@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 {8889, title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Nov}, pages = {1294-303}, abstract = {

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in \~{}70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (\~{}6\% increase in risk per year; P = 3 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

}, keywords = {Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Genome, Genome-Wide Association Study, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Older Adults, Phenotype, Reproduction, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3412}, author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Kathryn L Lunetta and Pervjakova, Natalia and Daniel I Chasman and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and T{\~o}nu Esko and Andrew D Johnson and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Lude L Franke and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Jennifer A Smith and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Wei Zhao and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Jouke-Jan Hottenga and Mangino, Massimo and Albert Vernon Smith and Toshiko Tanaka and Gon{\c c}alo R Abecasis and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Alice M. Arnold and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Manjeet K. Bolla and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Yii-Der I Chen and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Ellen W Demerath and Joe G Dennis and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and John D Eicher and Fasching, Peter A and Jessica Faul and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Melissa E Garcia and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Giorgia G Girotto and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Gu{\'e}nel, Pascal and Guo, Xiuqing and Christopher A Haiman and Hall, Per and Hamann, Ute and Henderson, Brian E and Lynne J Hocking and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and John L Hopper and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Charles Kooperberg and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Yongmei Liu and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Nicholas G Martin and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Lili Milani and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Michael A Nalls and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Anne B Newman and B{\o}rge G Nordestgaard and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Nicola Pirastu and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and David J Porteous and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Fernando Rivadeneira and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Cinzia Felicita Sala and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Kent D Taylor and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Th{\'e}r{\`e}se and Tryggvadottir, Laufey and Stephen T Turner and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Gonneke Willemsen and James F Wilson and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Alan F Wright and Yannoukakos, Drakoulis and Zemunik, Tatijana and Wei Zhang and Zygmunt, Marek and Bergmann, Sven and Dorret I Boomsma and Buring, Julie E and Luigi Ferrucci and Grant W Montgomery and Gudnason, Vilmundur and Timothy Spector and Cornelia M van Duijn and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Paolo P. Gasparini and Gieger, Christian and Tamara B Harris and Caroline Hayward and Sharon L R Kardia and Kraft, Peter and McKnight, Barbara and Andres Metspalu and Alanna C Morrison and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Andr{\'e} G Uitterlinden and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and David R Weir and Laura M Yerges-Armstrong and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Joanne M Murabito and Perry, John R B and Murray, Anna} } @article {8604, title = {Genetic diversity is a predictor of mortality in humans.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014 Dec 29}, pages = {159}, abstract = {

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{\textquoteright}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.

}, keywords = {Genome-Wide Association Study, Heterozygote, Humans, Mortality, Polymorphism, Single Nucleotide, Proportional Hazards Models}, issn = {1471-2156}, doi = {10.1186/s12863-014-0159-7}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301661/}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Albert Vernon Smith and Kathryn L Lunetta and Michael A Nalls and Jennifer A Smith and Toshiko Tanaka and Gail Davies and Lei Yu and Saira S Mirza and Teumer, Alexander and Coresh, Josef and Pankow, James S and Franceschini, Nora and Scaria, Anish and Oshima, Junko and Psaty, Bruce M and Gudnason, Vilmundur and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Tamara B Harris and Li, Hanyue and Karasik, David and Douglas P Kiel and Melissa E Garcia and Yongmei Liu and Jessica Faul and Sharon L R Kardia and Wei Zhao and Luigi Ferrucci and Allerhand, Michael and David C Liewald and Redmond, Paul and John M Starr and Philip L de Jager and Nese Direk and Mohammed Arfan Ikram and Andr{\'e} G Uitterlinden and Homuth, Georg and Lorbeer, Roberto and Hans-J{\"o}rgen Grabe and Lenore J Launer and Joanne M Murabito and Andrew B Singleton and David R Weir and Bandinelli, Stefania and Ian J Deary and David A Bennett and Henning Tiemeier and Kocher, Thomas and Lumley, Thomas and Dan E Arking} }