title: Discovery of sexual dimorphisms in metabolic and genetic biomarkers.
abstract: Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
authors.affiliation: Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Mittelstrass
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Yu
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.forename: Werner
authors.initials: W
authors.lastname: Roemisch-Margl
authors.forename: Alexey
authors.initials: A
authors.lastname: Polonikov
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.forename: Heinz Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Rui
authors.initials: R
authors.lastname: Wang-Sattler
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000097:blood; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005998:Glycine / Q000097:blood; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics
chemical_list: D000596:Amino Acids; D005819:Genetic Markers; D008055:Lipids; C116917:acylcarnitine; D002331:Carnitine; D005998:Glycine