Multivariate genomic scan implicates novel loci and haem metabolism in human ageing

被引：103

作者：

Timmers, Paul R. H. J. ^{[1
]}

Wilson, James F. ^{[1
,2
]}

Joshi, Peter K. ^{[1
]}

Deelen, Joris ^{[3
,4
]}

机构：

[1] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst, Edinburgh, Midlothian, Scotland

[2] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[3] Max Planck Inst Biol Ageing, Cologne, Germany

[4] Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国医学研究理事会;

关键词：

APOLIPOPROTEIN-E; LIFE-SPAN; LONGEVITY; MORTALITY; GWAS; HERITABILITY; POPULATION; GENETICS; FAMILY; FOXO3;

D O I：

10.1038/s41467-020-17312-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes, of which five (near FOXO3, SLC4A7, LINC02513, ZW10, and FGD6) have not been reported previously at genome-wide significance. The majority of these 10 loci are associated with cardiovascular disease and some affect the expression of genes known to change their activity with age. In total, we implicate 78 genes, and find these to be enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. Finally, we identify a pathway worthy of further study: haem metabolism.

引用

页数：10

共 62 条

[1] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[2] Apolipoprotein E, an important player in longevity and age-related diseases [J].

Ang, Lisa S. ;

Cruz, Rani P. ;

Hendel, Alon ;

Granville, David J. .

EXPERIMENTAL GERONTOLOGY, 2008, 43 (07) :615-622

[3] Antagonistic pleiotropy and mutation accumulation influence human senescence and disease [J].

Antonio Rodriguez, Juan ;

Marigorta, Urko M. ;

Hughes, David A. ;

Spataro, Nino ;

Bosch, Elena ;

Navarro, Arcadi .

NATURE ECOLOGY & EVOLUTION, 2017, 1 (03)

[4] Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging [J].

Atamna, H ;

Killilea, DW ;

Killilea, AN ;

Ames, BN .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (23) :14807-14812

[5]

Atkins JL, 2019, GENOME WIDE ASS STUD, DOI DOI 10.1101/19007559

[6] Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis [J].

Benyamin, Beben ;

Esko, Tonu ;

Ried, Janina S. ;

Radhakrishnan, Aparna ;

Vermeulen, Sita H. ;

Traglia, Michela ;

Goegele, Martin ;

Anderson, Denise ;

Broer, Linda ;

Podmore, Clara ;

Luan, Jian'an ;

Kutalik, Zoltan ;

Sanna, Serena ;

van der Meer, Peter ;

Tanaka, Toshiko ;

Wang, Fudi ;

Westra, Harm-Jan ;

Franke, Lude ;

Mihailov, Evelin ;

Milani, Lili ;

Haeldin, Jonas ;

Winkelmann, Juliane ;

Meitinger, Thomas ;

Thiery, Joachim ;

Peters, Annette ;

Waldenberger, Melanie ;

Rendon, Augusto ;

Jolley, Jennifer ;

Sambrook, Jennifer ;

Kiemeney, Lambertus A. ;

Sweep, Fred C. ;

Sala, Cinzia F. ;

Schwienbacher, Christine ;

Pichler, Irene ;

Hui, Jennie ;

Demirkan, Ayse ;

Isaacs, Aaron ;

Amin, Najaf ;

Steri, Maristella ;

Waeber, Gerard ;

Verweij, Niek ;

Powell, Joseph E. ;

Nyholt, Dale R. ;

Heath, Andrew C. ;

Madden, Pamela A. F. ;

Visscher, Peter M. ;

Wright, Margaret J. ;

Montgomery, Grant W. ;

Martin, Nicholas G. ;

Hernandez, Dena .

NATURE COMMUNICATIONS, 2014, 5

[7] Answering the ultimate question "What is the Proximal Cause of Aging?" [J].

Blagosklonny, Mikhail V. .

AGING-US, 2012, 4 (12) :861-877

[8] GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy [J].

Broer, Linda ;

Buchman, Aron S. ;

Deelen, Joris ;

Evans, Daniel S. ;

Faul, Jessica D. ;

Lunetta, Kathryn L. ;

Sebastiani, Paola ;

Smith, Jennifer A. ;

Smith, Albert V. ;

Tanaka, Toshiko ;

Yu, Lei ;

Arnold, Alice M. ;

Aspelund, Thor ;

Benjamin, Emelia J. ;

De Jager, Philip L. ;

Eirkisdottir, Gudny ;

Evans, Denis A. ;

Garcia, Melissa E. ;

Hofman, Albert ;

Kaplan, Robert C. ;

Kardia, Sharon L. R. ;

Kiel, Douglas P. ;

Oostra, Ben A. ;

Orwoll, Eric S. ;

Parimi, Neeta ;

Psaty, Bruce M. ;

Rivadeneira, Fernando ;

Rotter, Jerome I. ;

Seshadri, Sudha ;

Singleton, Andrew ;

Tiemeier, Henning ;

Uitterlinden, Andre G. ;

Zhao, Wei ;

Bandinelli, Stefania ;

Bennett, David A. ;

Ferrucci, Luigi ;

Gudnason, Vilmundur ;

Harris, Tamara B. ;

Karasik, David ;

Launer, Lenore J. ;

Perls, Thomas T. ;

Slagboom, P. Eline ;

Tranah, Gregory J. ;

Weir, David R. ;

Newman, Anne B. ;

van Duijn, Cornelia M. ;

Murabito, Joanne M. .

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2015, 70 (01) :110-118

[9] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[10] The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 [J].

Buniello, Annalisa ;

MacArthur, Jacqueline A. L. ;

Cerezo, Maria ;

Harris, Laura W. ;

Hayhurst, James ;

Malangone, Cinzia ;

McMahon, Aoife ;

Morales, Joannella ;

Mountjoy, Edward ;

Sollis, Elliot ;

Suveges, Daniel ;

Vrousgou, Olga ;

Whetzel, Patricia L. ;

Amode, Ridwan ;

Guillen, Jose A. ;

Riat, Harpreet S. ;

Trevanion, Stephen J. ;

Hall, Peggy ;

Junkins, Heather ;

Flicek, Paul ;

Burdett, Tony ;

Hindorff, Lucia A. ;

Cunningham, Fiona ;

Parkinson, Helen .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D1005-D1012

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