Several strategies may be used to study genome variation and specific genetic variants in iPSC‐derived neurons. With one strategy, groups of participants may be selected from repository specimens using SNPs from GWAS data and specific clinical diagnoses or other phenotypic data. While retaining variable background genomes, this approach is limited by the relatively small number, by genetics standards, of iPSC lines that can be reasonably produced and cultured (generally 8–12 in most studies). Another strategy, incorporating genome editing, such as the CRISPR/Cas9 system, may be used to create isogenic pairs of cell lines, one with a variant and one without, but retaining identical genomic backgrounds. This approach is most appropriate for studying one or a few closely linked variants. But for studying complex, polygenic changes in the context of diverse genetic backgrounds, construction of isogenic lines is impractical due to the large number of targets, so participant selection may utilize a summary statistic such as polygenic risk score to focus on specific risk groups.
