The left amygdala is genetically sexually-dimorphic: multi-omics analysis of structural MRI volumes

Brain anatomy plays a key role in complex behaviors and mental disorders that are sexually divergent. While our understanding of the sex differences in the brain anatomy remains relatively limited, particularly of the underlying genetic and molecular mechanisms that contribute to these differences. We performed the largest study of sex differences in brain volumes (N = 33,208) by examining sex differences both in the raw brain volumes and after controlling the whole brain volumes. Genetic correlation analysis revealed sex differences only in the left amygdala. We compared transcriptome differences between males and females using data from GTEx and characterized cell-type compositions using GTEx bulk amygdala RNA-seq data and LIBD amygdala single-cell reference profiles. We also constructed polygenic risk scores (PRS) to investigate sex-specific genetic correlations between left amygdala volume and mental disorders (N = 25,576~105,318) of Psychiatric Genomics Consortium and other traits of UKB (N = 347,996). Although there were pronounced sex differences in brain volumes, there was no difference in the heritability between sexes. There was a significant sex-specific genetic correlation between male and female left amygdala. We identified sex-differentiated genetic effects of PRSs for schizophrenia on left amygdala volume, as well as significant sex-differentiated genetic correlations between PRSs of left amygdala and six traits in UKB. We also found several sex-differentially expressed genes in the amygdala. These findings not only advanced the current knowledge of genetic basis of sex differences in brain anatomy, but also presented an important clue for future research on the mechanism of sex differences in mental disorders and targeted treatments.