Postpartum depression (PPD), a prevalent subtype of major depressive disorder, is more heritable than other psychiatric conditions, such as anxiety and bipolar disorder, but the genetics of PPD are understudied in comparison.
To address this, University of North Carolina School of Medicine researchers led an international team of researchers in the largest-ever meta-analysis of genome-wide association studies (GWAS) to investigate the genetic architecture of postpartum depression.
According to their research, approximately 14% of the observed variation in PPD cases can be attributed to prevalent genetic factors. A patient’s PPD is frequently not caused solely by environmental factors, such as past trauma. Instead, PPD susceptibility has a substantial genetic component.
Shared Genetic Risk Factors
The researchers, led by first author Jerry Guintivano, PhD, assistant professor of psychiatry at the UNC School of Medicine, also uncovered the genetic architecture of postpartum depression, which they claim correlates significantly with the genetic architecture of major depression, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, and polycystic ovary syndrome.
This suggests that the interaction of the same genes implicated in these other psychiatric and hormone-related disorders is most likely what causes PPD symptoms.
“We studied about 1.1 million regions of the human genome, and we can see that PPD has a similar genetic signature to these other psychiatric conditions. The genetic risk factors for PPD appear to be shared by other disorders, such as major depression, bipolar disorder, and anxiety,”
Guintivano said,
Additionally, the researchers discovered that genetic regions containing GABAergic neurons are associated with PPD, specifically in the thalamus and hypothalamus. The secretion of the neurotransmitter GABA is controlled by GABAergic neurons.
Future Research
Brexanolone, the only FDA-approved PPD treatment, is known to circulate throughout the body and brain. UNC researchers had discovered earlier this year that the drug worked through GABAergic neurons to treat postpartum depression symptoms so effectively. But now, this new research suggests brexanolone likely acts on GABAergic neurons in two particular brain regions.
“We view our finding as a refinement of the mechanism by which brexanolone works,” Guintivano said. “We now have preliminary evidence suggesting we should target GABAergic neurons in the thalamus and hypothalamus for future research.”
Although the researchers revealed more than ever before about the genetics of postpartum depression, their data set was still limited. The most effective genome-wide association studies collect information from hundreds of thousands of individuals with a specific disease, such as severe depression or schizophrenia.
Guintivano and colleagues used 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) for their study, totaling 18,770 PPD cases and 58,461 controls.
Although this was the largest PPD GWAS to date, Guintivano said there were still too few postpartum depression cases to pinpoint specific locations within the genome that are associated with PPD risk.
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).
Reference:
- Jerry Guintivano, Enda M. Byrne, Jacqueline Kiewa, Shuyang Yao, Anna E. Bauer, Karolina A. Aberg, Mark J. Adams, Archie Campbell, Megan L. Campbell, Karmel W. Choi, Elizabeth C. Corfield, Alexandra Havdahl, Donald Hucks, Nastassja Koen, Yi Lu, Merete L. Mægbæk, Jimmy Mullaert, Roseann E. Peterson, Laura M. Raffield, Hannah M. Sallis, Julia M. Sealock, Alicia Walker, Hunna J. Watson, Ying Xiong, Jessica M.K. Yang, Richard J.L. Anney, Katherine Gordon-Smith, Leon Hubbard, Lisa A. Jones, Raluca Mihaescu, Mette Nyegaard, Antonio F. Pardiñas, Amy Perry, Nazmus Saquib, Aladdin H. Shadyab, Alexander Viktorin, Ole A. Andreassen, Tim B. Bigdeli, Lea K. Davis, Cindy-Lee Dennis, Arianna Di Florio, Caroline Dubertret, Yen-Chen A. Feng, Benicio N. Frey, Sophie Grigoriadis, Emilie Gloaguen, Ian Jones, James L. Kennedy, Holly Krohn, Theodora Kunovac Kallak, Yun Li, Nicholas G. Martin, Andrew M. McIntosh, Jeannette Milgrom, Trine Munk-Olsen, Tim Oberlander, Catherine M. Olsen, Nicolas Ramoz, Ted Reichborn-Kjennerud, Emma Robertson Blackmore, David Rubinow, Alkistis Skalkidou, Jordan W. Smoller, Dan J. Stein, Zachary N. Stowe, Valerie Taylor, Sarah Tebeka, Martin Tesli, Ryan J. Van Lieshout, Edwin J.C.G. van den Oord, Simone N. Vigod, Thomas Werge, Lars T. Westlye, David C. Whiteman, Heather J. Zar, Naomi Wray, Samantha Meltzer-Brody, Patrick Sullivan. Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression. American Journal of Psychiatry, 2023; DOI: 10.1176/appi.ajp.20230053
Last Updated on November 11, 2023