Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression

Guintivano, J., Byrne, E., Kiewa, J., Yao, S., Bauer, A., Aberg, K., Adams, M., Campbell, A., Campbell, M., Choi, K., Corfield, E., Havdahl, A., Hucks, D., Koen, N., Lu, Y., Mægbæk, M., Mullaert, J., Peterson, R., Raffield, L., Sallis, H., Sealock, J., Walker, A., Watson, H., Xiong, Y., Yang, J., Anney, R., Gordon-Smith, Katherine ORCID: https://orcid.org/0000-0003-4083-1143, Hubbard, L., Jones, Lisa ORCID: https://orcid.org/0000-0002-5122-8334, Mihaescu, R., Nyegaard, M., Pardiñas, A., Perry, Amy ORCID: https://orcid.org/0000-0002-9381-6636, Saquib, N., Shadyab, A., Viktorin, A., Andreassen, O., Bigdeli, T., Davis, L., Dennis, C., Di Florio, A., Dubertret, C., Feng, Y., Frey, B., Grigoriadis, S., Gloaguen, E., Jones, I., Kennedy, J., Krohn, H., Kallak, T., Li, Y., Martin, N., McIntosh, A., Milgrom, J., Munk-Olsen, T., Oberlander, T., Olsen, C., Ramoz, N., Reichborn-Kjennerud, T., Robertson Blackmore, E., Rubinow, D., Skalkidou, A., Smoller, J., Stein, D., Stowe, Z., Taylor, V., Tebeka, S., Tesli, M., Lieshout, R., van den Oord, E., Vigod, S., Werge, T., Westlye, L., Whiteman, D., Zar, H., MDD Working Group, T., Wray, N., Meltzer-Brody, S. and Sullivan, P. (2023) Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression. The American Journal of Psychiatry. ISSN Print: 0002-953X Online: 1535-7228

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Abstract

Objective:
Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.

Method:
Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)–based heritability (), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.

Results:
No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.

Conclusions:
While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

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