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SCHIZOPHRENIA POLYGENIC RISK IS NEGATIVELY ASSOCIATED WITH BODY MASS INDEX IN TWO POPULATION COHORTS

Olaoluwa Okusaga — Chris Chatzinakos2, Gleda Kutrolli2, Rachel L. Kember3, Tim Bigdeli2, Roseann E. Peterson2 1Michael E DeBakey VA Medical Center/Baylor College of Medicine, 2SUNY Downstate Medical Center, 3University of Pennsylvania Olaoluwa Okusaga, Michael E DeBakey VA Medical Center/Baylor College of Medicine

2026 ASCP Annual Meeting

Background

Obesity is highly prevalent among individuals with schizophrenia and contributes to cardiovascular mortality and reduced life expectancy. Despite this, a few studies have reported a negative association between schizophrenia polygenic risk scores (PRS) and body mass index (BMI). However, the nature of the relationship between schizophrenia genetic liability and BMI remains unclear. To further clarify this association, we evaluated the relationship between schizophrenia PRS and BMI across two independent biobanks.

Methods

Data were derived from two sources: 1) The Health and Retirement Study (HRS); and 2) UK biobank (UKB, conducted using the UK Biobank Resource application number 30782). Data on age, sex, and BMI for each participant were extracted from both biobanks. In UKB, we calculated schizophrenia PRS based on the most recent PGC GWAS, but for HRS, we employed the precalculated schizophrenia PRS (based on PGC 2) on the HRS website. In separate analyses in HRS and UKB, we evaluated the association between schizophrenia PRS and BMI using linear regression, with BMI as the dependent variable and schizophrenia PRS as the primary independent variable. Covariates included age, sex, and the first ten genetic principal components in both datasets, with years of education additionally included in the HRS analyses.

Results

7,984 middle-aged and older adults (3612 male, 4372 female, mean age 65.4 years) were included in the HRS analyses and 458,547 participants in UKB (209792 male, 248755 female, mean age 57.3 years). All the participants were of European ancestry. Schizophrenia PRS were negatively associated with BMI in HRS (β= -0.04; 95% CI -0.004 to -0.08, p < 0.05, R² = 0.05) and UKB (- 0.140; 95% CI −0.154 to −0.126, p < 1×10⁻⁵, ΔR² = 0.0008).

Discussion

We replicated the negative association between Schizophrenia PGS and BMI in two different cohorts and life stages. Specifically in UKB, a one-unit increase in SCZ-PRS was associated with an approximately 0.14 unit decrease in BMI. Our findings contribute to the accumulating evidence suggesting that the high rates of obesity observed among persons with schizophrenia is not explained by genetic liability to high BMI but is likely related to several extrinsic factors including antipsychotic medications, sedentary lifestyle, and diet. Additional research is warranted to examine how schizophrenia genetic liability impacts BMI and metabolic traits across the life course.

Learning Objective 1: Show that obesity is highly prevalent among individuals with schizophrenia

Learning Objective 2: Demonstrate that genetic liability for schizophrenia is inversely related to BMI

References

  1. Zheutlin, A. B., Dennis, J., Karlsson Linnér, R., et al. Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems. The American journal of psychiatry. 2019;176(10) 846–855.
  2. Solmi, F., Mascarell, M. C., Zammit, S., et al. Polygenic risk for schizophrenia, disordered eating behaviors and body mass index in adolescents. The British journal of psychiatry. 2019;215(1), 428–433.