Genome-wide association analyses identify 44 risk variants and refine the genetic architecture ofmajor depressive disorder

Statistical analysis. In each cohort, logistic regression association tests were conducted for imputed marker dosages with principal components covariates to control for population stratification. Ancestry was evaluated using principal components analysis applied to directly genotyped SNPs. 99 In the anchor cohorts and GERA, we determined that all individuals in the final analyses were of European ancestry. European ancestry was confirmed in the other expanded cohorts by the collaborating research teams using similar procedures. We tested 20 principal components for association with MDD and included five principal components covariates for the anchor cohorts and GERA (all other cohorts adopted similar strategies). There was no evidence of stratification artifacts or uncontrolled test statistic inflation in the results from each anchor and extended cohort (e.g., l GC was 0.995–1.043 in the anchor cohorts). The results were combined across samples using an inverse-weighted fixed effects model. 100 Reported SNPs have imputation marker INF O score ≥ 0.6 and allele frequencies ≥0.01 and ≤0.99, and effective sample size equivalent to > 100,000 cases. For all cohorts, X-chromosome association results were conducted separately by sex, and then meta-analysed across sexes. 22 For two cohorts (GenScot and UKBB), we first conducted association analysis for genotyped SNPs by sex, then imputed association results using LD from the 1000 Genomes reference sample. 101