Familial Occurrence and Heritability of Stroke

Clustering of clinical strokes among related family members is an indication of the aggregate genetic, environmental, and lifestyle factors shared by these family members, all of which could increase susceptibility to stroke. A family history of stroke or other atherosclerotic events, such as a myocardial infarction, is a moderate risk factor for stroke, as observed in twin, cohort, and case-control studies (Flossmann et al., Stroke 35(1):212–227, 2004). With the exception of some rare Mendelian disorders, most stroke occurring in a clinical or population sample has a complex inheritance pattern, but the relative importance of genetic factors can be estimated by studying the familial occurrence of stroke. Patterns of familial aggregation can also help prioritize which subgroups to investigate further as more likely to share common underlying genetic variation; thus we could define subgroups by age, sex, ethnicity, presence of vascular risk factors, or stroke subtype (Yates, Lancet 1(7324):65–69, 1964; Marshall, J Med Genet 8(1):84–89, 1971). Focused investigations within these subgroups using modern genotyping techniques (phenotyping ‘splitting’) can increase the yield in identifying gene variants associated with stroke (NINDS Stroke Genetics Network and International Stroke Genetics Consortium, Lancet Neurol 15:174–184, 2016; Lancet Neurol 15(7):695–707, 2016). As a predisposing risk factor, family history can be used clinically for risk prediction and to encourage primary disease prevention (Banerjee, Int J Clin Pract 66(6):536–543, 2012). Polygenic risk scores are being developed to complement family history, but need further study to clinically implement for stroke risk prediction.