A challenge for developmental research following-up GWAS discoveries is that effect sizes for individual single-nucleotide polymorphisms (SNPs) are small; the largest effects for smoking quantity approach a change of 1 cigarette per day per risk allele. Moreover, many of the longitudinal studies with data necessary to investigate developmental phenotypes are underpowered to test single-SNP effects.23 However, there is evidence that smoking-associated loci make additive contributions to risk, recommending aggregating risk alleles.24-27 Summing risk alleles across GWAS-identified SNPs to compute a “genetic risk score” (GRS) yields a quantitative index of genetic risk with a normal distribution28 and a potentially larger effect size.
