Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals

Abstract

BACKGROUND: Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors. METHODS AND RESULTS: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.5 years; 55% women) stratified by childhood adoption status (5747 adoptees). We estimated hazard ratios (HRs) per affected family member, and for polygenic risk scores in Cox models adjusted for baseline age and sex. A total of 12 518 strokes and 23 923 MIs occurred over a 13-year follow-up. In nonadoptees, family history of stroke and heart disease was associated with increased stroke and MI risk, with the strong-est association of family history of stroke for incident stroke (HR, 1.16 [95% CI, 1.12–1.19]) and family history of heart disease for incident MI (HR, 1.48 [95% CI, 1.45–1.50]). In adoptees, family history of stroke associated with incident stroke (HR, 1.41 [95% CI, 1.06–1.86]), but family history of heart disease was not associated with incident MI (P>0.5). Polygenic risk scores showed strong disease-specific associations in both groups. In nonadoptees, the stroke polygenic risk score mediated 6% risk between family history of stroke and incident stroke, and the MI polygenic risk score mediated 13% risk between family history of heart disease and incident MI. CONCLUSIONS: Family history of stroke and heart disease increases risk for their respective conditions. Family history of stroke contains substantial potentially modifiable nongenetic risk, indicating a need for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.