Age-Related Macular Degeneration—a Genome Scan in Extended Families

Abstract

We performed a genomewide scan and genetic linkage analysis, to identify loci associated with age-related macular degeneration (AMD). We collected 70 families, ranging from small nuclear families to extended multigenerational pedigrees and consisting of a total of 344 affected and 217 unaffected members available for genotyping. We performed linkage analyses using parametric and allele-sharing models. We performed the analyses on the complete pedigrees but also subdivided the families into nuclear pedigrees. Finally, to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (neovascular AMD and geographic atrophy) and by age of affected family members at the time of our evaluation. We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. In the combined sample, we have detected the following loci with scores exceeding a LOD=2 cutoff under at least one of the models considered: 1q31 (HLOD=2.07 at D1S518), 3p13 (HLOD=2.19 at D3S1304/D3S4545), 4q32 (HLOD=2.66 at D4S2368, for the subset of families with predominantly dry AMD), 9q33 (LODZlr=2.01 at D9S930/D9S934), and 10q26 (HLOD=3.06 at D10S1230). Using correlation analysis, we have found a statistically significant correlation between LOD scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of AMD. Our study has identified new loci that should be considered in future mapping and mutational analyses of AMD and has strengthened the evidence in support of loci suggested by other studies.

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

“…Previously several groups reported that the AMD 10q locus has been associated with both GA and wet AMD phenotypes. [13][14][15][16] Our expanded findings are in agreement with these findings.…”

Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late stage disease

“…We also observed suggestive evidence for linkage with the CNV phenotype on chromosomes 9 and 19. The chromosome 9 signal overlaps with two previously reported findings Majewski et al 2003). Using the broader AMD classification and GA phenotypes, we observed the strongest evidence for linkage ( ) on chromosome 5.…”

“…With the broad AMD phenotype, we observed suggestive evidence of linkage on chromosome 1, at marker GATA51H01 ( ; ; 205 LOD p 1.55 P p .004 cM). Linkage in this region has been reported in three other affected relative pair studies Majewski et al 2003;Seddon et al 2003) and in the study of a single large pedigree with AMD (Klein et al 1998).…”

“…To evaluate whether there was evidence for interaction between different loci, we calculated Pearson's correlation coefficient between the LOD score contributions of each family to different pairs of loci. When testing for interaction, we used a two-sided test, similar to the analysis performed by Majewski et al (2003).…”

“…A followup genome scan, including some of the same samples, however, indicated linkage to 1q31 and 17q25 . Recently, three independent genomewide scans have provided evidence for a number of suggestive AMD susceptibility loci, which include the locus at 1q (Majewski et al 2003;Schick et al 2003;Seddon et al 2003). Recently, a Gln5345Arg change in the HEMI-CENTIN-1 gene was reported to be associated with the disease in the original AMD family that exhibited linkage to chromosome 1q25-31 .…”