Largest-Ever Genetic Study of PPD: Correlations Between PPD and Other Psychiatric Disorders, Evidence of Involvement of GABAergic Systems

Postpartum depression (PPD) occurs commonly after childbirth. While PPD is thought to be a subtype of major depressive disorder (MDD), there are important clinical differences, most notably its temporal association with the perinatal period. Previous studies have documented that PPD is heritable, yet we know little about the genetic factors associated with this disorder.

As is the case with MDD, there is not a single gene that confers risk for PPD. Instead we conceptualize PPD as a depressive illness that emerges as a result of the complex interplay of genetic, hormonal, environmental, and psychosocial factors.

To better understand the genetic basis of PPD, a recent study from Guntivano and colleagues has conducted meta-analyses of genome-wide association studies (GWASs).

The Details of the Analysis

Meta-analyses were conducted on 18 cohorts of European ancestry (including 17,339 cases of PPD 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). A total of 18,770 PPD cases and 58,461 controls were included, and the team was able to perform multiple GWAS meta-analyses and post-GWAS analyses. 

GWAS is used to investigate the association between specific genes and genetic variations across the entire genome and vulnerability to a particular disease–in this study, PPD–in large populations. In the GWAS analyses included here, single nucleotide polymorphisms or SNPs were used as genetic markers to identify variations in DNA sequences across individuals with and without PPD. The frequency of different alleles at each SNP locus is then compared between the groups to identify SNPs that are statistically associated with PPD. 

In this study, no SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. 

Guntivano and colleagues also examined genetic correlations between PPD and other psychiatric disorders, observing that the correlation between PPD and MDD was close to 1. This may be explained by the fact that about half of the PPD cases included in the study were derived from cohorts of women with MDD who had also experienced PPD. The researchers also identified significant positive correlations of PPD with bipolar I and II disorders, anxiety disorders, posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder, schizophrenia, and insomnia.

There were also significant correlations between PPD and age at menarche and polycystic ovary syndrome (PCOS), suggesting common genes associated with these disorders.

One of the most interesting aspects of this report was a post-GWAS analysis in which Guintivano and colleagues integrated the GWAS results with RNA sequencing data to investigate SNP enrichment in 27 human tissue types from the Genotype-Tissue Expression (GTEx) project. Here they found no enrichment in any of the tissues.

However, they also looked at 39 different cell types derived from central and peripheral nervous systems of mice. Here, the strongest signals identified were found in inhibitory neurons in the thalamus and cholinergic neurons in the septal nuclei of the hypothalamus. Both of these cell types are GABAergic neurons that release GABA or gamma-aminobutyric acid, the main inhibitory neurotransmitter in the human brain. Furthermore, these cell types were more enriched when testing PPD-associated genes compared to MDD genes, a finding that suggests unique triggers for PPD, as well as novel targets for PPD treatment.

What’s Next? What are the Clinical Implications?

This study reports the first ever GWAS meta-analysis focusing specifically on PPD and the largest genetic study of PPD to date. Analyzing data from 20 international cohorts, including a total of 18,770 PPD cases and 58,461 control subjects, GWAS meta-analyses indicated that the majority of the genetic data for PPD parallel data observed for MD. The analyses also observed significant genetic correlations for PPD with bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. 

The current study represents a monumental undertaking. The ultimate goal of genome-wide association studies (GWAS) is to uncover genetic variations linked to complex traits or diseases. However, due to the challenges inherent in this approach, such as the small effect sizes of individual genetic variants, the complexity of gene-environment interactions, and limitations in sample sizes and diversity, many GWASs have not been able to fully elucidate the genetic architecture of many traits and diseases. The issue of psychiatric comorbidity in women with PPD likely makes it even more difficult to identify important, PPD-specific genetic factors.

In an accompanying commentary, Adams and colleagues note how to improve the utility of future genetic studies:

… when data are gathered on PPD, it is often included with MDD and missing important details, such as time of onset after childbirth. Future studies should ensure that lifetime data on PPD are gathered, with standardized criteria and postpartum cutoff point to separate it from MDD. While gathering data from different ancestry groups is important, data on childhood trauma, poverty, discrimination, and intimate partner violence should also be collected. There is a vital need for better clinical assessment of PPD in maternal health services, and using standardized diagnostic interviews, checking for comorbidities, and collecting biological samples longitudinally would provide a massive source of data for future GWAS studies. This would not only increase statistical power to detect novel genes associated with PPD, but also provide a clinical framework for early detection, treatment, and support for PPD.

The most interesting findings in this report comes from the post-GWAS cell-type enrichment analyses. This approach implicated GABA-ergic inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern of enrichment that differentiated PPD from MDD. The finding suggests that while there is considerable overlap between PPD and MDD, there may be genetic factors that distinguish the two. Even more interesting is that this finding parallels the development of a novel type of treatment for PPD, neuroactive steroids derived from allopregnanolone. Brexanolone (Zulresso) and zuranolone (Zurzuvae) are both allosteric modulators of the GABA-A receptor.

In a commentary in the same issue, Zachary Stowe, MD puts the finding of this study into a historical context, highlighting the importance of large, multisite collaborative efforts to not only understand the genetic underpinnings of perinatal mood and anxiety disorders, but also to improve our ability to accurately detect and diagnose and to develop and refine treatments for this vulnerable population.

Ruta Nonacs, MD PhD

References

Adams JAM, Chandra P, Mehta D. The First Large GWAS Meta-Analysis for Postpartum Depression. Am J Psychiatry. 2023 Dec 1;180(12):862-864.

Guintivano J, Byrne EM, Kiewa J, Yao S, et al. Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression. Am J Psychiatry. 2023 Dec 1; 180(12):884-895. 

Stowe ZN. Perinatal Mental Health: Advances and Opportunities. Am J Psychiatry. 2023 Dec 1; 180(12):874-877.