A Whole-Genome Screen of a Quantitative Trait of Age-Related Maculopathy in Sibships from the Beaver Dam Eye Study

Abstract

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.

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

“…Using the broader AMD classification and GA phenotypes, we observed the strongest evidence for linkage ( ) on chromosome 5. This LOD 1 2.0 peak is 25 cM telomeric to a recent linkage finding (Schick et al 2003).…”

“…2 and 3; table 3) identified a subset of the regions observed in the singlepoint analysis. With the AMD and GA traits, multipoint analysis modestly increased the evidence for linkage on chromosome 1 ( ; ) near the peak LOD p 2.13 P p .0009 that was reported in other affected relative pair studies Majewski et al 2003;Seddon et al 2003); it also increased the evidence for linkage on chromosome 5 ( ; ) near the linkage LOD p 2.55 P p .0003 finding of Schick et al (2003). In contrast, evidence for linkage was weakened for the chromosome 9 and 22 findings.…”

“…Four groups have recently published whole genome scan linkage results; however, so far only suggestive evidence has been obtained for AMD susceptibility loci Majewski et al 2003;Schick et al 2003;Seddon et al 2003). Identification of numerous putative chromosomal locations in these studies is consistent with the underlying genetic complexity of AMD pathogenesis.…”

“…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 .…”

The complement system and age-related macular degeneration

“…Linkage studies and candidate gene screening suggest that one such locus associated with AMD may exist at 1q25-32. [20][21][22] A recent breakthrough in this research is the identification of the gene within the interval of chromosome 1 that is involved in AMD. This gene encodes CFH.…”