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

Panagiotaropoulou, G. ORCID: https://orcid.org/0000-0001-9516-6158, Hellberg, K., Coleman, J. ORCID: https://orcid.org/0000-0002-6759-0944, Seok, D., Kalman, J. ORCID: https://orcid.org/0000-0003-0930-4214, Mitchell, P., Schofield, P., Forstner, A., Bauer, M., Scott, L., Pato, C., Pato, M., Li, Q., Kirov, G. ORCID: https://orcid.org/0000-0002-3427-3950, Landén, M. ORCID: https://orcid.org/0000-0002-4496-6451, Jonsson, L. ORCID: https://orcid.org/0000-0002-3175-103X, Müller-Myhsok, B., Smoller, J., Binder, E., Brückl, T., Czamara, D., Van der Auwera, S., Grabe, H., Homuth, G., Schmidt, C., Potash, J., DePaulo, J., Goes, F., MacKinnon, D., Mondimore, F., Weissman, M., Shi, J., Frye, M., Biernacka, J., Reif, A., Witt, S., Kahn, R., Boks, M., Owen, M., Gordon-Smith, Katherine ORCID: https://orcid.org/0000-0003-4083-1143, Mitchell, B., Martin, N., Medland, S., Jones, Lisa ORCID: https://orcid.org/0000-0002-5122-8334, Knowles, J., Levinson, D. ORCID: https://orcid.org/0000-0001-8223-1301, O'Donovan, M. ORCID: https://orcid.org/0000-0001-7073-2379, Lewis, C. ORCID: https://orcid.org/0000-0002-8249-8476, Breen, G., Werge, T., Schork, A., Ophoff, R. ORCID: https://orcid.org/0000-0002-8287-6457, Ripke, S. and Olde Loohuis, L. ORCID: https://orcid.org/0000-0002-3327-7837 (2025) Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses. The British Journal of Psychiatry. pp. 1-12. ISSN Print: 0007-1250 Online: 1472-1465

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Abstract

Background
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).

Aims
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.

Method
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.

Results
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, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.

Conclusions
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.

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