Association of Polygenic Risk for Psychiatric Disorders with Cardiometabolic Disease

IMPORTANCEIndividuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVEIdentify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN, SETTING, AND PARTICIPANTSThree Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURESExposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTSThe MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCEAssociations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking. Key PointsO_ST_ABSQuestionC_ST_ABSIs genetic liability to specific psychiatric disorders associated with an increased risk of clinically diagnosed cardiometabolic diseases even after adjusting for cross-disorder psychiatric pleiotropy, body mass index, and smoking status? FindingsIn this study of cohorts in Sweden, Estonia, and Norway, genetic liability to major depressive disorder (MDD) showed stronger associations with cardiometabolic disease (CMD) compared to other psychiatric disorders. Genetic liability to anxiety disorder and PTSD showed associations with CMD that were attenuated when adjusting for cross-disorder psychiatric pleiotropy. Genetic liability to ADHD showed strong associations with obesity and type 2 diabetes that were strongly attenuated when adjusting for body mass index, and smoking status. Genetic liability to schizophrenia showed inverse associations with CMD. MeaningThese findings suggest that MDD has a distinctive genetic relationship with CMD compared to other psychiatric disorders and that the well-established phenotypic association between schizophrenia and CMD is not related to genetic factors.