1. Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene.
- Author
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Cummings AC, Jiang L, Velez Edwards DR, McCauley JL, Laux R, McFarland LL, Fuzzell D, Knebusch C, Caywood L, Reinhart-Mercer L, Nations L, Gilbert JR, Konidari I, Tramontana M, Cuccaro ML, Scott WK, Pericak-Vance MA, and Haines JL
- Subjects
- Aged, Aged, 80 and over, Apolipoproteins E genetics, Female, Genetic Linkage, Genome-Wide Association Study, Humans, Male, Alzheimer Disease genetics, Amish genetics, alpha Catenin genetics
- Abstract
To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analysed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P= 9.0 × 10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P= 0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P= 7.92 × 10-7). A very strong, genome-wide significant multipoint peak [recessive heterogeneity multipoint LOD (HLOD) = 6.14, dominant HLOD = 6.05] was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31 and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P= 1.29 × 10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analyses in isolated populations to identify novel loci for traits with complex genetic architecture., (© 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.)
- Published
- 2012
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