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.
Original language | English (US) |
---|---|
Article number | e1002025 |
Journal | PLoS Genetics |
Volume | 7 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2011 |
Externally published | Yes |
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
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In: PLoS Genetics, Vol. 7, No. 4, e1002025, 04.2011.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms
AU - Zhai, Guangju
AU - Teumer, Alexander
AU - Stolk, Lisette
AU - Perry, John R.B.
AU - Vandenput, Liesbeth
AU - Coviello, Andrea D.
AU - Koster, Annemarie
AU - Bell, Jordana T.
AU - Bhasin, Shalender
AU - Eriksson, Joel
AU - Eriksson, Anna
AU - Ernst, Florian
AU - Ferrucci, Luigi
AU - Frayling, Timothy M.
AU - Glass, Daniel
AU - Grundberg, Elin
AU - Haring, Robin
AU - HedmanÅ, Åsa K.
AU - Hofman, Albert
AU - Kiel, Douglas P.
AU - Kroemer, Heyo K.
AU - Liu, Yongmei
AU - Lunetta, Kathryn L.
AU - Maggio, Marcello
AU - Lorentzon, Mattias
AU - Mangino, Massimo
AU - Melzer, David
AU - Miljkovic, Iva
AU - Nica, Alexandra
AU - Penninx, Brenda W.J.H.
AU - Vasan, Ramachandran S.
AU - Rivadeneira, Fernando
AU - Small, Kerrin S.
AU - Soranzo, Nicole
AU - Uitterlinden, André G.
AU - Völzke, Henry
AU - Wilson, Scott G.
AU - Xi, Li
AU - Zhuang, Wei Vivian
AU - Harris, Tamara B.
AU - Murabito, Joanne M.
AU - Ohlsson, Claes
AU - Murray, Anna
AU - de Jong, Frank H.
AU - Spector, Tim D.
AU - Wallaschofski, Henri
N1 - Funding Information: TwinsUK: The study was funded by the Wellcome Trust, Arthritis Research Campaign, European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and Seventh Framework Programme grant 200800 Treat OA/(FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413, and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. TDS is an NIHR senior investigator. The project also received support from a Biotechnology and Biological Sciences Research Council project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute (NEI) via an NIH/Center for Inherited Disease Research (CIDR) genotyping project. We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping; Le Centre National de Génotypage, France, for genotyping; Duke University, NC, USA, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki. Genotyping was also done by CIDR as part of an NEI/NIH project grant. Funding Information: GOOD: Financial support was received from the Swedish Research Council (K2010-54X-09894-19-3, 2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, the Novo Nordisk foundation and the European Commission grant HEALTH-F2-2008-201865-GEFOS. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. We would also like to thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands for advice regarding the grid resources. Funding Information: InCHIANTI: The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001–2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004–2010) were financed by the U.S. National Institute on Aging ( Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. JRBP is funded by a Sir Henry Wellcome Postdoctoral Fellowship (092447/Z/10/Z). Funding Information: RS1: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI) - Netherlands Consortium of Healthy Aging (NCHA) project nr. 050-060-810, and funding from the European Commision (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008-35627, TREAT-OA). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We thank Pascal Arp, Mila Jhamai, Dr Michael Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practioners and pharmacists. We would like to thank Dr. Tobias A. Knoch, Karol Estrada, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. Funding Information: SHIP: Computing resources have been made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg - West Pomerania. Genome- wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg – West Pomerania (03IS2061A). The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. The DHEAS reagents used were sponsored by Siemens Healthcare Diagnostics, Eschborn, formerly DPC Biermann GmbH, Bad Nauheim, Germany. Novo Nordisc provided partial grant support for the determination of serum samples and data analysis. Funding Information: FHS: DHEAS-genotype genome-wide association analyses were supported by the National Institute of Aging (Genetics of Reproductive Life Period and Health Outcomes, R21AG032598; JMM, KL, DPK, WVZ). “The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.” DPK received support from NIH (Grant R01 AR/AG 41398). Funding Information: Health ABC: This study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.” This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging.
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955580001&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955580001&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002025
DO - 10.1371/journal.pgen.1002025
M3 - Article
C2 - 21533175
AN - SCOPUS:79955580001
SN - 1553-7390
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
IS - 4
M1 - e1002025
ER -