Stratified GenomicSEM 36 analyses were then conducted to examine differential and shared enrichment of sensation seeking and alcohol consumption genomic factor variances and their covariance within multiple brain‐related functional annotations. Specifically, a model was fit allowing the variances of each factor and the covariance between them to vary across annotations to test for enrichment of these parameters. Functional annotations included (1) baseline annotations from 1000 Genomes Project Phase 3 (BaselineLD v2.2) 37 ; (2) annotations for tissue‐specific epigenomic marks across seven brain regions and five different post‐translational modifications (H3K36me3, H3K4me1, H3K4me3, H3K9ac and H3K27ac) using data from the Roadmap Epigenomics Consortium 38 ; and (3) annotations for tissue‐specific gene expression across 13 brain regions constructed using RNA sequencing data from the Genotype‐Tissue Expression project version 8 (GTEx v8). 39 GTEx v8 annotations were constructed using stratified linkage disequilibrium score regression (LDSC) applied to specifically expressed genes (LDSC‐SEG; Supporting Information Methods). 40 In total, enrichment analyses were based on 97 binary annotations. Tissue‐specific heritability enrichment analysis of AUD was conducted using LDSC‐SEG. A 5% false discovery rate (FDR) correction was used within each model parameter (i.e., variance/covariance of GenomicSEM factors and heritability of AUD) to account for multiple testing.
