does not contain Asian-descent or Hispanic individuals. It remains unclear whether the relatively greater similarity between these and European populations 50 would support the generalization of our GRS. However, GWAS of Asian and Hispanic samples 28,51 suggest that a European-descent population-derived GRS may omit important risk loci for these populations. As more GWAS of non-European populations become available, our 3-stage approach can be used to derive additional population-specific GRSs. Fourth, there is mounting evidence that many genetic factors predisposing individuals to obesity are sex specific 52 and that GWAS that fail to model such sex specificity may not detect important risk variants 53. Results from GWAS modeling gene-by-sex interaction support this hypothesis 47,54,55. As more such GWAS become available, our 3-stage approach can be used to derive sex-specific GRSs for obesity. Finally, the ARIC sample is limited to individuals in middle age. There is evidence that genetic risk for obesity has dynamic consequences across development 56,57. It will be important in subsequent investigations to evaluate our obesity GRS in longitudinal cohorts that capture a broader section of the life course, and particularly in young people, as they are a key prevention target 58.
