A Prospective Analysis of Genetic Variants Associated with Human Lifespan

Wright, Kevin M.; Rand, Kristin A.; Kermany, Amir R.; Noto, Keith; Curtis, Don; Garrigan, Daniel; Slinkov, Dmitri; Dorfman, Ilya; Granka, Julie M.; Byrnes, Jake; Myres, Natalie M.; Ball, Catherine A.; Ruby, J. Graham

doi:10.1534/g3.119.400448

Cited by 48 publications

(42 citation statements)

References 72 publications

(117 reference statements)

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“…Genotyping and quality control procedures have been previously described elsewhere. 28 Briefly, customer genotype data for this study were generated using an Illumina genotyping array with approximately 730,000 SNPs and processed either with Illumina or with Quest/Athena Diagnostics. To ensure quality of each dataset, a sample passes a number of quality control (QC) checks, which includes identifying duplicate samples, removing individuals with a per-sample call rate <98%, and identifying discrepancies between reported sex and genetically inferred sex.…”

Section: Methodsmentioning

confidence: 99%

“…The full questions and possible responses for the two questions used as primary outcomes in this study are presented in Supplementary Table 1. Analyses presented here were performed with data collected between April 22-May 28, 2020.To participate in the COVID-19 survey, participants must meet the following criteria: they must be 18 years of age or older, a resident of the United States, be an existing AncestryDNA customer who has consented to participate in research28 , and be able to complete a short survey. The survey is designed to assess self-reported COVID-19 positivity and severity, as well as susceptibility and known risk factors including community exposure and known contacts with individuals diagnosed with COVID-19.…”

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confidence: 99%

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AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci

Roberts¹,

Park²,

Coignet³

et al. 2020

Preprint

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Human infection with SARS-CoV-2, the causative agent of COVID-19, leads to a remarkably diverse spectrum of outcomes, ranging from asymptomatic to fatal. Recent reports suggest that both clinical and genetic risk factors may contribute to COVID-19 susceptibility and severity. To investigate genetic risk factors, we collected over 500,000 COVID-19 survey responses between April and May 2020 with accompanying genetic data from the AncestryDNA database. We conducted sex-stratified and meta-analyzed genome-wide association studies (GWAS) for COVID-19 susceptibility (positive nasopharyngeal swab test, ncases=2,407) and severity (hospitalization, ncases=250). The severity GWAS replicated associations with severe COVID-19 near ABO and SLC6A20 (P<0.05). Furthermore, we identified three novel loci with P<5x10-8. The strongest association was near IVNS1ABP, a gene involved in influenza virus replication, and was associated only in males. The other two novel loci harbor genes with established roles in viral replication or immunity: SRRM1 and the immunoglobulin lambda locus. We thus present new evidence that host genetic variation likely contributes to COVID-19 outcomes and demonstrate the value of large-scale, self-reported data as a mechanism to rapidly address a health crisis.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci

Roberts¹,

Park²,

Coignet³

et al. 2020

Preprint

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“…In addition to general population regression analyses and case-control analyses in extreme-aged cohorts, an alternative approach to identify aging-related variants is using parental ages of death regressed on offspring genotypes. Recent parental lifespan studies from large populations including the UK Biobank and AncestryDNA genotype data have identified APOE, LPA, CHRNA3/5, LDLR, SH2B3/ATXN2, CDKN2B-AS1 and other study-specific variants as associated with parental ages (Joshi et al, 2017;Pilling et al, 2017;Timmers et al, 2019;Wright et al, 2019). In parallel with our case-control analyses on extreme-aged cohorts, it will be of high interest to extend these analyses to include parental lifespan analyses on exome sequence data to identify rare, coding variants associated with aging.…”

Section: Discussionmentioning

confidence: 99%

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Sin‐Chan

Gosalia

Gao

et al. 2020

Preprint

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Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males greater than 92 years, Females greater than 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

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“…Longevity also consistently varies among genetically diverse individuals of the same species, indicating that variability of lifespan is not constrained at the level of species, and that the molecular determinants of lifespan appear to be phenotypically plastic within the same genetic pool [16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Across eukaryotes, species longevity can differ over many orders of magnitude, from the 2-day replicative lifespan (RLS) of budding yeast ( Saccharomyces cerevisiae ) to organisms that live for centuries, such as the Greenland shark ( Somniosus microcephalus ), which can live for more than 500 years [13–15]. Longevity also consistently varies among genetically diverse individuals of the same species, indicating that variability of lifespan is not constrained at the level of species, and that the molecular determinants of lifespan appear to be phenotypically plastic within the same genetic pool [16–21].…”

Section: Introductionmentioning

confidence: 99%

Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

Kaya

Phua

Lee

et al. 2020

Preprint

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The question of why and how some species or individuals within a population live longer than others is among the most important questions in the biology of aging. A particularly useful model to understand the genetic basis and selective forces acting on the plasticity of lifespan are closely related species or ecologically diverse individuals of the same species widely different in lifespan. Here, we analyzed 76 diverse wild isolates of two closely related budding yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus and discovered a diversity of natural intra-species lifespan variation. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. We identified sets of genes and metabolites to regulate aging pathways, many of which have not been previously associated with lifespan regulation. We also identified and characterized long-lived strains with elevated intermediary metabolites and differentially regulated genes for NAD metabolism and the control of epigenetic landscape through chromatin silencing. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness. Overall, our study shows how the environment and natural selection interact to shape diversity of lifespan.

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A Prospective Analysis of Genetic Variants Associated with Human Lifespan

Cited by 48 publications

References 72 publications

AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci

AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

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