@article {10225, title = {A meta-analysis of genome-wide association studies identifies multiple longevity genes.}, journal = {Nature Communications}, volume = {10}, year = {2019}, month = {08/2019}, pages = {3669}, abstract = {

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.

}, keywords = {genes, Genome-Wide Association Study, GWA, longevity genes, meta-analysis}, issn = {2041-1723}, doi = {10.1038/s41467-019-11558-2}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31413261}, author = {Deelen, Joris and Daniel S Evans and Dan E Arking and Tesi, Niccol{\`o} and Nygaard, Marianne and Liu, Xiaomin and Wojczynski, Mary K and Biggs, Mary L and van der Spek, Ashley and Atzmon, Gil and Erin B Ware and Sarnowski, Chlo{\'e} and Albert Vernon Smith and Sepp{\"a}l{\"a}, Ilkka and Cordell, Heather J and Dose, Janina and Amin, Najaf and Alice M. Arnold and Kristin L. Ayers and Barzilai, Nir and Becker, Elizabeth J and Beekman, Marian and Blanch{\'e}, H{\'e}l{\`e}ne and Christensen, Kaare and Christiansen, Lene and Collerton, Joanna C and Cubaynes, Sarah and Steven R Cummings and Davies, Karen and Debrabant, Birgit and Deleuze, Jean-Fran{\c c}ois and Duncan, Rachel and Jessica Faul and Franceschi, Claudio and Galan, Pilar and Gudnason, Vilmundur and Tamara B Harris and Huisman, Martijn and Hurme, Mikko A and Jagger, Carol and Jansen, Iris and Jylh{\"a}, Marja and K{\"a}h{\"o}nen, Mika and Karasik, David and Sharon L R Kardia and Kingston, Andrew and Kirkwood, Thomas B L and Lenore J Launer and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Lyytik{\"a}inen, Leo-Pekka and Martin-Ruiz, Carmen and Min, Junxia and Nebel, Almut and Anne B Newman and Nie, Chao and Nohr, Ellen A and Orwoll, Eric S and Thomas T Perls and Province, Michael A and Psaty, Bruce M and Olli T Raitakari and Reinders, Marcel J T and Robine, Jean-Marie and Rotter, Jerome I and Sebastiani, Paola and Jennifer A Smith and S{\o}rensen, Thorkild I A and Kent D Taylor and Andr{\'e} G Uitterlinden and van der Flier, Wiesje and Sven J van der Lee and Cornelia M van Duijn and van Heemst, Diana and James W Vaupel and David R Weir and Ye, Kenny and Zeng, Yi and Zheng, Wanlin and Holstege, Henne and Douglas P Kiel and Kathryn L Lunetta and Eline P Slagboom and Joanne M Murabito} } @article {9172, title = {The complex genetics of gait speed: genome-wide meta-analysis approach.}, journal = {Aging (Albany NY)}, volume = {9}, year = {2017}, pages = {209-246}, abstract = {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.}, keywords = {Genetics, GWAS}, issn = {1945-4589}, doi = {10.18632/aging.101151}, author = {Ben-Avraham, Dan and Karasik, David and Joe Verghese and Kathryn L Lunetta and John D Eicher and Vered, Rotem and Deelen, Joris and Alice M. Arnold and Aron S Buchman and Toshiko Tanaka and Jessica Faul and Nethander, Maria and Myriam Fornage and Hieab H Adams and Amy M Matteini and Michele L Callisaya and Albert Vernon Smith and Lei Yu and Philip L de Jager and Denis A Evans and Gudnason, Vilmundur and Hofman, Albert and Pattie, Alison and Corley, Janie and Lenore J Launer and David S Knopman and Parimi, Neeta and Stephen T Turner and Bandinelli, Stefania and Beekman, Marian and Gutman, Danielle and Sharvit, Lital and Simon P Mooijaart and David C Liewald and Jeanine J Houwing-Duistermaat and Ohlsson, Claes and Moed, Matthijs and Vincent J Verlinden and Mellstr{\"o}m, Dan and Jos N van der Geest and Karlsson, Magnus and Dena G Hernandez and McWhirter, Rebekah and Yongmei Liu and Thomson, Russell and Tranah, Gregory J and Andr{\'e} G Uitterlinden and David R Weir and Wei Zhao and John M Starr and Mohammed Arfan Ikram and David A Bennett and Steven R Cummings and Ian J Deary and Tamara B Harris and Sharon L R Kardia and Thomas H Mosley and Velandai K Srikanth and Beverly G Windham and Anne B Newman and Jeremy D Walston and Gail Davies and Daniel S Evans and Eline P Slagboom and Luigi Ferrucci and Douglas P Kiel and Joanne M Murabito and Atzmon, Gil} } @article {8614, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 10}, pages = {792-800}, abstract = {

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~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~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~{\texttimes}~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.

