Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses.

Panagiotaropoulou, Georgia, Hellberg, Kajsa-Lotta Georgii, Coleman, Jonathan R. I., Seok, Darsol, Kalman, Janos, Bipolar Disorder Working Group of the Psychiatric Genomics Conso, Major Depressive Disorder Working Group of the Psychiatric Genom, 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 ORCID: https://orcid.org/0000-0002-3427-3950, 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, J.Raymond, 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. ORCID: https://orcid.org/0000-0003-4798-0862, Gordon-Smith, Katherine, Mitchell, Brittany L., Martin, Nicholas G., Medland, Sarah E., Jones, Lisa., Knowles, James A., Levinson, Douglas F., O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Lewis, Cathryn M., Breen, Gerome, Werge, Thomas, Schork, Andrew J., Ophoff, Roel A., Ripke, Stephan and Olde Loohuis, Loes 2025. Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses. The British Journal of Psychiatry 10.1192/bjp.2024.125

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Abstract

Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD). We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis. Based on individual genotypes from case-control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses. Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, = 25 966). We observe strong genetic correlation between our case-case GWAS and that of case-control BPD. We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients 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 BPD and, importantly, BPD-D from MDD.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Cambridge University Press
ISSN:	0007-1250
Date of First Compliant Deposit:	28 January 2025
Last Modified:	28 Jan 2025 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/175681

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