TY - JOUR T1 - A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Newman, Anne B A1 - Walter, Stefan A1 - Lunetta, Kathryn L A1 - Garcia, Melissa E A1 - Slagboom, P Eline A1 - Christensen, Kaare A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Benjamin, Emelia J A1 - Christiansen, Lene A1 - D'Agostino, Ralph B A1 - Fitzpatrick, Annette L A1 - Franceschini, Nora A1 - Glazer, Nicole L A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Kaplan, Robert A1 - Karasik, David A1 - Kelly-Hayes, Margaret A1 - Kiel, Douglas P A1 - Launer, Lenore J A1 - Marciante, Kristin D A1 - Massaro, Joseph M A1 - Miljkovic, Iva A1 - Nalls, Michael A A1 - Hernandez, Dena A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome A1 - Seshadri, Sudha A1 - Smith, Albert V A1 - Taylor, Kent D A1 - Tiemeier, Henning A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vaupel, James W A1 - Walston, Jeremy A1 - Westendorp, Rudi G J A1 - Harris, Tamara B A1 - Lumley, Thomas A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

VL - 65 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. JF - Hum Mol Genet Y1 - 2012 A1 - Mangino, Massimo A1 - Hwang, Shih-Jen A1 - Spector, Timothy D A1 - Hunt, Steven C A1 - Kimura, Masayuki A1 - Fitzpatrick, Annette L A1 - Christiansen, Lene A1 - Petersen, Inge A1 - Elbers, Clara C A1 - Harris, Tamara A1 - Chen, Wei A1 - Srinivasan, Sathanur R A1 - Kark, Jeremy D A1 - Benetos, Athanase A1 - El Shamieh, Said A1 - Visvikis-Siest, Sophie A1 - Christensen, Kaare A1 - Berenson, Gerald S A1 - Valdes, Ana M A1 - Viñuela, Ana A1 - Garcia, Melissa A1 - Arnett, Donna K A1 - Broeckel, Ulrich A1 - Province, Michael A A1 - Pankow, James S A1 - Kammerer, Candace A1 - Liu, Yongmei A1 - Nalls, Michael A1 - Tishkoff, Sarah A1 - Thomas, Fridtjof A1 - Ziv, Elad A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Smith, Erin A1 - Schork, Nicholas J A1 - Levy, Daniel A1 - Aviv, Abraham KW - Genome-Wide Association Study KW - Humans KW - Kruppel-Like Transcription Factors KW - Telomere KW - Telomere Homeostasis KW - Telomere-Binding Proteins AB -

