Authors
Huisheng Zhu, Yuval B Simons, Jeffrey P Spence, Guy Sella, Jonathan K Pritchard
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 36. Pages e2609814123. Sep 08, 2026. Epub Sep 01, 2026.
Abstract
Genome-wide association studies (GWAS) have identified hundreds of significant loci for psychiatric disorders, yet the strength of these associations remains modest compared to other human complex traits with similar numbers of hits. Whether this pattern reflects statistical artifacts or real biological differences-and, if the latter, what underlies it-remains unclear. In addition to psychiatric disorders, we find that other traits with functional enrichment in the central nervous system (CNS), whether binary or quantitative, also share similar genetic architectures, characterized by GWAS hits of limited statistical significance and generally higher allele frequencies. In comparing the architecture of binary and quantitative traits, we adjust for statistical power in their respective studies. After this adjustment, we fit an evolutionary model of architecture and show that CNS-enriched traits have large mutational target sizes, with contributing variants and genes experiencing stronger selection than those for other traits. Our findings reveal heterogeneity among complex traits and provide insights into traits that more effectively capture fitness-relevant processes. More broadly, our results suggest that the genetic architectures of complex traits are shaped by the tissues through which these traits are mediated.
PMID:
42679042
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.
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