Mount Sinai researchers find strong Genetic Link in Postpartum Psychosis illness

Researchers at the Icahn School of Medicine at Mount Sinai have uncovered a substantial genetic component to postpartum psychosis, a rare but severe psychiatric illness that occurs in the days to weeks after childbirth. The findings, published May 14 in Molecular Psychiatry provide new evidence that the condition has a substantial biological and genetic basis and may help guide future research into prediction, prevention, and treatment.

The study, which combined whole genome sequencing with population-level family data, identified rare damaging mutations in the gene HMGCR as associated with increased risk for postpartum psychosis. The researchers also found significant genetic overlap between postpartum psychosis and bipolar disorder, schizophrenia, and several autoimmune diseases, including rheumatoid arthritis, Sjögren’s syndrome, myasthenia gravis, and Crohn’s disease.

Postpartum psychosis affects approximately 1 in 1,000 mothers and is considered a psychiatric emergency because of the elevated risk of suicide and infanticide. Symptoms can include delusions, hallucinations, severe mood changes, confusion, and disorganized behavior.

“Our findings show that postpartum psychosis is a biological illness with a substantial genetic basis,” said Behrang Mahjani, PhD, Assistant Professor in the Departments of Psychiatry, Genetics and Genomic Sciences and Artificial Intelligence and Human Health at the Icahn School of Medicine and senior author of the paper. “It is not a parenting failure or a personal weakness, and women affected by it deserve the same medical seriousness afforded to other severe illnesses.”

This condition has historically been understudied, particularly at the genetic level, and we hope these results help move the field toward a more mechanistic understanding of why some women become vulnerable during the postpartum period.”

The study estimated that approximately 55 percent of risk for postpartum psychosis is attributable to inherited genetic factors based on family data, while whole genome sequencing analyses estimated heritability from common genetic variants at approximately 46 percent.

Researchers were particularly surprised by the identification of HMGCR, which encodes the rate-limiting enzyme in cholesterol biosynthesis. The study also revealed broader-than-expected overlap between postpartum psychosis and immune-related conditions. Researchers say the findings are consistent with longstanding clinical observations that autoimmune disease activity often changes during the postpartum period and suggest that immune biology may play a role in the illness.

“Cholesterol biosynthesis was not a pathway we had anticipated, but once HMGCR emerged, the biology became highly coherent in light of the changing dynamics of cholesterol during and after pregnancy, because cholesterol serves as the precursor for steroid hormone synthesis and prior reports linking low serum cholesterol to first episode psychosis and suicidal behavior,” said Dr. Mahjani. “The postpartum period is marked by dramatic hormonal and metabolic shifts, and this gene sits directly within pathways affected during that transition.”

The research, with analyses performed by Seulgi Jung, PhD, a postdoctoral fellow in the Mahjani Lab at Mount Sinai, is the first study to apply whole genome sequencing to postpartum psychosis, allowing investigators to examine rare damaging mutations across the genome rather than focusing solely on common genetic risk variants. The team combined data from Swedish national health registers with genomic information from the National Institutes of Health’s All of Us Research Program, enabling researchers to study one of psychiatry’s rarest and least understood conditions at an unprecedented scale.

“It is important to understand that multiple genes are involved in postpartum psychosis and that HMGCR can be used as a research tool for further scientific discovery,” said Veerle Bergink, MD, PhD, Director of the Women’s Mental Health Research Center at Mount Sinai and an author of the paper.

Future work will focus on expanding sample sizes and improving ancestral diversity. The team is now pursuing functional studies of HMGCR and other candidate genes in neuronal and immune cell models relevant to pregnancy and the postpartum period. Researchers also plan to integrate genetic findings with hormonal and immunological changes associated with childbirth to better understand why the illness emerges during such a tightly defined window.

“In the long term, our goal is to understand postpartum psychosis well enough to predict it, prevent it where possible, and develop treatments that target the underlying biology rather than symptoms alone,” said Dr. Bergink.

The investigators also emphasized the importance of large-scale collaborative research infrastructure in enabling discoveries for rare conditions.

“This work would not have been possible without the NIH’s All of Us Research Program and the participants who contributed their data,” said Dr. Mahjani. “For rare and historically neglected illnesses such as postpartum psychosis, equitable access to large genomic datasets is essential for scientific progress.”

Reference:

Jung, S., Caballero, M., Kępińska, A. et al. Genetic architecture of postpartum psychosis: from common to rare genetic variation. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03637-w