Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

Authors: Deelen J; Beekman M; Uh HW; Broer L; Ayers KL; Tan Q; Kamatani Y; Bennet AM; Tamm R; Trompet S; Guðbjartsson DF; Flachsbart F; Rose G; Viktorin A; Fischer K; Nygaard M; Cordell HJ; Crocco P; van den Akker EB; Böhringer S; Helmer Q; Nelson CP; Saunders GI; Alver M; Andersen-Ranberg K; Breen ME; van der Breggen R; Caliebe A; Capri M; Cevenini E; Collerton JC; Dato S; Davies K; Ford I; Gampe J; Garagnani P; de Geus EJ; Harrow J; van Heemst D; Heijmans BT; Heinsen FA; Hottenga JJ; Hofman A; Jeune B; Jonsson PV; Lathrop M; Lechner D; Martin-Ruiz C; Mcnerlan SE; Mihailov E; Montesanto A; Mooijaart SP; Murphy A; Nohr EA; Paternoster L; Postmus I; Rivadeneira F; Ross OA; Salvioli S; Sattar N; Schreiber S; Stefánsson H; Stott DJ; Tiemeier H; Uitterlinden AG; Westendorp RG; Willemsen G; Samani NJ; Galan P; Sørensen TI; Boomsma DI; Jukema JW; Rea IM; Passarino G; de Craen AJ; Christensen K; Nebel A; Stefánsson K; Metspalu A; Magnusson P; Blanché H; Christiansen L; Kirkwood TB; van Duijn CM; Franceschi C; Houwing-Duistermaat JJ; Slagboom PE

Abstract: The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (>/= 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged >/= 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Journal: Human molecular genetics
Volume: 23
Issue: 16
Pages: 4420-32
Date: April 2, 2014
PMID: 24688116
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Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, Mcnerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE (2014) Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Human molecular genetics 23: 4420-32.

Longevity Variant Associations (p-value):
  • rs4420638 (3.4e-36)
  • rs2149954 (1.74e-08)

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