The complex genetics of gait speed: genome-wide meta-analysis approach

Ben-Avraham, Danny; Karasik, David; Verghese, Joe; Lunetta, Kathryn L.; Smith, Jennifer A.; Eicher, John D.; Vered, Rotem; Deelen, Joris; Arnold, Alice M.; Buchman, Aron S.; Tanaka, Toshiko; Faul, Jessica D.; Nethander, Maria; Fornage, Myriam; Adams, Hieab H.H.; Matteini, Amy M.; Callisaya, Michele L.; Smith, Albert V.; Yu, Lei; Jager, Philip L. De; Evans, Denis A.; Gudnason, Vilmundur; Hofman, Albert; Pattie, Alison; Corley, Janie; Launer, Lenore J.; Knopman, D. S.; Parimi, Neeta; Turner, Stephen T.; Bandinelli, Stefania; Beekman, Marian; Gutman, Danielle; Sharvit, Lital; Mooijaart, Simon P.; Liewald, David C.; Houwing-Duistermaat, Jeanine J.; Ohlsson, Claes; Moed, Matthijs; Verlinden, Vincent J. A.; Mellström, Dan; Geest, Jos N. van der; Karlsson, Magnus; Hernandez, Dena G.; McWhirter, Rebekah; Liu, Yongmei; Thomson, Russell; Tranah, Gregory J.; Uitterlinden, André G.; Weir, David R.; Zhao, Wei; Starr, John M.; Johnson, Andrew D.; Ikram, M. Arfan; Bennett, David A.; Cummings, Steven R.; Deary, Ian J.; Harris, Tamara B.; Kardia, Sharon L.R.; Mosley, Thomas H.; Srikanth, Velandai; Windham, Beverly G; Newman, Anne B.; Walston, Jeremy D.; Davies, Gail; Evans, Daniel S.; Slagboom, Eline; Ferrucci, Luigi; Kiel, Douglas P.; Murabito, Joanne M.; Atzmon, Gil

doi:10.18632/aging.101151

Cited by 23 publications

(20 citation statements)

References 68 publications

(70 reference statements)

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“…Analysing ordered categorical variables on the linear scale proves problematic when interpreting SNP effect sizes, SNP-heritability and causal effect estimates in MR. We converted heritability estimates from the observed scale to the liability scale, which is more interpretable as it models self-reported walking pace as a continuous trait. This unobserved latent scale is not the actual walking pace, which can be measured under controlled conditions 7 , but reflects genetic and environmental factors that influence the self-reported category.…”

Section: Discussionmentioning

confidence: 99%

“…These questions can be addressed with knowledge of the genetics of walking pace. To date, studies examining the genetic component of walking pace have analysed objectively measured gait speed, where speed is assessed by timing participants to walk a distance of up to 8 m. These studies focussed on older adults, giving insight into the biological mechanisms underlying age-related diseases and physical mobility 7 , 8 . Genome-wide significant markers of objectively measured gait speed were not identified in these studies, which had a maximum sample size of 31,479.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival

Timmins

Zaccardi

Nelson

et al. 2020

Commun BiolHas correction 2020-11-10 Has erratum 2020-11-10

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Walking is a simple form of exercise, widely promoted for its health benefits. Self-reported walking pace has been associated with a range of cardiorespiratory and cancer outcomes, and is a strong predictor of mortality. Here we perform a genome-wide association study of self-reported walking pace in 450,967 European ancestry UK Biobank participants. We identify 70 independent associated loci (P < 5 × 10−8), 11 of which are novel. We estimate the SNP-based heritability as 13.2% (s.e. = 0.21%), reducing to 8.9% (s.e. = 0.17%) with adjustment for body mass index. Significant genetic correlations are observed with cardiometabolic, respiratory and psychiatric traits, educational attainment and all-cause mortality. Mendelian randomization analyses suggest a potential causal link of increasing walking pace with a lower cardiometabolic risk profile. Given its low heritability and simple measurement, these findings suggest that self-reported walking pace is a pragmatic target for interventions aiming for general benefits on health.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival

Timmins

Zaccardi

Nelson

et al. 2020

Commun BiolHas correction 2020-11-10 Has erratum 2020-11-10

View full text Add to dashboard Cite

show abstract

“…Recent genome-wide association (GWA) studies have identified genomic regions associated with lung function [ 16 , 17 ] and grip strength (a commonly used measure of muscle strength) [ 18 ]. A GWA study of gait speed did not identify any genome-wide significant signals [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936

Harris

Riggio

Evenden

et al. 2017

Aging

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Gene expression is influenced by both genetic variants and the environment. As individuals age, changes in gene expression may be associated with decline in physical and cognitive abilities. We measured transcriptome-wide expression levels in lymphoblastoid cell lines derived from members of the Lothian Birth Cohort 1936 at mean ages 70 and 76 years. Changes in gene expression levels were identified for 1,741 transcripts in 434 individuals. Gene Ontology enrichment analysis indicated an enrichment of biological processes involved in the immune system. Transcriptome-wide association analysis was performed for eleven cognitive, fitness, and biomedical aging-related traits at age 70 years (N=665 to 781) and with mortality. Transcripts for genes (F2RL3, EMILIN1 and CDC42BPA) previously identified as being differentially methylated or expressed in smoking or smoking-related cancers were overexpressed in smokers compared to non-smokers and the expression of transcripts for genes (HERPUD1, GAB2, FAM167A and GLS) previously associated with stress response, autoimmune disease and cancer were associated with telomere length. No associations between expression levels and other traits, or mortality were identified.

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“…In such a context, meta-analytical approaches may be able to provide a more comprehensive screening of low-frequency genetic variants associated with aging and capture their pleiotropic effects 32 . Yet, a recent meta-analysis of gait speed GWASs conducted in 31,478 older adults from 17 cohorts of the CHARGE consortium did not find any genome-wide significant signals 34 .…”

Section: Discussionmentioning

confidence: 97%

Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort

Heckerman

Traynor

Picca

et al. 2017

Sci Rep

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Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n = 286) and replicated in the inCHIANTI study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p = 5.61 × 10−8; rs1788355, p = 5.73 × 10−8). This association was not replicated in the inCHIANTI population. Our findings suggest that specific SNPs may be associated with a key measure of physical performance in older adults. GWASs using larger samples are needed to confirm these preliminary results to enhance our comprehension of complex age-associated phenomena.

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The complex genetics of gait speed: genome-wide meta-analysis approach

Cited by 23 publications

References 68 publications

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival

Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936

Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort

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