Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

Pilling, Luke C.; Kuo, Chia‐Ling; Sicinski, Kamil; Tamosauskaite, Jone; Kuchel, George A.; Harries, Lorna W.; Herd, Pamela; Wallace, Robert B.; Ferrucci, Luigi; Melzer, David

doi:10.18632/aging.101334

Cited by 160 publications

(195 citation statements)

References 45 publications

Supporting

Mentioning

176

Contrasting

Order By: Relevance

“…Gene names are as reported by discovery, and have been 159 coloured based on overlap between confidence intervals (CIs) of effect estimates. Note, rs151091095 160 near USP2-AS1 is a proxy (r 2 = 1.00) for rs139137459, the SNP reported by Pilling et al;rs113946246 161 near ANKRD20A9P is a proxy (r 2 = 0.97) for rs2440012, the SNP reported by Zeng et al;no proxies 162 could be found for 13:31871514_T_G. Dark blue -Nominal replication (P<0.05, one-sided test).…”

mentioning

confidence: 88%

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Timmers

Mounier

Läll

et al. 2018

Preprint

View full text Add to dashboard Cite

26We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped 27 subjects and data on mortality risk factors to validate previously unreplicated findings near 28 CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify 29 and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. 30 We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory 31 evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal 32 brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are 33 gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and 34 synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, 35and lung cancer -but not other cancers-explain the most variance, possibly reflecting modern 36 susceptibilities, whilst cancer may act through many rare variants, or the environment. 37Resultant polygenic scores predict a mean lifespan difference of around five years of life 38 across the deciles. 39 Results 95Genome-wide association analysis 96 97We carried out GWAS of survival in a discovery sample of 635,205 parents (68% deceased) 98 of unambiguously British ancestry subjects from UK Biobank, and a replication sample of 99 377,035 parents (47% deceased) of other European ancestry subjects from UK Biobank and 100 26 additional populations cohorts (LifeGen ; Table S1). In each sample, we performed a sex-101 stratified analysis and then combined the allelic effects in fathers and mothers into a single 102 parental survival association in two ways. First, we assumed genetic variants with common 103 effect sizes (CES) for both parents, maximising power if the effect is indeed the same, 104 secondly, we allowed for potentially different effect sizes (PDES), maximising power to detect 105 sexually dimorphic variants, including those only affecting one sex. 106 107We find fourteen genomic regions containing SNPs with genome-wide significant (P < 5x10 -108 8 ) association in the discovery cohort, for one or both analyses (Fig. 1a). Ten of these loci 109 have been previously reported using similar data (6), but only 4 have been successfully 110 replicated so far (3-5, 10). We calculate the effects of previously replicated SNPs to be −1.06 111 (near APOE), −0.42 (CHRNA3/5), −0.76 (LPA), and +0.56 (HLA-DQA1) years of life gained 112 per minor allele, estimated from the meta-analysis of discovery and replication cohorts. We 113 also find evidence for replication (P < 0.05, one-sided test) for an additional 3 loci near 114 ATXN2/BRAP (−0.28), FURIN/FES (−0.25), and CDKN2B-AS1 (−0.25), which were previously 115 identified at genome-wide significance by Pilling et al(6) ( Table 1). 116 117While we were unable to replicate the remaining seven loci, this may be due to lack of power 118 for SNPs at or near 13q21.33 and C20orf187, where 95% confidence intervals (CIs) for 119 replication effect overlap with...

show abstract

mentioning

confidence: 88%

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Timmers

Mounier

Läll

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…As the definition of heritable longevity was not yet established, the construction and application of the family selection scores have not yet been adopted as state of the art in longevity research. As such, the majority of genealogical 5, 6, 10–14, 45 and genetic studies 24–26, 31–34 focus only on single, and thus including sporadic, long-lived individuals (singletons), with some exceptions focusing for example on parental age 28, 29 or multiple siblings 7, 25 . In previous work, we showed that longevity defined as top 10% survivors or more extreme is transmitted to subsequent generations 16 .…”

Section: Mainmentioning

confidence: 99%

Longevity Relatives Count score identifies heritable longevity carriers and suggests case improvement in genetic studies

Berg

Rodríguez-Girondo

Mandemakers

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractLongevity loci represent key mechanisms of a life-long decreased mortality and decreased/compressed morbidity. However, identifying such loci is challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with the heritable longevity trait amongst long-living phenocopies. To avoid phenocopies, family selection scores have been constructed but these have not yet been adopted as state of the art in longevity research. Here we aim to identify individuals with the heritable longevity trait by using current insights and a novel family score based on these insights. We use a unique dataset connecting living study participants to their deceased ancestors covering 37,825 persons from 1,326 five-generational families, living between 1788 and 2019. Our main finding suggests that longevity is transmitted for at least 2 subsequent generations only when at least 20% of all relatives are long-lived. This proves the importance of family data to avoid phenocopies in genetic studies.

show abstract

“…581 DNA methylation age was computed according to the algorithm described by Hannum as the independent variable. We also defined a weighted continuous genetic risk score 605 calculated as described in (Pilling et al, 2017) for these 10 SNPs and tested its associations 606…”

Section: Dna Methylation Analysis 554mentioning

confidence: 99%

“…Pilling et al, 2017). For parental attained age (Martingale residuals) a negative BETA = reduced hazard, i.e.…”

mentioning

confidence: 99%

Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Robinson

Hyam

Karaman

et al. 2018

Preprint

View full text Add to dashboard Cite

AbstractMarkers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.

show abstract

Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

Cited by 160 publications

References 45 publications

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Longevity Relatives Count score identifies heritable longevity carriers and suggests case improvement in genetic studies

Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Contact Info

Product

Resources

About