New research published in Molecular Psychiatry indicates that postpartum psychosis is heavily influenced by both common and rare genetic factors, with about half of the risk tied to genetics. The study also identified a specific gene involved in cholesterol production that provides evidence for shared biological pathways between postpartum psychosis, schizophrenia, and certain autoimmune conditions.
Postpartum psychosis is a rare but severe mental health emergency that occurs in roughly 1 to 2 out of every 1,000 mothers shortly after childbirth. It involves an abrupt onset of symptoms like mania, severe depression, confusion, and psychosis, which is when a person loses touch with reality through hallucinations or delusions. The condition poses heavy risks to both the mother and the infant, often requiring immediate medical hospitalization.
Earlier research established that this vulnerability has deep biological roots. A 2001 study showed that the tendency to experience a severe psychotic episode triggered specifically by childbirth runs strongly in families. Moving beyond familial history, a 2013 study discovered that women experiencing their first episode of postpartum psychosis show disruptions in their immune systems.
Alongside these immune factors, metabolic changes have also been implicated, as a 2017 meta-analysis suggested that people going through their first psychotic episode tend to have altered cholesterol levels. These findings paved the way for large-scale genetic sequencing to pinpoint the exact genes and shared biological pathways involved. To build on these insights, researchers led by Seulgi Jung and study co-author Behrang Mahjani, an assistant professor at the Icahn School of Medicine at Mount Sinai who directs the Mahjani Lab, aimed to detail the specific genetic architecture of postpartum psychosis.
“Postpartum psychosis is a severe but understudied psychiatric disorder,” Mahjani told PsyPost. “Our previous study showed that sisters of women with postpartum psychosis have a markedly elevated risk, but its heritability had not been quantified and no specific risk genes had been identified. We therefore examined the contribution of both common and rare genetic variation to the disorder.”
The researchers first used data from Swedish national registers to estimate the overall genetic risk of the disorder. They examined health records from over 1.6 million mothers who gave birth to their first child between 1980 and 2017. Among this massive group, 2,514 mothers, or 0.15 percent, developed postpartum psychosis.
By tracking the health records of the mothers’ sisters and cousins, the researchers estimated the heritability of postpartum psychosis to be 55 percent. This indicates that more than half of the variation in who develops the condition can be attributed to genetic factors, a rate similar to that of bipolar disorder.
“The genetic contribution is substantial,” Mahjani explained. “Heritability in this range means that inherited variation accounts for a large share of the differences in vulnerability between individuals, comparable to what is seen for bipolar disorder and schizophrenia.”
“This supports the view that postpartum psychosis reflects an underlying biological vulnerability rather than being simply a psychological reaction to the stress of childbirth,” he added.
To see how much of this heritability comes from common genetic variations, the team turned to the All of Us Research Program, a large national database of genetic and health information. They focused on whole-genome sequencing data from 198 mothers of European ancestry who had experienced postpartum psychosis, comparing them to 2,013 matched controls.
The team found that common genetic variants explained about 45.6 percent of the risk for postpartum psychosis. Because this is slightly lower than the 55 percent heritability estimated from family histories, it suggests that rarer genetic variations also play a role in the disorder.
The researchers then looked closely at rare genetic changes, specifically focusing on protein-truncating variants. These are severe mutations that essentially break a gene, preventing it from producing a functional protein. They analyzed a larger sample of 461 cases of postpartum psychosis and 4,610 unaffected controls.
Women with postpartum psychosis had an unusually high number of these disruptive mutations in genes that are generally highly constrained, meaning the genes do not usually tolerate mutations well without causing major biological problems. Based on these mutation patterns, the researchers estimated that there are around 81 specific genes that contribute to the risk of postpartum psychosis.
When analyzing which individual genes were most affected, the gene HMGCR stood out strongly. This gene contains the instructions for making a key enzyme that controls how the body produces cholesterol. A second gene, DNMT1, which helps maintain how DNA is regulated and read by the body, also showed a possible, though less certain, link to the disorder.
“The rare variants in HMGCR have large effects in the people who carry them, which is what allowed us to detect the gene despite a relatively modest sample,” Mahjani noted.
However, he cautioned against oversimplifying this connection. “HMGCR should not be read as ‘the postpartum psychosis gene,'” he said. “It is one of the many genes contributing to risk, and like other severe psychiatric disorders the condition is highly polygenic.”
To explore the broader impact of these genes, the researchers checked for mutations in HMGCR and DNMT1 across hundreds of thousands of individuals in two large medical biobanks. They found that rare mutations in HMGCR were also linked to conditions like vascular dementia and unspecified mental disorders, indicating the gene influences brain health outside of the postpartum period.
Finally, the researchers compared their list of genetic risk factors for postpartum psychosis against genes known to cause other illnesses. They found that a substantial percentage of the top risk genes for bipolar disorder and schizophrenia were also linked to postpartum psychosis. Additionally, they noted a genetic overlap with autoimmune diseases like rheumatoid arthritis, myasthenia gravis, and Crohn’s disease, with HMGCR appearing as a top risk gene for both schizophrenia and rheumatoid arthritis.
“The results were largely consistent with what genetic studies of related psychiatric disorders would predict,” Mahjani said.
There are a few things to keep in mind regarding this study. First, definitions of postpartum psychosis can vary across different medical records. The registry data used in the study often lacked the precise end dates of episodes, which makes it harder to classify the exact duration of the illness.
The researchers also did not separate women whose postpartum psychosis was their very first psychiatric episode from those who had a pre-existing condition, such as bipolar disorder. As a result, some of the genetic patterns they found might reflect severe mental illness in general rather than factors entirely unique to the postpartum period.
Additionally, the genetic sequencing data relied heavily on individuals of European ancestry, meaning the results might not fully capture the genetic risk factors present in other populations. Future studies with more diverse groups will help provide a more complete picture of the condition’s genetic roots.
“Our immediate priority is to replicate these findings in larger samples,” Mahjani said of the team’s next steps. “Beyond that, we want to understand how the genes we identified actually function in the disorder, and how genetic vulnerability interacts with the hormonal and immune changes that occur during and after pregnancy.”
“Mainly that postpartum psychosis has been remarkably understudied relative to its severity,” he concluded. “Progress will depend on continued access to the kind of large-scale genomic resources that made this work possible, such as the All of Us Research Program, and on studies large enough to identify additional risk genes with confidence.”
The study, “Genetic architecture of postpartum psychosis: from common to rare genetic variation,” was authored by Seulgi Jung, Madison Caballero, Adrianna Kępińska, Shelby Smout, Trine Munk-Olsen, Thalia K. Robakis, Veerle Bergink, and Behrang Mahjani.