Similar and different: systematic investigation of proteogenomic variation between sexes and its relevance for human diseases
Koprulu, M.; Wheeler, E.; Kerrison, N. D.; Denaxas, S.; Carrasco-Zanini, J.; Orkin, C. M.; Hemingway, H.; Wareham, N. J.; Pietzner, M.; Langenberg, C.
Show abstract
To better understand sex differences in human health and disease, we conducted a systematic, large-scale investigation of sex differences in the genetic regulation of the plasma proteome (>5,000 targets), including their disease relevance. Plasma levels of two-thirds of protein targets differed significantly by sex. In contrast, genetic effects on protein targets were remarkably similar, with very few protein quantitative loci (pQTLs, n=74) showing significant sex-differential effects (for 3.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). Most of these 74 pQTLs represented directionally concordant effects significant in both sexes, with only 21 pQTLs showing evidence of sexual dimorphism, i.e. effects restricted to one sex (n=20) or with opposite directions between sexes (n=1 for CDH15). None of the sex-differential pQTLs translated into sex-differential disease risk. Our results demonstrate strong similarity in the genetic regulation of the plasma proteome between sexes with important implications for genetically guided drug target discovery and validation.
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