%0 Journal Article %J Exp Gerontol %D 2009 %T Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. %A Walston, Jeremy D %A Matteini, Amy M %A Nievergelt, Caroline %A Lange, Leslie A %A Fallin, Dani M %A Barzilai, Nir %A Ziv, Elad %A Pawlikowska, Ludmila %A Kwok, Pui %A Cummings, Steve R %A Kooperberg, Charles %A LaCroix, Andrea %A Tracy, Russell P %A Atzmon, Gil %A Lange, Ethan M %A Reiner, Alex P %K Aged %K Aged, 80 and over %K Aging %K Cardiovascular Diseases %K Case-Control Studies %K Female %K Genetic Variation %K Genotype %K Humans %K Inflammation %K Interleukin-6 %K Longevity %K Male %K Phenotype %K Poly (ADP-Ribose) Polymerase-1 %K Poly(ADP-ribose) Polymerases %K Risk Factors %X

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

%B Exp Gerontol %V 44 %P 350-5 %8 2009 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/19249341?dopt=Abstract %R 10.1016/j.exger.2009.02.004 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2014 %T Heritability of and mortality prediction with a longevity phenotype: the healthy aging index. %A Sanders, Jason L %A Minster, Ryan L %A Barmada, M Michael %A Matteini, Amy M %A Boudreau, Robert M %A Christensen, Kaare %A Mayeux, Richard %A Borecki, Ingrid B %A Zhang, Qunyuan %A Perls, Thomas %A Newman, Anne B %K Aged %K Aging %K Cardiovascular Diseases %K Female %K Genetic Predisposition to Disease %K Genotype %K Health Behavior %K Humans %K Longevity %K Male %K Phenotype %K Retrospective Studies %K Risk Factors %K Survival Rate %K United States %X

BACKGROUND: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.

METHODS: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.

RESULTS: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.

CONCLUSION: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.

%B J Gerontol A Biol Sci Med Sci %V 69 %P 479-85 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23913930?dopt=Abstract %R 10.1093/gerona/glt117 %0 Journal Article %J J Mol Med (Berl) %D 2015 %T Association of mitochondrial DNA levels with frailty and all-cause mortality. %A Ashar, Foram N %A Moes, Anna %A Moore, Ann Z %A Grove, Megan L %A Chaves, Paulo H M %A Coresh, Josef %A Newman, Anne B %A Matteini, Amy M %A Bandeen-Roche, Karen %A Boerwinkle, Eric %A Walston, Jeremy D %A Arking, Dan E %K African Americans %K Aged %K Aged, 80 and over %K Aging %K DNA, Mitochondrial %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Dosage %K Geriatric Assessment %K Humans %K Kaplan-Meier Estimate %K Male %K Mortality %K Odds Ratio %K Population Surveillance %K Prospective Studies %K Surveys and Questionnaires %K United States %X

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

%B J Mol Med (Berl) %V 93 %P 177-186 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25471480?dopt=Abstract %R 10.1007/s00109-014-1233-3 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index. %A Minster, Ryan L %A Sanders, Jason L %A Singh, Jatinder %A Kammerer, Candace M %A Barmada, M Michael %A Matteini, Amy M %A Zhang, Qunyuan %A Wojczynski, Mary K %A Daw, E Warwick %A Brody, Jennifer A %A Arnold, Alice M %A Lunetta, Kathryn L %A Murabito, Joanne M %A Christensen, Kaare %A Perls, Thomas T %A Province, Michael A %A Newman, Anne B %K Aging %K Apolipoproteins E %K Forkhead Transcription Factors %K Genetic Linkage %K Genome-Wide Association Study %K Humans %K Longevity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.

METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.

RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.

CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 1003-8 %8 2015 Aug %G ENG %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25758594?dopt=Abstract %R 10.1093/gerona/glv006 %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 Matteini, Amy M %A Tanaka, Toshiko %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A Eicher, John D %A Johnson, Andrew D %A Arnold, Alice M %A Callisaya, Michele L %A Davies, Gail %A Evans, Daniel S %A Holtfreter, Birte %A Lohman, Kurt %A Lunetta, Kathryn L %A Mangino, Massimo %A Smith, Albert V %A Smith, Jennifer A %A Teumer, Alexander %A Yu, Lei %A Arking, Dan E %A Buchman, Aron S %A Chibinik, Lori B %A De Jager, Philip L %A Evans, Denis A %A Faul, Jessica D %A Garcia, Melissa E %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A Liewald, David C %A Liu, Yongmei %A Lopez, Lorna %A Rivadeneira, Fernando %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A Starr, John M %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Weir, David R %A Yaffe, Kristine %A Zhao, Wei %A Zhuang, Wei Vivian %A Zmuda, Joseph M %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Ferrucci, Luigi %A Harris, Tamara B %A Kardia, Sharon L R %A Kocher, Thomas %A Kritchevsky, Stephen B %A Psaty, Bruce M %A Seshadri, Sudha %A Spector, Timothy D %A Srikanth, Velandai K %A Windham, B Gwen %A Zillikens, M Carola %A Newman, Anne B %A Walston, Jeremy D %A Kiel, Douglas P %A Murabito, Joanne M %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 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %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 Verghese, Joe %A Lunetta, Kathryn L %A Smith, Jennifer A %A Eicher, John D %A Vered, Rotem %A Deelen, Joris %A Arnold, Alice M %A Buchman, Aron S %A Tanaka, Toshiko %A Faul, Jessica D %A Nethander, Maria %A Fornage, Myriam %A Adams, Hieab H %A Matteini, Amy M %A Callisaya, Michele L %A Smith, Albert V %A Yu, Lei %A De Jager, Philip L %A Evans, Denis A %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Launer, Lenore J %A Knopman, Davis S %A Parimi, Neeta %A Turner, Stephen T %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Mooijaart, Simon P %A Liewald, David C %A Houwing-Duistermaat, Jeanine J %A Ohlsson, Claes %A Moed, Matthijs %A Verlinden, Vincent J %A Mellström, Dan %A van der Geest, Jos N %A Karlsson, Magnus %A Hernandez, Dena %A McWhirter, Rebekah %A Liu, Yongmei %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Weir, David R %A Zhao, Wei %A Starr, John M %A Johnson, Andrew D %A Ikram, M Arfan %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Harris, Tamara B %A Kardia, Sharon L R %A Mosley, Thomas H %A Srikanth, Velandai K %A Windham, Beverly G %A Newman, Ann B %A Walston, Jeremy D %A Davies, Gail %A Evans, Daniel S %A Slagboom, Eline P %A Ferrucci, Luigi %A Kiel, Douglas P %A Murabito, Joanne M %A Atzmon, Gil %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 %8 2017 Jan 10 %G eng %N 1 %R 10.18632/aging.101151 %0 Journal Article %J Nat Commun %D 2017 %T Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. %A Willems, Sara M %A Wright, Daniel J %A Day, Felix R %A Trajanoska, Katerina %A Joshi, Peter K %A Morris, John A %A Matteini, Amy M %A Garton, Fleur C %A Grarup, Niels %A Oskolkov, Nikolay %A Thalamuthu, Anbupalam %A Mangino, Massimo %A Liu, Jun %A Demirkan, Ayse %A Lek, Monkol %A Xu, Liwen %A Wang, Guan %A Oldmeadow, Christopher %A Gaulton, Kyle J %A Lotta, Luca A %A Miyamoto-Mikami, Eri %A Rivas, Manuel A %A White, Tom %A Loh, Po-Ru %A Aadahl, Mette %A Amin, Najaf %A Attia, John R %A Austin, Krista %A Benyamin, Beben %A Brage, Søren %A Cheng, Yu-Ching %A Cięszczyk, Paweł %A Derave, Wim %A Eriksson, Karl-Fredrik %A Eynon, Nir %A Linneberg, Allan %A Lucia, Alejandro %A Massidda, Myosotis %A Mitchell, Braxton D %A Miyachi, Motohiko %A Murakami, Haruka %A Padmanabhan, Sandosh %A Pandey, Ashutosh %A Papadimitriou, Ioannis %A Rajpal, Deepak K %A Sale, Craig %A Schnurr, Theresia M %A Sessa, Francesco %A Shrine, Nick %A Tobin, Martin D %A Varley, Ian %A Wain, Louise V %A Wray, Naomi R %A Lindgren, Cecilia M %A MacArthur, Daniel G %A Waterworth, Dawn M %A McCarthy, Mark I %A Pedersen, Oluf %A Khaw, Kay-Tee %A Kiel, Douglas P %A Pitsiladis, Yannis %A Fuku, Noriyuki %A Franks, Paul W %A North, Kathryn N %A van Duijn, Cornelia M %A Mather, Karen A %A Hansen, Torben %A Hansson, Ola %A Spector, Tim %A Murabito, Joanne M %A Richards, J Brent %A Rivadeneira, Fernando %A Langenberg, Claudia %A Perry, John R B %A Wareham, Nick J %A Scott, Robert A %X

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

%B Nat Commun %V 8 %P 16015 %8 2017 Jul 12 %G eng %R 10.1038/ncomms16015