TY - JOUR T1 - Sarcopenia Definition & Outcomes Consortium Defined Low Grip Strength in Two Cross-Sectional, Population-Based Cohorts JF - JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Y1 - 2020 A1 - Patel, Sheena M. A1 - Kate A Duchowny A1 - Douglas P Kiel A1 - Correa-de-Araujo, Rosaly A1 - Fielding, Roger A. A1 - Travison, Thomas A1 - Magaziner, Jay A1 - Manini, Todd A1 - Xue, Qian-Li A1 - Anne B Newman A1 - Pencina, Karol M. A1 - Santanasto, Adam J. A1 - Bhasin, Shalender A1 - Peggy M Cawthon KW - Gait KW - muscle KW - Physical performance KW - sarcopenia AB - BACKGROUND/OBJECTIVES The extent to which the prevalence of muscle weakness in the US population varies by different putative grip strength constructs developed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) has not been described. DESIGN Cross-sectional analysis. SETTING Two nationally representative cohorts-2010 and 2012 waves of the Health and Retirement Survey and round 1 (2011) of the National Health and Aging Trends Survey. PARTICIPANTS Adults aged 65 years and older (n = 12,984) were included in these analyses. MEASUREMENTS We analyzed three constructs of muscle weakness developed by the SDOC, and found to be associated with mobility disability for men and women, respectively: absolute grip strength (<35.5 kg and 20 kg); grip strength standardized to body mass index (<1.05 kg/kg/m(2) and 0.79 kg/kg/m(2)); and grip strength standardized to weight (<0.45 kg/kg and 0.337 kg/kg). We estimated the prevalence of muscle weakness defined by each of these constructs in the overall older US population, and by age, sex, race, and ethnicity. We also estimated the sensitivity and specificity of each of the grip strength constructs to discriminate slowness (gait speed <0.8 m/s) in these samples. RESULTS The prevalence of muscle weakness ranged from 23% to 61% for men and from 30% to 66% for women, depending on the construct used. There was substantial variation in the prevalence of muscle weakness by race and ethnicity. The sensitivity and specificity of these measures for discriminating slowness varied widely, ranging from 0.30 to 0.92 (sensitivity) and from 0.17 to 0.88 (specificity). CONCLUSIONS The prevalence of muscle weakness, defined by the putative SDOC grip strength constructs, depends on the construct of weakness used. VL - 68 IS - 7 ER - TY - JOUR T1 - A meta-analysis of genome-wide association studies identifies multiple longevity genes. JF - Nature Communications Y1 - 2019 A1 - Deelen, Joris A1 - Daniel S Evans A1 - Dan E Arking A1 - Tesi, Niccolò A1 - Nygaard, Marianne A1 - Liu, Xiaomin A1 - Wojczynski, Mary K A1 - Biggs, Mary L A1 - van der Spek, Ashley A1 - Atzmon, Gil A1 - Erin B Ware A1 - Sarnowski, Chloé A1 - Albert Vernon Smith A1 - Seppälä, Ilkka A1 - Cordell, Heather J A1 - Dose, Janina A1 - Amin, Najaf A1 - Alice M. Arnold A1 - Kristin L. Ayers A1 - Barzilai, Nir A1 - Becker, Elizabeth J A1 - Beekman, Marian A1 - Blanché, Hélène A1 - Christensen, Kaare A1 - Christiansen, Lene A1 - Collerton, Joanna C A1 - Cubaynes, Sarah A1 - Steven R Cummings A1 - Davies, Karen A1 - Debrabant, Birgit A1 - Deleuze, Jean-François A1 - Duncan, Rachel A1 - Jessica Faul A1 - Franceschi, Claudio A1 - Galan, Pilar A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Huisman, Martijn A1 - Hurme, Mikko A A1 - Jagger, Carol A1 - Jansen, Iris A1 - Jylhä, Marja A1 - Kähönen, Mika A1 - Karasik, David A1 - Sharon L R Kardia A1 - Kingston, Andrew A1 - Kirkwood, Thomas B L A1 - Lenore J Launer A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lyytikäinen, Leo-Pekka A1 - Martin-Ruiz, Carmen A1 - Min, Junxia A1 - Nebel, Almut A1 - Anne B Newman A1 - Nie, Chao A1 - Nohr, Ellen A A1 - Orwoll, Eric S A1 - Thomas T Perls A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Olli T Raitakari A1 - Reinders, Marcel J T A1 - Robine, Jean-Marie A1 - Rotter, Jerome I A1 - Sebastiani, Paola A1 - Jennifer A Smith A1 - Sørensen, Thorkild I A A1 - Kent D Taylor A1 - André G Uitterlinden A1 - van der Flier, Wiesje A1 - Sven J van der Lee A1 - Cornelia M van Duijn A1 - van Heemst, Diana A1 - James W Vaupel A1 - David R Weir A1 - Ye, Kenny A1 - Zeng, Yi A1 - Zheng, Wanlin A1 - Holstege, Henne A1 - Douglas P Kiel A1 - Kathryn L Lunetta A1 - Eline P Slagboom A1 - Joanne M Murabito KW - genes KW - Genome-Wide Association Study KW - GWA KW - longevity genes KW - meta-analysis AB -

