%0 Journal Article %J Aging (Albany NY) %D 2017 %T The complex genetics of gait speed: genome-wide meta-analysis approach. %A Ben-Avraham, Dan %A Karasik, David %A Joe Verghese %A Kathryn L Lunetta %A John D Eicher %A Vered, Rotem %A Deelen, Joris %A Alice M. Arnold %A Aron S Buchman %A Toshiko Tanaka %A Jessica Faul %A Nethander, Maria %A Myriam Fornage %A Hieab H Adams %A Amy M Matteini %A Michele L Callisaya %A Albert Vernon Smith %A Lei Yu %A Philip L de Jager %A Denis A Evans %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Lenore J Launer %A David S Knopman %A Parimi, Neeta %A Stephen T Turner %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Simon P Mooijaart %A David C Liewald %A Jeanine J Houwing-Duistermaat %A Ohlsson, Claes %A Moed, Matthijs %A Vincent J Verlinden %A Mellström, Dan %A Jos N van der Geest %A Karlsson, Magnus %A Dena G Hernandez %A McWhirter, Rebekah %A Yongmei Liu %A Thomson, Russell %A Tranah, Gregory J %A André G Uitterlinden %A David R Weir %A Wei Zhao %A John M Starr %A Mohammed Arfan Ikram %A David A Bennett %A Steven R Cummings %A Ian J Deary %A Tamara B Harris %A Sharon L R Kardia %A Thomas H Mosley %A Velandai K Srikanth %A Beverly G Windham %A Anne B Newman %A Jeremy D Walston %A Gail Davies %A Daniel S Evans %A Eline P Slagboom %A Luigi Ferrucci %A Douglas P Kiel %A Joanne M Murabito %A Atzmon, Gil %K Genetics %K GWAS %X Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. %B Aging (Albany NY) %V 9 %P 209-246 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28077804?dopt=Abstract %R 10.18632/aging.101151 %0 Journal Article %J Aging Cell %D 2016 %T GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. %A Amy M Matteini %A Toshiko Tanaka %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A John D Eicher %A Andrew D Johnson %A Alice M. Arnold %A Michele L Callisaya %A Gail Davies %A Daniel S Evans %A Holtfreter, Birte %A Kurt Lohman %A Kathryn L Lunetta %A Mangino, Massimo %A Albert Vernon Smith %A Jennifer A Smith %A Teumer, Alexander %A Lei Yu %A Dan E Arking %A Aron S Buchman %A Chibinik, Lori B %A Philip L de Jager %A Jessica Faul %A Melissa E Garcia %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A David C Liewald %A Yongmei Liu %A Lopez, Lorna %A Fernando Rivadeneira %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A John M Starr %A Thomson, Russell %A Tranah, Gregory J %A André G Uitterlinden %A Völker, Uwe %A Völzke, Henry %A David R Weir %A Kristine Yaffe %A Wei Zhao %A Wei Vivian Zhuang %A Zmuda, Joseph M %A David A Bennett %A Steven R Cummings %A Ian J Deary %A Luigi Ferrucci %A Tamara B Harris %A Sharon L R Kardia %A Kocher, Thomas %A Stephen B Kritchevsky %A Psaty, Bruce M %A Seshadri, Sudha %A Timothy Spector %A Velandai K Srikanth %A Beverly G Windham %A Zillikens, M Carola %A Anne B Newman %A Jeremy D Walston %A Douglas P Kiel %A Joanne M Murabito %K Adult %K Aged %K Chromatin Immunoprecipitation %K Cohort Studies %K Epigenesis, Genetic %K Genome-Wide Association Study %K Hand Strength %K Humans %K Molecular Sequence Annotation %K Muscle Strength %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %X

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

%B Aging Cell %V 15 %P 792-800 %8 2016 10 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. %A Broer, Linda %A Aron S Buchman %A Deelen, Joris %A Daniel S Evans %A Jessica Faul %A Kathryn L Lunetta %A Sebastiani, Paola %A Jennifer A Smith %A Albert Vernon Smith %A Toshiko Tanaka %A Lei Yu %A Alice M. Arnold %A Aspelund, Thor %A Emelia J Benjamin %A Philip L de Jager %A Guðny Eiríksdóttir %A Melissa E Garcia %A Hofman, Albert %A Kaplan, Robert C %A Sharon L R Kardia %A Douglas P Kiel %A Ben A Oostra %A Orwoll, Eric S %A Parimi, Neeta %A Psaty, Bruce M %A Fernando Rivadeneira %A Rotter, Jerome I %A Seshadri, Sudha %A Andrew B Singleton %A Henning Tiemeier %A André G Uitterlinden %A Wei Zhao %A Bandinelli, Stefania %A David A Bennett %A Luigi Ferrucci %A Gudnason, Vilmundur %A Tamara B Harris %A Karasik, David %A Lenore J Launer %A Thomas T Perls %A Eline P Slagboom %A Tranah, Gregory J %A David R Weir %A Anne B Newman %A Cornelia M van Duijn %A Joanne M Murabito %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cell Adhesion Molecules %K Cohort Studies %K Female %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome-Wide Association Study %K Humans %K Longevity %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Kainic Acid %X

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 110-8 %8 2015 Jan %G eng %U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296168/ %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract %R 10.1093/gerona/glu166