Sex-specific genetic regulation of proteomics in cerebrospinal fluid uncovers genetic causes for sex differences in neurodegeneration

Sex-specific genetic regulation of cerebrospinal fluid (CSF) protein levels may contribute to differential vulnerability to neurodegenerative diseases. To systematically identify sex differences in the genetic regulation of CSF proteome and their link to neurodegeneration, we performed sex-stratified pQTL analysis of 6,361 proteins in 1,713 males and 1,640 females, separately. We identified 1,729 pQTLs significant in either sex. They included 407 sex-specific pQTLs (genetic regulation in only one sex) and 159 sex-biased pQTLs (regulation in both sexes, but with different magnitudes of regulation between sexes). The HLA locus on chromosome 6 and the APOE locus on chromosome 19, two known pleiotropic regions, regulated several proteins in a sex-dependent way. Pathway enrichment revealed several biological processes that were shared and distinctive of sex. Using proteome-wide association study (PWAS) and colocalization, we identified 22 proteins associated and colocalized with AD risk loci. TMEM106B and ACE proteins were identified in only one sex. Four proteins were associated and colocalized with PD risk loci. These findings provide insights into dissecting the underlying mechanisms contributing to sex differences in neurodegeneration.