}, keywords = {Adult, Aged, Chromatin Immunoprecipitation, Cohort Studies, Epigenesis, Genetic, Genome-Wide Association Study, Hand Strength, Humans, Molecular Sequence Annotation, Muscle Strength, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Amy M Matteini and Toshiko Tanaka and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and John D Eicher and Andrew D Johnson and Alice M. Arnold and Michele L Callisaya and Gail Davies and Daniel S Evans and Holtfreter, Birte and Kurt Lohman and Kathryn L Lunetta and Mangino, Massimo and Albert Vernon Smith and Jennifer A Smith and Teumer, Alexander and Lei Yu and Dan E Arking and Aron S Buchman and Chibinik, Lori B and Philip L de Jager and Jessica Faul and Melissa E Garcia and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and David C Liewald and Yongmei Liu and Lopez, Lorna and Fernando Rivadeneira and Rotter, Jerome I and Siggeirsdottir, Kristin and John M Starr and Thomson, Russell and Tranah, Gregory J and Andr{\'e} G Uitterlinden and V{\"o}lker, Uwe and V{\"o}lzke, Henry and David R Weir and Kristine Yaffe and Wei Zhao and Wei Vivian Zhuang and Zmuda, Joseph M and David A Bennett and Steven R Cummings and Ian J Deary and Luigi Ferrucci and Tamara B Harris and Sharon L R Kardia and Kocher, Thomas and Stephen B Kritchevsky and Psaty, Bruce M and Seshadri, Sudha and Timothy Spector and Velandai K Srikanth and Beverly G Windham and Zillikens, M Carola and Anne B Newman and Jeremy D Walston and Douglas P Kiel and Joanne M Murabito} } @article {8606, title = {GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Jan}, pages = {110-8}, abstract = {

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 {\texttimes} 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 {\texttimes} 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{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Apolipoproteins E, Cell Adhesion Molecules, Cohort Studies, Female, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome-Wide Association Study, Humans, Longevity, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Kainic Acid}, issn = {1758-535X}, doi = {10.1093/gerona/glu166}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296168/}, author = {Broer, Linda and Aron S Buchman and Deelen, Joris and Daniel S Evans and Jessica Faul and Kathryn L Lunetta and Sebastiani, Paola and Jennifer A Smith and Albert Vernon Smith and Toshiko Tanaka and Lei Yu and Alice M. Arnold and Aspelund, Thor and Emelia J Benjamin and Philip L de Jager and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Melissa E Garcia and Hofman, Albert and Kaplan, Robert C and Sharon L R Kardia and Douglas P Kiel and Ben A Oostra and Orwoll, Eric S and Parimi, Neeta and Psaty, Bruce M and Fernando Rivadeneira and Rotter, Jerome I and Seshadri, Sudha and Andrew B Singleton and Henning Tiemeier and Andr{\'e} G Uitterlinden and Wei Zhao and Bandinelli, Stefania and David A Bennett and Luigi Ferrucci and Gudnason, Vilmundur and Tamara B Harris and Karasik, David and Lenore J Launer and Thomas T Perls and Eline P Slagboom and Tranah, Gregory J and David R Weir and Anne B Newman and Cornelia M van Duijn and Joanne M Murabito} } @article {8620, title = {GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.}, journal = {Science}, volume = {340}, year = {2013}, month = {2013 Jun 21}, pages = {1467-71}, abstract = {

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02\%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2\% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

