Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

被引：135

作者：

McCartney, Daniel L. ^{[1
]}

Min, Josine L. ^{[2
,3
]}

Richmond, Rebecca C. ^{[2
,3
]}

Lu, Ake T. ^{[4
]}

Sobczyk, Maria K. ^{[2
,3
]}

Davies, Gail ^{[5
]}

Broer, Linda ^{[6
]}

Guo, Xiuqing ^{[7
]}

Jeong, Ayoung ^{[8
,9
]}

Jung, Jeesun ^{[10
]}

Kasela, Silva ^{[11
]}

Katrinli, Seyma ^{[12
]}

Kuo, Pei-Lun ^{[13
]}

Matias-Garcia, Pamela R. ^{[14
,15
,16
]}

Mishra, Pashupati P. ^{[17
,18
]}

Nygaard, Marianne ^{[19
,20
]}

Palviainen, Teemu ^{[21
]}

Patki, Amit ^{[22
]}

Raffield, Laura M. ^{[23
]}

Ratliff, Scott M. ^{[24
]}

Richardson, Tom G. ^{[24
]}

Robinson, Oliver ^{[25
]}

Soerensen, Mette ^{[19
,20
,26
]}

Sun, Dianjianyi ^{[27
]}

Tsai, Pei-Chien ^{[28
,29
,30
]}

van der Zee, Matthijs D. ^{[31
,32
]}

Walker, Rosie M. ^{[1
]}

Wang, Xiaochuan ^{[33
]}

Wang, Yunzhang ^{[34
]}

Xia, Rui ^{[35
]}

Xu, Zongli ^{[36
]}

Yao, Jie ^{[7
]}

Zhao, Wei ^{[24
]}

Correa, Adolfo ^{[37
]}

Boerwinkle, Eric ^{[38
]}

Dugue, Pierre-Antoine ^{[33
,39
,40
]}

Durda, Peter ^{[41
]}

Elliott, Hannah R. ^{[2
,3
]}

Gieger, Christian ^{[14
,15
]}

de Geus, Eco J. C. ^{[31
,32
]}

Harris, Sarah E. ^{[5
]}

Hemani, Gibran ^{[2
,3
]}

Imboden, Medea ^{[8
,9
]}

Kahonen, Mika ^{[43
,44
]}

Kardia, Sharon L. R. ^{[24
]}

Kresovich, Jacob K. ^{[24
,36
]}

Li, Shengxu ^{[45
]}

Lunetta, Kathryn L. ^{[46
]}

Mangino, Massimo ^{[28
,47
]}

Mason, Dan ^{[48
]}

机构：

[1] Univ Edinburgh, Inst Genet & Canc, Ctr Genom & Expt Med, Crewe Rd South, Edinburgh EH4 2XU, Scotland

[2] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, England

[3] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, England

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[5] Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh EH8 9JZ, Midlothian, Scotland

[6] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[7] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[8] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[9] Univ Basel, Basel, Switzerland

[10] NIAAA, NIH, Bethesda, MD USA

[11] Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia

[12] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA

[13] NIA, Longitudinal Study Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA

[14] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Bavaria, Germany

[15] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Bavaria, Germany

[16] Tech Univ Munich, TUM Sch Med, Munich, Germany

[17] Tampere Univ, Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland

[18] Tampere Univ, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Hlth Technol, Tampere 33520, Finland

[19] Univ Southern Denmark, Dept Publ Hlth, Epidemiol Biostat & Biodemog, Odense, Denmark

[20] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark

[21] Univ Helsinki, Inst Mol Med Finland, FIMM, HiLIFE, Helsinki, Finland

[22] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA

[23] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[24] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[25] Imperial Coll London, Sch Publ Hlth, MRC Ctr Environm & Hlth, London, England

[26] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, Odense, Denmark

[27] Peking Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Hlth Sci Ctr, Beijing, Peoples R China

[28] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[29] Chang Gung Univ, Dept Biomed Sci, Taoyuan, Taiwan

[30] Chang Gung Mem Hosp, Dept Pediat, Div Pediat Infect Dis, Taoyuan, Taiwan

[31] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[32] Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands

[33] Canc Council Victoria, Canc Epidemiol Div, 615 St Kilda Rd, Melbourne, Vic 3004, Australia

[34] Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden

[35] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA

[36] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA

[37] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[38] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA

[39] Monash Univ, Sch Clin Sci Monash Hlth, Precis Med, Clayton, Vic 3168, Australia

[40] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, 207 Bouverie St, Melbourne, Vic 3010, Australia

[41] Univ Vermont, Dept Pathol & Lab Med, Larner Coll Med, Burlington, VT 05446 USA

[42] Genet DNA Methylat Consortium, Bristol, Avon, England

[43] Tampere Univ, Dept Clin Physiol, Tampere Univ Hosp, Tampere 33521, Finland

[44] Tampere Univ, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Hlth Technol, Tampere 33521, Finland

[45] Childrens Minnesota, Res Inst, Minneapolis, MN 55404 USA

[46] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[47] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 9RT, England

[48] Bradford Teaching Hosp NHS Fdn Trust, Bradford Inst Hlth Res, Bradford, W Yorkshire, England

[49] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland

[50] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA

来源：

GENOME BIOLOGY | 2021年 / 22卷 / 01期

基金：

英国医学研究理事会;

关键词：

DNA methylation; GWAS; Epigenetic clock; MENDELIAN RANDOMIZATION; SUSCEPTIBILITY LOCI; AGE; METAANALYSIS; GWAS; ENRICHMENT; REGRESSION; INSIGHTS; PROVIDES; BLOOD;

D O I：

10.1186/s13059-021-02398-9

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

引用

页数：25

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