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P3‐226: Dissecting genetic variation at the nicastrin locus using functional genomics
Author(s) -
Hamilton Gillian,
Powell John,
Wade-Martins Richard
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1793
Subject(s) - haplotype , biology , functional genomics , genetics , locus (genetics) , gene , genetic variation , computational biology , genomics , genome , genotype
in the elderly. While evidence for an underlying genetic etiology of AD is strong, it has proven to be quite challenging to elucidate. The APOE gene accounts for less than half of the susceptibility and thus other genetic factors are likely to be involved. Genetic heterogeneity is a major complicating factor hindering further gene identification. To overcome this problem and maximize our power to identify AD risk genes, we are studying the genetically isolated and well-defined Amish populations of middle Ohio and northern Indiana. To date we have enrolled over 1550 Amish individuals with over 100 of these having either probable or possible dementia. Methods: We have undertaken a whole-genome SNP linkage screen (Illumina Linkage Panel IVb) using 672 Amish individuals (103 with AD) within 21 sub-pedigrees ranging in total size from 18 to 157 individuals. We performed both 2-pt linkage analysis (using dominant and recessive models within the Superlink program) and a novel test of association using the MQLS test (by Thornton & McPeek), on 5,645 SNPs. Re ults: Preliminary linkage analysis found 162 SNPs with 2-pt lod scores 1.0. Suggestive linkage to AD was found for 18 SNPs across 16 independent loci (2-pt lod scores 2.0: 1q, 2p, 2q, 3q22, 3q26, 4q, 5q, 7q, 8p, 13q, 14q23, 14q24, 16p, 18q, 20q, 21q). The MQLS test also identified 284 SNPs with nominally significant p-values (p 0.05). Subsequently, we utilized the Simwalk program to perform multipoint linkage analysis for multiple 3-SNP sliding windows across each of the regions identified by the 2-pt analysis. Five of these regions continued to demonstrate strong evidence for linkage (1q, 3q22, 5q, 18q, and 21q), with three of these also demonstrating MQLS p-values 0.05 (1q, 3q22, 18q). Additional follow-up of these more narrowed regions is currently ongoing. Conclusions: Our genome scan suggests that a number of regions within our Amish population may contain AD susceptibility genes, with the strongest current evidence suggesting involvement of chr 1q, 3q, and 18q.