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Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

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.

SUBMITTER: Joshi PK

PROVIDER: S-EPMC5715013 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Joshi Peter K PK Pirastu Nicola N Kentistou Katherine A KA Fischer Krista K Hofer Edith E Schraut Katharina E KE Clark David W DW Nutile Teresa T Barnes Catriona L K CLK Timmers Paul R H J PRHJ Shen Xia X Gandin Ilaria I McDaid Aaron F AF Hansen Thomas Folkmann TF Gordon Scott D SD Giulianini Franco F Boutin Thibaud S TS Abdellaoui Abdel A Zhao Wei W Medina-Gomez Carolina C Bartz Traci M TM Trompet Stella S Lange Leslie A LA Raffield Laura L van der Spek Ashley A Galesloot Tessel E TE Proitsi Petroula P Yanek Lisa R LR Bielak Lawrence F LF Payton Antony A Murgia Federico F Concas Maria Pina MP Biino Ginevra G Tajuddin Salman M SM Seppälä Ilkka I Amin Najaf N Boerwinkle Eric E Børglum Anders D AD Campbell Archie A Demerath Ellen W EW Demuth Ilja I Faul Jessica D JD Ford Ian I Gialluisi Alessandro A Gögele Martin M Graff MariaElisa M Hingorani Aroon A Hottenga Jouke-Jan JJ Hougaard David M DM Hurme Mikko A MA Ikram M Arfan MA Jylhä Marja M Kuh Diana D Ligthart Lannie L Lill Christina M CM Lindenberger Ulman U Lumley Thomas T Mägi Reedik R Marques-Vidal Pedro P Medland Sarah E SE Milani Lili L Nagy Reka R Ollier William E R WER Peyser Patricia A PA Pramstaller Peter P PP Ridker Paul M PM Rivadeneira Fernando F Ruggiero Daniela D Saba Yasaman Y Schmidt Reinhold R Schmidt Helena H Slagboom P Eline PE Smith Blair H BH Smith Jennifer A JA Sotoodehnia Nona N Steinhagen-Thiessen Elisabeth E van Rooij Frank J A FJA Verbeek André L AL Vermeulen Sita H SH Vollenweider Peter P Wang Yunpeng Y Werge Thomas T Whitfield John B JB Zonderman Alan B AB Lehtimäki Terho T Evans Michele K MK Pirastu Mario M Fuchsberger Christian C Bertram Lars L Pendleton Neil N Kardia Sharon L R SLR Ciullo Marina M Becker Diane M DM Wong Andrew A Psaty Bruce M BM van Duijn Cornelia M CM Wilson James G JG Jukema J Wouter JW Kiemeney Lambertus L Uitterlinden André G AG Franceschini Nora N North Kari E KE Weir David R DR Metspalu Andres A Boomsma Dorret I DI Hayward Caroline C Chasman Daniel D Martin Nicholas G NG Sattar Naveed N Campbell Harry H Esko Tōnu T Kutalik Zoltán Z Wilson James F JF

Nature communications 20171013 1

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 ...[more]

PMID: 29030599

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Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Project description:ObjectiveSystemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.MethodsDRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581).ResultsInitial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024).ConclusionAssociations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Dataset Information

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Publications

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

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