While the polygenic nature of complex traits has made individual risk variant and gene identification efforts challenging, this polygenicity can be leveraged with tools such as genome‐wide polygenic scoring 115 (PGS or PRS, Figure 1). Many approaches to creating polygenic scores, from linkage disequilibrium (LD) clumping or pruning and thresholding approaches, to modern Bayesian methods, and even functional polygenic signatures, are available. Recent methodological advances in the field include within‐sibling association studies 116 and polygenic score comparisons 117 that further parse direct genetic effects from indirect effects and confounding factors, and the estimation of parental “genetic nurture” effects using polygenic scores based upon the parental alleles not passed to the offspring. 118 , 119 , 120 These more recent approaches place findings emerging from larger consortium‐based GWAS in the family‐based context to illuminate mechanisms of genetic risk (see, Figure 1 for an overview of the methods discussed); the extent to which these have been applied in COGA is discussed in detail below.
