Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2017 Oct 13;8(1):910.
doi: 10.1038/s41467-017-00934-5.

Genome-wide Meta-Analysis Associates HLA-DQA1/DRB1 and LPA and Lifestyle Factors With Human Longevity

Peter K Joshi  1 Nicola Pirastu  2 Katherine A Kentistou  2   3 Krista Fischer  4 Edith Hofer  5   6 Katharina E Schraut  2   3 David W Clark  2 Teresa Nutile  7 Catriona L K Barnes  2 Paul R H J Timmers  2 Xia Shen  2   8 Ilaria Gandin  9   10 Aaron F McDaid  11   12 Thomas Folkmann Hansen  13   14 Scott D Gordon  15 Franco Giulianini  16 Thibaud S Boutin  17 Abdel Abdellaoui  18 Wei Zhao  19 Carolina Medina-Gomez  20   21 Traci M Bartz  22 Stella Trompet  23   24 Leslie A Lange  25 Laura Raffield  26 Ashley van der Spek  21 Tessel E Galesloot  27 Petroula Proitsi  28 Lisa R Yanek  29 Lawrence F Bielak  19 Antony Payton  30 Federico Murgia  31 Maria Pina Concas  32 Ginevra Biino  33 Salman M Tajuddin  34 Ilkka Seppälä  35 Najaf Amin  21 Eric Boerwinkle  36 Anders D Børglum  14   37   38 Archie Campbell  39 Ellen W Demerath  40 Ilja Demuth  41   42   43 Jessica D Faul  44 Ian Ford  45 Alessandro Gialluisi  46 Martin Gögele  31 MariaElisa Graff  47 Aroon Hingorani  48 Jouke-Jan Hottenga  18 David M Hougaard  14   49 Mikko A Hurme  50 M Arfan Ikram  21 Marja Jylhä  51 Diana Kuh  28 Lannie Ligthart  18 Christina M Lill  52 Ulman Lindenberger  53   54 Thomas Lumley  55 Reedik Mägi  4 Pedro Marques-Vidal  56 Sarah E Medland  15 Lili Milani  4 Reka Nagy  17 William E R Ollier  57 Patricia A Peyser  19 Peter P Pramstaller  31 Paul M Ridker  16   58 Fernando Rivadeneira  20   21 Daniela Ruggiero  7 Yasaman Saba  59 Reinhold Schmidt  5 Helena Schmidt  59 P Eline Slagboom  60 Blair H Smith  61 Jennifer A Smith  19   44 Nona Sotoodehnia  62 Elisabeth Steinhagen-Thiessen  41 Frank J A van Rooij  21 André L Verbeek  27 Sita H Vermeulen  27 Peter Vollenweider  56 Yunpeng Wang  14   63 Thomas Werge  13   14 John B Whitfield  15 Alan B Zonderman  34 Terho Lehtimäki  35 Michele K Evans  34 Mario Pirastu  32 Christian Fuchsberger  31 Lars Bertram  64   65 Neil Pendleton  66 Sharon L R Kardia  19 Marina Ciullo  7   46 Diane M Becker  29 Andrew Wong  28 Bruce M Psaty  67   68 Cornelia M van Duijn  21 James G Wilson  69 J Wouter Jukema  24 Lambertus Kiemeney  27 André G Uitterlinden  20   21 Nora Franceschini  47 Kari E North  47 David R Weir  44 Andres Metspalu  4 Dorret I Boomsma  18 Caroline Hayward  17 Daniel Chasman  16   58 Nicholas G Martin  15 Naveed Sattar  70 Harry Campbell  2 Tōnu Esko  4   71 Zoltán Kutalik  11   12 James F Wilson  2   17
Affiliations
Free PMC article
Meta-Analysis

Genome-wide Meta-Analysis Associates HLA-DQA1/DRB1 and LPA and Lifestyle Factors With Human Longevity

