Identifying genetic differences between bipolar disorder and major depression through multiple GWAS
Authors: Panagiotaropoulou Georgia , Hellberg Kajsa-Lotta Georgii , Coleman Jonathan R. I. , Seok Darsol , Kalman Janos ,   the Bipolar Disorder Working Group of the Psychiatric Genetics Consortium,   the Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium,   the iPSYCH Study Consortium, Mitchell Philip B. , Schofield Peter R. , Forstner Andreas J. , Bauer Michael , Scott Laura J. , Pato Carlos N. , Pato Michele T. , Li Qingqin S. , Kirov George , Landén Mikael , Jonsson Lina , Müller-Myhsok Bertram , Smoller Jordan W. , Binder Elisabeth B. , Brückl Tanja M. , Czamara Darina , Van der Auwera Sandra , Grabe Hans J. , Homuth Georg , Schmidt Carsten O. , Potash James B. , DePaulo Raymond J. , Goes Fernando S. , MacKinnon Dean F. , Mondimore Francis M. , Weissman Myrna M. , Shi Jianxin , Frye Mark A. , Biernacka Joanna M. , Reif Andreas , Witt Stephanie H. , Kahn René R. , Boks Marco M. , Owen Michael J. , Gordon-Smith Katherine , Mitchell Brittany L. , Martin Nicholas G. , Medland Sarah E. , Jones Lisa , Knowles James A. , Levinson Douglas F. , O’Donovan Michael C. , Lewis Cathryn M. , Breen Gerome , Werge Thomas , Schork Andrew J. , Ophoff Roel , Ripke Stephan , Loohuis Loes Olde 
Published: January 2024

AbstractBackgroundAccurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD).AimsHere, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis.MethodsBased on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses.ResultsWhile our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD.ConclusionsWe find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls – MDD — BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.