anne; Saltvedt, Ingvild; Engedal, Knut; Hughes, Timothy; Bergh, Sverre; Bråthen, Geir; Bogdanovic, Nenad; Bettella, Francesco; Wang, Yunpeng; Athanasiu, Lavinia; Bahrami, Shahram; Le Hellard, Stephanie; Giddaluru, Sudheer; Dale, Anders M; Sando, Sigrid Botne; Steinberg, Stacy; Stefansson, Hreinn; Snaedal, Jon; Desikan, Rahul S; Stefansson, Kari; Aarsland, Dag; Djurovic, Srdjan; Fladby, Tormod & Andreassen, Ole Andreas (2018). Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci. Scientific Reports.  ISSN 2045-2322.  8 . doi: 10.1038/s41598-018-36429-6 Full text in Research Archive.
• Bahrami, Shahram & Drabløs, Finn Sverre (2016). Gene regulation in the immediate-early response process. Advances in Biological Regulation.  ISSN 2212-4926.  62, s 37- 49 . doi: 10.1016/j.jbior.2016.05.001
• Ehsani, Rezvan; Bahrami, Shahram & Drabløs, Finn Sverre (2016). Feature-based classification of human transcription factors into hypothetical sub-classes related to regulatory function.. BMC Bioinformatics.  ISSN 1471-2105.  17(459) . doi: 10.1186/s12859-016-1349-2 Full text in Research Archive.
• Bahrami, Shahram; Ehsani, Rezvan & Drabløs, Finn (2015). A property-based analysis of human transcription factors. BMC Research Notes.  ISSN 1756-0500.  8(1) . doi: 10.1186/s13104-015-1039-6 Full text in Research Archive.

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• Smeland, Olav Bjerkehagen; Bahrami, Shahram; Frei, Oleksandr; Shadrin, Alexey A.; Savage, Jeanne E.; Watanabe, Kyoko; Krull, Florian; Bettella, Francesco; Steen, Nils Eiel; Ueland, Torill; Posthuma, Danielle; Djurovic, Srdjan; Dale, Anders & Andreassen, Ole Andreas (2018). Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder and intelligence.
• Bahrami, Shahram & Drabløs, Finn Sverre (2016). Identification and analysis of genes in immediate-early response processes.
• Bahrami, Shahram; Ehsani, Rezvan & Drabløs, Finn (2014). An overrepresentation analysis of human transcription factors.
• Bahrami, Shahram; Ehsani, Rezvan & Drabløs, Finn (2014). From gene sets to properties; some potential pitfalls and tripwires.

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