Given massive polygeneticity of complex behavior, one method for testing hypotheses about the genetic underpinnings of behavior (including samples with moderate sample sizes) is an enrichment analysis (Aliev et al., 2015). Like a candidate gene approach, an enrichment analysis examines associations with a circumscribed and hypothesis-driven set of genetic variants, rather than testing associations with every marker across the genome. Enrichment is detected if there are more significant associations between the genetic variants and the phenotype of interest than would be expected by chance. Still, unlike a well-powered genome-wide association study (which may require sample sizes in the tens or hundreds of thousands), an enrichment analysis cannot specify which variants within a set are driving an enrichment effect. That is, enrichment indicates that there is a genetic signal from a circumscribed set of genetic variants, but does not identify which specific associations are “true” effects. Results from an enrichment analysis can thus be conceptualized as intermediate to results from twin studies (which estimate the entirety of the genetic variance but are silent about which genetic variants are involved) and results from GWAS (which account for only small fractions of total phenotypic variability but can identify specific variants).