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

VL - 21 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23001564?dopt=Abstract ER - TY - JOUR T1 - FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. JF - Hum Mol Genet Y1 - 2014 A1 - Qi, Qibin A1 - Kilpeläinen, Tuomas O A1 - Downer, Mary K A1 - Tanaka, Toshiko A1 - Smith, Caren E A1 - Sluijs, Ivonne A1 - Sonestedt, Emily A1 - Chu, Audrey Y A1 - Renstrom, Frida A1 - Lin, Xiaochen A1 - Ängquist, Lars H A1 - Huang, Jinyan A1 - Liu, Zhonghua A1 - Li, Yanping A1 - Asif Ali, Muhammad A1 - Xu, Min A1 - Ahluwalia, Tarunveer Singh A1 - Boer, Jolanda M A A1 - Chen, Peng A1 - Daimon, Makoto A1 - Eriksson, Johan A1 - Perola, Markus A1 - Friedlander, Yechiel A1 - Gao, Yu-Tang A1 - Heppe, Denise H M A1 - Holloway, John W A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Kim, Yu-Mi A1 - Laaksonen, Maarit A A1 - Jääskeläinen, Tiina A1 - Lee, Nanette R A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Lu, Wei A1 - Luben, Robert N A1 - Manichaikul, Ani A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Monda, Keri L A1 - Ngwa, Julius S A1 - Perusse, Louis A1 - van Rooij, Frank J A A1 - Xiang, Yong-Bing A1 - Wen, Wanqing A1 - Wojczynski, Mary K A1 - Zhu, Jingwen A1 - Borecki, Ingrid B A1 - Bouchard, Claude A1 - Cai, Qiuyin A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Hansen, Torben A1 - Christiansen, Lene A1 - Hofman, Albert A1 - Johansson, Ingegerd A1 - Jørgensen, Torben A1 - Karasawa, Shigeru A1 - Khaw, Kay-Tee A1 - Kim, Mi-Kyung A1 - Kristiansson, Kati A1 - Li, Huaixing A1 - Lin, Xu A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Mikkilä, Vera A1 - Mozaffarian, Dariush A1 - North, Kari A1 - Pedersen, Oluf A1 - Raitakari, Olli A1 - Rissanen, Harri A1 - Tuomilehto, Jaakko A1 - van der Schouw, Yvonne T A1 - Uitterlinden, André G A1 - Zillikens, M Carola A1 - Franco, Oscar H A1 - Shyong Tai, E A1 - Ou Shu, Xiao A1 - Siscovick, David S A1 - Toft, Ulla A1 - Verschuren, W M Monique A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Zheng, Wei A1 - Ridker, Paul M A1 - Kang, Jae H A1 - Liang, Liming A1 - Jensen, Majken K A1 - Curhan, Gary C A1 - Pasquale, Louis R A1 - Hunter, David J A1 - Mohlke, Karen L A1 - Uusitupa, Matti A1 - Cupples, L Adrienne A1 - Rankinen, Tuomo A1 - Orho-Melander, Marju A1 - Wang, Tao A1 - Chasman, Daniel I A1 - Franks, Paul W A1 - Sørensen, Thorkild I A A1 - Hu, Frank B A1 - Loos, Ruth J F A1 - Nettleton, Jennifer A A1 - Qi, Lu KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins AB -

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract ER - TY - JOUR T1 - DCAF4, a novel gene associated with leucocyte telomere length. JF - J Med Genet Y1 - 2015 A1 - Mangino, Massimo A1 - Christiansen, Lene A1 - Stone, Rivka A1 - Hunt, Steven C A1 - Horvath, Kent A1 - Eisenberg, Dan T A A1 - Kimura, Masayuki A1 - Petersen, Inge A1 - Kark, Jeremy D A1 - Herbig, Utz A1 - Reiner, Alex P A1 - Benetos, Athanase A1 - Codd, Veryan A1 - Nyholt, Dale R A1 - Sinnreich, Ronit A1 - Christensen, Kaare A1 - Nassar, Hisham A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Bataille, Veronique A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Samani, Nilesh J A1 - Martin, Nicholas G A1 - Tishkoff, Sarah A1 - Schork, Nicholas J A1 - Kyvik, Kirsten Ohm A1 - Dalgård, Christine A1 - Spector, Timothy D A1 - Aviv, Abraham KW - Alleles KW - Carrier Proteins KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Humans KW - Leukocytes KW - Melanoma KW - Risk Factors KW - Telomere KW - Telomere Homeostasis AB -

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

VL - 52 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract ER - TY - JOUR T1 - Telomeres and the natural lifespan limit in humans. JF - Aging (Albany NY) Y1 - 2017 A1 - Steenstrup, Troels A1 - Kark, Jeremy D A1 - Verhulst, Simon A1 - Thinggaard, Mikael A1 - Hjelmborg, Jacob V B A1 - Dalgård, Christine A1 - Kyvik, Kirsten Ohm A1 - Christiansen, Lene A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Petersen, Inge A1 - Kimura, Masayuki A1 - Benetos, Athanase A1 - Labat, Carlos A1 - Sinnreich, Ronit A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Hunt, Steven C A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Barbieri, Michelangela A1 - Paolisso, Giuseppe A1 - Gadalla, Shahinaz M A1 - Savage, Sharon A A1 - Christensen, Kaare A1 - Yashin, Anatoliy I A1 - Arbeev, Konstantin G A1 - Aviv, Abraham AB -

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

VL - 9 IS - 4 ER -