The pivotal role of the X-chromosome in the genetic architecture of the human brain

Genes on the X-chromosome are extensively expressed in the human brain. However, little is known for the X-chromosomes impact on the brain anatomy, microstructure, and functional network. We examined 1,045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X-chromosome interactions, while proposing an atlas outlining dosage compensation (DC) for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we discovered unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X-chromosomes role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes. One-sentence SummaryWe investigated the genetic impact of the X-chromosome and the sex differences in the human brain.