Multivariate Genomic Scan Implicates Novel Loci and Haem Metabolism in Human Ageing

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jul 18

PMID 32678081

Citations 66

Authors

Paul R H J Timmers

James F Wilson

Peter K Joshi

Joris Deelen

Affiliations

Soon will be listed here.

Abstract

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.

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References

Sebastiani P, Gurinovich A, Bae H, Andersen S, Malovini A, Atzmon G . Four Genome-Wide Association Studies Identify New Extreme Longevity Variants. J Gerontol A Biol Sci Med Sci. 2017; 72(11):1453-1464. PMC: 5861867. DOI: 10.1093/gerona/glx027. View

Ruby J, Wright K, Rand K, Kermany A, Noto K, Curtis D . Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating. Genetics. 2018; 210(3):1109-1124. PMC: 6218226. DOI: 10.1534/genetics.118.301613. View

Sebastiani P, Perls T . The genetics of extreme longevity: lessons from the new England centenarian study. Front Genet. 2012; 3:277. PMC: 3510428. DOI: 10.3389/fgene.2012.00277. View

Ellervik C, Marott J, Tybjaerg-Hansen A, Schnohr P, Nordestgaard B . Total and cause-specific mortality by moderately and markedly increased ferritin concentrations: general population study and metaanalysis. Clin Chem. 2014; 60(11):1419-28. DOI: 10.1373/clinchem.2014.229013. View

Finucane H, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P . Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015; 47(11):1228-35. PMC: 4626285. DOI: 10.1038/ng.3404. View

Kenyon C . The genetics of ageing. Nature. 2010; 464(7288):504-12. DOI: 10.1038/nature08980. View

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Ang L, Cruz R, Hendel A, Granville D . Apolipoprotein E, an important player in longevity and age-related diseases. Exp Gerontol. 2008; 43(7):615-622. DOI: 10.1016/j.exger.2008.03.010. View

Haller T, Kals M, Esko T, Magi R, Fischer K . RegScan: a GWAS tool for quick estimation of allele effects on continuous traits and their combinations. Brief Bioinform. 2013; 16(1):39-44. PMC: 4293375. DOI: 10.1093/bib/bbt066. View

10.

Blagosklonny M . Answering the ultimate question "what is the proximal cause of aging?". Aging (Albany NY). 2013; 4(12):861-77. PMC: 3615154. DOI: 10.18632/aging.100525. View

11.

Timmers P, Mounier N, Lall K, Fischer K, Ning Z, Feng X . Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. Elife. 2019; 8. PMC: 6333444. DOI: 10.7554/eLife.39856. View

12.

Visconti A, Duffy D, Liu F, Zhu G, Wu W, Chen Y . Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure. Nat Commun. 2018; 9(1):1684. PMC: 5940788. DOI: 10.1038/s41467-018-04086-y. View

13.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

14.

Walter S, Atzmon G, Demerath E, Garcia M, Kaplan R, Kumari M . A genome-wide association study of aging. Neurobiol Aging. 2011; 32(11):2109.e15-28. PMC: 3193030. DOI: 10.1016/j.neurobiolaging.2011.05.026. View

15.

Byars S, Huang Q, Gray L, Bakshi A, Ripatti S, Abraham G . Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLoS Genet. 2017; 13(6):e1006328. PMC: 5480811. DOI: 10.1371/journal.pgen.1006328. View

16.

Westra H, Peters M, Esko T, Yaghootkar H, Schurmann C, Kettunen J . Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013; 45(10):1238-1243. PMC: 3991562. DOI: 10.1038/ng.2756. View

17.

Moen I, Bergholdt H, Mandrup-Poulsen T, Nordestgaard B, Ellervik C . Increased Plasma Ferritin Concentration and Low-Grade Inflammation-A Mendelian Randomization Study. Clin Chem. 2017; 64(2):374-385. DOI: 10.1373/clinchem.2017.276055. View

18.

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

19.

Strittmatter W, Roses A . Apolipoprotein E and Alzheimer disease. Proc Natl Acad Sci U S A. 1995; 92(11):4725-7. PMC: 41779. DOI: 10.1073/pnas.92.11.4725. View

20.

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View