Common schizophrenia heritability concentrates in an evolutionarily young, brain-regulatory subset of fine-mapped credible-set variants

Abstract

Common variation explains a substantial fraction of schizophrenia heritability, yet why these risk alleles persist remains unresolved. Of 20,766 fine-mapped PGC3 schizophrenia credible-set variants, the 4,918 with an allele-age estimate, brain-versus-blood regulatory specificity and a haplotype-based selection signal were clustered into three age-ordered subsets (Young, Mid and Old), all predating the out-of-Africa dispersal (cluster medians {approx}113-508 kyr). The Young, brain-regulatory subset concentrated schizophrenia common-variant heritability after accounting for genome-wide allele age, frequency, linkage-disequilibrium and selection architecture (conditional coefficient Z = +3.05). The concentration generalized to East Asian schizophrenia (Z = +2.83), was balanced across sexes, and tracked genetic correlation across psychiatric disorders, including bipolar disorder, but not height or body-mass index. Their persistence at common frequency is most consistent with purifying selection and mutation-selection balance on these ancient, predominantly non-coding, brain-regulatory variants rather than recent adaptation.