title: Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.
abstract: Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p =  2.61 × 10(-19)), ARPC1A (rs740160; p =  1.56 × 10(-16)), TRIM4 (rs17277546; p =  4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p =  4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Vandenput
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Coviello
authors.forename: Annemarie
authors.initials: A
authors.lastname: Koster
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Shalender
authors.initials: S
authors.lastname: Bhasin
authors.forename: Joel
authors.initials: J
authors.lastname: Eriksson
authors.forename: Anna
authors.initials: A
authors.lastname: Eriksson
authors.forename: Florian
authors.initials: F
authors.lastname: Ernst
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Robin
authors.initials: R
authors.lastname: Haring
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggio
authors.forename: Mattias
authors.initials: M
authors.lastname: Lorentzon
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.forename: Iva
authors.initials: I
authors.lastname: Miljkovic
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nica
authors.forename: Brenda W J H
authors.initials: BW
authors.lastname: Penninx
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Li
authors.initials: L
authors.lastname: Xi
authors.forename: Wei Vivian
authors.initials: WV
authors.lastname: Zhuang
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000375:Aging / Q000097:blood* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D065729:Cytochrome P-450 CYP2C9; D004268:DNA-Binding Proteins; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood*; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C539073:ARPC1A protein, human; D051376:Actin-Related Protein 2-3 Complex; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C403245:ZKSCAN5 protein, human; D019314:Dehydroepiandrosterone Sulfate; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D015238:Sulfotransferases; C028152:alcohol sulfotransferase