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

VL - 10 UR - https://www.ncbi.nlm.nih.gov/pubmed/31413261 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/31413261?dopt=Abstract ER - TY - JOUR T1 - The complex genetics of gait speed: genome-wide meta-analysis approach. JF - Aging (Albany NY) Y1 - 2017 A1 - Ben-Avraham, Dan A1 - Karasik, David A1 - Joe Verghese A1 - Kathryn L Lunetta A1 - John D Eicher A1 - Vered, Rotem A1 - Deelen, Joris A1 - Alice M. Arnold A1 - Aron S Buchman A1 - Toshiko Tanaka A1 - Jessica Faul A1 - Nethander, Maria A1 - Myriam Fornage A1 - Hieab H Adams A1 - Amy M Matteini A1 - Michele L Callisaya A1 - Albert Vernon Smith A1 - Lei Yu A1 - Philip L de Jager A1 - Denis A Evans A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Pattie, Alison A1 - Corley, Janie A1 - Lenore J Launer A1 - David S Knopman A1 - Parimi, Neeta A1 - Stephen T Turner A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Gutman, Danielle A1 - Sharvit, Lital A1 - Simon P Mooijaart A1 - David C Liewald A1 - Jeanine J Houwing-Duistermaat A1 - Ohlsson, Claes A1 - Moed, Matthijs A1 - Vincent J Verlinden A1 - Mellström, Dan A1 - Jos N van der Geest A1 - Karlsson, Magnus A1 - Dena G Hernandez A1 - McWhirter, Rebekah A1 - Yongmei Liu A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - André G Uitterlinden A1 - David R Weir A1 - Wei Zhao A1 - John M Starr A1 - Mohammed Arfan Ikram A1 - David A Bennett A1 - Steven R Cummings A1 - Ian J Deary A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Thomas H Mosley A1 - Velandai K Srikanth A1 - Beverly G Windham A1 - Anne B Newman A1 - Jeremy D Walston A1 - Gail Davies A1 - Daniel S Evans A1 - Eline P Slagboom A1 - Luigi Ferrucci A1 - Douglas P Kiel A1 - Joanne M Murabito A1 - Atzmon, Gil KW - Genetics KW - GWAS AB - 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. VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28077804?dopt=Abstract ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Amy M Matteini A1 - Toshiko Tanaka A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - John D Eicher A1 - Andrew D Johnson A1 - Alice M. Arnold A1 - Michele L Callisaya A1 - Gail Davies A1 - Daniel S Evans A1 - Holtfreter, Birte A1 - Kurt Lohman A1 - Kathryn L Lunetta A1 - Mangino, Massimo A1 - Albert Vernon Smith A1 - Jennifer A Smith A1 - Teumer, Alexander A1 - Lei Yu A1 - Dan E Arking A1 - Aron S Buchman A1 - Chibinik, Lori B A1 - Philip L de Jager A1 - Jessica Faul A1 - Melissa E Garcia A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - David C Liewald A1 - Yongmei Liu A1 - Lopez, Lorna A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - John M Starr A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - André G Uitterlinden A1 - Völker, Uwe A1 - Völzke, Henry A1 - David R Weir A1 - Kristine Yaffe A1 - Wei Zhao A1 - Wei Vivian Zhuang A1 - Zmuda, Joseph M A1 - David A Bennett A1 - Steven R Cummings A1 - Ian J Deary A1 - Luigi Ferrucci A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Kocher, Thomas A1 - Stephen B Kritchevsky A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Timothy Spector A1 - Velandai K Srikanth A1 - Beverly G Windham A1 - Zillikens, M Carola A1 - Anne B Newman A1 - Jeremy D Walston A1 - Douglas P Kiel A1 - Joanne M Murabito KW - Adult KW - Aged KW - Chromatin Immunoprecipitation KW - Cohort Studies KW - Epigenesis, Genetic KW - Genome-Wide Association Study KW - Hand Strength KW - Humans KW - Molecular Sequence Annotation KW - Muscle Strength KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results AB -

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.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Aron S Buchman A1 - Deelen, Joris A1 - Daniel S Evans A1 - Jessica Faul A1 - Kathryn L Lunetta A1 - Sebastiani, Paola A1 - Jennifer A Smith A1 - Albert Vernon Smith A1 - Toshiko Tanaka A1 - Lei Yu A1 - Alice M. Arnold A1 - Aspelund, Thor A1 - Emelia J Benjamin A1 - Philip L de Jager A1 - Guðny Eiríksdóttir A1 - Melissa E Garcia A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Sharon L R Kardia A1 - Douglas P Kiel A1 - Ben A Oostra A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Andrew B Singleton A1 - Henning Tiemeier A1 - André G Uitterlinden A1 - Wei Zhao A1 - Bandinelli, Stefania A1 - David A Bennett A1 - Luigi Ferrucci A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Karasik, David A1 - Lenore J Launer A1 - Thomas T Perls A1 - Eline P Slagboom A1 - Tranah, Gregory J A1 - David R Weir A1 - Anne B Newman A1 - Cornelia M van Duijn A1 - Joanne M Murabito KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

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.

VL - 70 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296168/ IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Albert Vernon Smith A1 - Kathryn L Lunetta A1 - Michael A Nalls A1 - Jennifer A Smith A1 - Toshiko Tanaka A1 - Gail Davies A1 - Lei Yu A1 - Saira S Mirza A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Guðny Eiríksdóttir A1 - Tamara B Harris A1 - Li, Hanyue A1 - Karasik, David A1 - Douglas P Kiel A1 - Melissa E Garcia A1 - Yongmei Liu A1 - Jessica Faul A1 - Sharon L R Kardia A1 - Wei Zhao A1 - Luigi Ferrucci A1 - Allerhand, Michael A1 - David C Liewald A1 - Redmond, Paul A1 - John M Starr A1 - Philip L de Jager A1 - Nese Direk A1 - Mohammed Arfan Ikram A1 - André G Uitterlinden A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Hans-Jörgen Grabe A1 - Lenore J Launer A1 - Joanne M Murabito A1 - Andrew B Singleton A1 - David R Weir A1 - Bandinelli, Stefania A1 - Ian J Deary A1 - David A Bennett A1 - Henning Tiemeier A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Dan E Arking KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

VL - 15 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301661/ U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract ER -