Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Abstract

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Fig. 1

Population structure among GEHA study and the grouping of countries into three clusters. Cluster 1: Finland; Cluster 2: Northern Europe consisting of Ukraine, Poland, Germany, Denmark, The Netherlands, United Kingdom, Belgium and France; Cluster 3: Southern Europe consisting of Italy and Greece.

Fig. 2

Genome wide linkage graphs of among 2118 sibships of the GEHA study. The blue line displays the NPL LOD scores and the yellow line the age-weighted LOD scores.

Fig. 3

Chromosomal regions linked to longevity with LOD score above 3. The blue line displays the NPL LOD scores and the yellow line the age-weighted LOD scores.

Fig. 4

Genome wide linkage graphs of among 1145 female-only sibships and 263 male-only sibships of the GEHA study. The blue line displays the NPL LOD scores and the yellow line the age-weighted LOD scores.