Peter K Joshi et al. Nat Commun. .
Free PMC article

Abstract

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Genome-wide associations with parental lifespan. Association analysis was carried out using imputed allelic dosages. a Manhattan plot for LifeGen European ancestry, with both parents combined; b Q−Q plot comparing the expected (under the null hypothesis) and actual (observed) –log10 p-values for results in a; c Manhattan plot of meta-analysis of LifeGen Europeans (both parents combined) with CHARGE-EU 90+ published summary statistics. The meta-analysis used Z-scores and equal weights, as suggested by the near equality (9.5/9.4, LifeGen, CHARGE) of Z-test statistics at rs4420638. The additional (just) GW significant SNP lies between the two chromosome 6 hits in a; d Manhattan plot for LifeGen African fathers only. In Manhattan plots, the y-axis has been restricted to 15 to aid legibility
Fig. 2
Fig. 2
Locus zoom plots for four genome-wide significant associations with lifespan. Results from the meta-analysis of subjects of European ancestry analysis, for both parents combined. The displayed p-value corresponds to that of a two-sided test of association between the SNP and parent lifespan under the Cox model. a The rs34831921 variant, at the HLA-DQA1/DRB1 locus, P = 4.18E-08. b The rs55730499 variant, at the LPA locus, P = 8.67E-11. c The rs8042849 variant, at the CHRNA3/5 locus, P = 3.75E-14. d The rs429358 variant, at the APOE locus, P = 1.44E-27
Fig. 3
Fig. 3
Validation of associations reported elsewhere by lookup in LifeGen. A search of recent literature suggested the gene regions shown here were most likely to harbour associations with lifespan, beyond the four loci identified in Table 2, which are further explored in the Discussion. The most powerful LifeGen analysis (i.e., European ancestry, father and mother combined) was used for validation. The odds ratio (OR) for extreme long-livedness is presented for the reported life-shortening allele (i.e., the OR for long-livedness < 1) in the original study, but not necessarily in LifeGen. The LifeGen OR of being long-lived was estimated empirically on the assumption that the relationship between the LifeGen observed hazard ratio (HR) and the OR is stable across allelic effects, with APOE results from LifeGen and CHARGE-EU 90+ 6 being used to estimate the ratio of ln HR to ln OR (−4.7). These estimates will only fully align with the published ORs if the shape of the effect on lifespan is similar to APOE, as is true under the proportional hazards assumption, nonetheless the pattern is suggestive. Further details are shown in Supplementary Data 3
Fig. 4
Fig. 4
Age-specific and sex-specific effects of the 4 GWS associations in LifeGen and the validated candidate loci. The four GWS and three suggestive replicated loci were analysed for age-specific and sex-specific effects on lifespan. a The variants at APOE and CHRNA3/5 exhibit sexually dimorphic effects on parental mortality, while all other variants exhibit more modest often non-significant sex-specific differences. b The effects of each gene on male and female lifespan were meta-analysed and studied in the cases that died aged between 40 and 75 or after 75. APOE exerts a much greater effect in the older age group, while most of the other genes exhibit the opposite effect. FOXO3 appears neutral, if not positive, in the earlier age group. c Effects on mortality were studied in both age groups for both sexes. APOE has the strongest effect on females aged 75+, CHRNA3/5 acts on males aged 40−75 and all other genes display more ambiguous trends
Fig. 5
Fig. 5
Genetic correlations between trait clusters that associate with mortality. The upper panel shows whole genetic correlations, the lower panel, partial correlations. T2D, type 2 diabetes; BP, blood pressure; BC, breast cancer; CAD, coronary artery disease; Edu, educational attainment; RA, rheumatoid arthritis; AM, age at menarche; DL/WHR Dyslipidaemia/Waist-Hip ratio; BP, blood pressure

Similar articles

See all similar articles

Cited by 28 articles

See all "Cited by" articles

References

    1. Herskind AM, et al. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900. Hum. Genet. 1996;97:319–323. doi: 10.1007/BF02185763. - DOI - PubMed
    1. Deelen J, et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell. 2011;10:686–698. doi: 10.1111/j.1474-9726.2011.00705.x. - DOI - PMC - PubMed
    1. Broer L, et al. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. J. Gerontol. A Biol. Sci. Med. Sci. 2015;70:110–118. doi: 10.1093/gerona/glu166. - DOI - PMC - PubMed
    1. Joshi PK, et al. Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan. Nat. Commun. 2016;7:11174. doi: 10.1038/ncomms11174. - DOI - PMC - PubMed
    1. Pilling LC, et al. Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging. 2016;8:547–560. doi: 10.18632/aging.100930. - DOI - PMC - PubMed

Publication types

MeSH terms

Feedback