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Social risk factors show larger effect sizes than polygenic risk scores for bipolar disorder in cohort studyWhat matters more for bipolar disorder: your genes or your life experiences?

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Key Takeaway
Consider social risk factors alongside genetic risk in bipolar disorder assessment.

A cohort study analyzed data from 115,275 participants (7,000 BD cases; 108,275 controls) in the All of Us Research Program. Researchers examined associations between a polygenic risk score for bipolar disorder (PRSBD) and six social risk measures—perceived stress, discrimination in medical settings, neighborhood social cohesion, perceived neighborhood disorder, cost-related medication nonadherence, and adverse childhood experiences—with BD case status.

PRSBD was associated with BD case status across ancestry groups, explaining 1.86% of liability-scale variance in European ancestry, 0.60% in African ancestry, and 1.65% in Latino/Admixed American ancestries. However, each social risk factor exhibited a larger effect size than PRSBD, with perceived stress showing an odds ratio of 2.05 per standard deviation and adverse childhood experiences showing an OR of 2.68 for ≥4 ACEs.

Individuals in the lowest genetic risk decile with high social burden exhibited BD prevalence comparable to or exceeding those in the highest genetic risk decile with low social burden. The study did not report safety or tolerability data. As an observational cohort study, findings represent associations rather than causal relationships, and PRS explain only a fraction of disorder liability. The diminished predictive performance of PRS in non-European populations and real-world clinical cohorts represents a key limitation.

When we think about what leads to bipolar disorder, we often focus on genetics. But a new study of more than 115,000 people suggests the story is more complicated. Researchers looked at a genetic risk score for bipolar disorder alongside six measures of social hardship, including stress, discrimination in healthcare, and adverse childhood experiences. They found that each social factor was more strongly linked to having the condition than the genetic score was.

The data came from the diverse All of Us Research Program, which included 7,000 people with bipolar disorder. The genetic score, which estimates inherited risk, explained only a small fraction of who developed the condition—less than 2% of the variance in people of European ancestry, and even less in other groups. In contrast, the link to social factors was clearer. For example, people who reported four or more adverse childhood events were more than two and a half times as likely to have bipolar disorder.

Perhaps the most striking finding was about risk profiles. People in the lowest 10% for genetic risk, but who faced high social burdens, had rates of bipolar disorder that matched or even exceeded those in the top 10% for genetic risk who had low social burdens. This paints a picture where a difficult life can weigh as heavily as a genetic predisposition.

It's important to remember this is an observational study. It shows associations, not causes. It can't tell us if these stressful experiences directly trigger bipolar disorder, or if other factors are at play. The genetic scores used also work better for people of European ancestry, highlighting a need for more inclusive research. Still, the results strongly suggest that to understand mental health, we need to look at a person's whole life, not just their DNA.

What this means for you:
For bipolar disorder, life's hardships may weigh as heavily as your genes.

Study Details

Study typeCohort
Sample sizen = 115,275
EvidenceLevel 3
PublishedApr 2026
View Original Abstract ↓
Polygenic risk scores (PRS) have shown increasing utility for risk stratification across complex diseases, but for psychiatric disorders such as bipolar disorder (BD), current PRS explain only a fraction of disorder liability (~1-9%), with predictive performance further diminished in non-European populations and real-world clinical cohorts. To explore the potential of integrating social and environmental risk factors alongside genetic liability to improve risk prediction, we evaluated the relationship between a PRS for BD (PRSBD) and six social risk measures - perceived stress, discrimination in medical settings, neighborhood social cohesion, perceived neighborhood disorder, cost-related medication nonadherence, and adverse childhood experiences - to BD case status in 115,275 participants (7,000 cases; 108,275 controls) from the All of Us Research Program. PRSBD was associated with BD case status across ancestry groups, though liability-scale variance explained was attenuated relative to what has been reported for curated research cohorts (R2 = 1.86% in European, 0.60% in African, 1.65% in Latino/Admixed American ancestries). Each social risk factor tested exhibited a larger effect size than PRSBD, with perceived stress (OR = 2.05 per SD) and adverse childhood experiences (OR = 2.68 for [≥]4 ACEs) demonstrating the strongest associations. Individuals in the lowest genetic risk decile with high social burden exhibited BD prevalence comparable to or exceeding those in the highest genetic risk decile with low social burden. These findings demonstrate the substantial explanatory power of social risk factors and support the development of integrated genetic-social risk frameworks for more accurate and equitable psychiatric risk prediction.
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