Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

Abstract

Excessive familial clustering of age related macular degeneration (ARMD) has established the importance genetic factors in the etiology of ARMD. The aim of this study was to examine the genetic basis of ARMD. The authors conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale. Model-free linkage analysis was performed, and tests of heterogeneity and epistasis were conducted. The authors found evidence of a major locus on chromosome 15q. This locus was present as a weak linkage signal in their previous genome scan for ARMD, in the Beaver Dam Eye Study sample, but is otherwise novel. In this genome scan, they observed a total of 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11, and 20q13), with a nominal multipoint significance level of P ≤ .01 or LOD ≥ 1.18. Family-by-family analysis of the data, performed using model-free linkage methods, suggested that there is evidence of heterogeneity in these families. The authors conducted tests for heterogeneity, which suggest that ARMD susceptibility loci on chromosomes 9p24, 10q26, and 15q21 are not present in all families. In summary, this study shows evidence for a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD.—Valérie Biousse