Family History–Wide Association Study to Identify Clinical and Environmental Risk Factors for Common Chronic Diseases

Family history is a strong risk factor for many common chronic diseases and summarizes shared environmental and genetic risk, but how this increased risk is mediated is unknown. We developed a “family history–wide association study” (FamWAS) to systematically and comprehensively test clinical and environmental quantitative traits (CEQTs) for their association with family history of disease. We implemented our method on 457 CEQTs for association with family history of diabetes, asthma, and coronary heart disease (CHD) in 42,940 adults spanning 8 waves of the 1999–2014 US National Health and Nutrition Examination Survey. We conducted pooled analyses of the 8 survey waves and analyzed trait associations using survey-weighted logistic regression. We identified 172 (37.6% of total), 32 (7.0%), and 78 (17.1%) CEQTs associated with family history of diabetes, asthma, and CHD, respectively, in subcohorts of individuals without the respective disease. Twenty associated CEQTs were shared across family history of diabetes, asthma, and CHD, far more than expected by chance. FamWAS can examine traits not previously studied in association with family history and uncover trait overlap, highlighting a putative shared mechanism by which family history influences disease risk.