}, keywords = {Cognition, Educational Status, Endophenotypes, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1095-9203}, doi = {10.1126/science.1235488}, author = {Cornelius A Rietveld and Sarah E Medland and Derringer, Jaime and Yang, Jian and T{\~o}nu Esko and Martin, Nicolas W and Westra, Harm-Jan and Shakhbazov, Konstantin and Abdel Abdellaoui and Agrawal, Arpana and Albrecht, Eva and Alizadeh, Behrooz Z and Amin, Najaf and Barnard, John and Baumeister, Sebastian E and Benke, Kelly S and Bielak, Lawrence F and Boatman, Jeffrey A and Patricia A. Boyle and Gail Davies and Christiaan de Leeuw and Eklund, Niina and Daniel S Evans and Rudolf Ferhmann and Fischer, Krista and Gieger, Christian and Gjessing, H{\r a}kon K and H{\"a}gg, Sara and Harris, Jennifer R and Caroline Hayward and Holzapfel, Christina and Carla A Ibrahim-Verbaas and Ingelsson, Erik and Jacobsson, Bo and Joshi, Peter K and Jugessur, Astanand and Marika A Kaakinen and Kanoni, Stavroula and Karjalainen, Juha and Kolcic, Ivana and Kristiansson, Kati and Kutalik, Zolt{\'a}n and J. Lahti and Lee, Sang H and Lin, Peng and Penelope A Lind and Yongmei Liu and Kurt Lohman and Loitfelder, Marisa and McMahon, George and Vidal, Pedro Marques and Osorio Meirelles and Lili Milani and Myhre, Ronny and Nuotio, Marja-Liisa and Christopher J Oldmeadow and Katja E Petrovic and Wouter J Peyrot and Polasek, Ozren and Quaye, Lydia and Reinmaa, Eva and Rice, John P and Rizzi, Thais S and Schmidt, Helena and Schmidt, Reinhold and Albert Vernon Smith and Jennifer A Smith and Toshiko Tanaka and Antonio Terracciano and van der Loos, Matthijs J H M and Vitart, Veronique and V{\"o}lzke, Henry and J{\"u}rgen Wellmann and Lei Yu and Wei Zhao and Allik, J{\"u}ri and John R. Attia and Bandinelli, Stefania and Bastardot, Fran{\c c}ois and Jonathan P. Beauchamp and David A Bennett and Klaus Berger and Laura Bierut and Dorret I Boomsma and B{\"u}ltmann, Ute and Campbell, Harry and Chabris, Christopher F and Cherkas, Lynn and Chung, Mina K and Francesco Cucca and de Andrade, Mariza and Philip L de Jager and De Neve, Jan-Emmanuel and Ian J Deary and George Dedoussis and Deloukas, Panos and Dimitriou, Maria and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Elderson, Martin F and Johan G Eriksson and Jessica Faul and Luigi Ferrucci and Melissa E Garcia and Gr{\"o}nberg, Henrik and Gu{\dh}nason, Vilmundur and Hall, Per and Harris, Juliette M and Tamara B Harris and Nicholas D Hastie and Andrew C Heath and Dena G Hernandez and Hoffmann, Wolfgang and Hofman, Adriaan and Holle, Rolf and Holliday, Elizabeth G and Jouke-Jan Hottenga and Iacono, William G and Illig, Thomas and J{\"a}rvelin, Marjo-Riitta and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kirkpatrick, Robert M and Kowgier, Matthew and Latvala, Antti and Lenore J Launer and Lawlor, Debbie A and Lehtim{\"a}ki, Terho and Li, Jingmei and Paul Lichtenstein and Lichtner, Peter and David C Liewald and Pamela A F Madden and Patrik K E Magnusson and M{\"a}kinen, Tomi E and Masala, Marco and McGue, Matt and Andres Metspalu and Mielck, Andreas and Michael B Miller and Grant W Montgomery and Mukherjee, Sutapa and Nyholt, Dale R and Ben A Oostra and Palmer, Lyle J and Aarno Palotie and Brenda W J H Penninx and Markus Perola and Peyser, Patricia A and Preisig, Martin and Katri R{\"a}ikk{\"o}nen and Olli T Raitakari and Realo, Anu and Ring, Susan M and Ripatti, Samuli and Fernando Rivadeneira and Rudan, Igor and Rustichini, Aldo and Veikko Salomaa and Sarin, Antti-Pekka and Schlessinger, David and Rodney J Scott and Snieder, Harold and St Pourcain, Beate and John M Starr and Sul, Jae Hoon and Surakka, Ida and Svento, Rauli and Teumer, Alexander and Henning Tiemeier and van Rooij, Frank J A and Van Wagoner, David R and Vartiainen, Erkki and Viikari, Jorma and Vollenweider, Peter and Vonk, Judith M and Waeber, G{\'e}rard and David R Weir and Wichmann, H-Erich and Elisabeth Widen and Gonneke Willemsen and James F Wilson and Alan F Wright and Dalton C Conley and Davey-Smith, George and Lude L Franke and Groenen, Patrick J F and Hofman, Albert and Johannesson, Magnus and Sharon L R Kardia and Krueger, Robert F and David I Laibson and Nicholas G Martin and Meyer, Michelle N and Posthuma, Danielle and A. Roy Thurik and Nicholas J Timpson and Andr{\'e} G Uitterlinden and Cornelia M van Duijn and Peter M Visscher and Daniel J. Benjamin and Cesarini, David and Philipp D Koellinger} }