P1‐100: Genome‐wide association study for late‐onset Alzheimer's disease in the Mid‐Western U.S. Amish

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Late Onset Alzheimer disease (LOAD) is the leading cause of dementia in the elderly. While evidence for an underlying genetic etiology of LOAD is strong, it has proven to be quite challenging to elucidate. Polymorphisms in APOE account 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 LOAD risk genes, we are studying the genetically isolated and well-defined Amish populations of middle Ohio and northern Indiana. To date we have enrolled ∼2200 Amish individuals with 132 of these having either probable or possible dementia. Through the use of the Anabaptist Genealogy Database (AGDB), we have accurately defined the kinship coefficients and the family structure among our participants. We performed a genome-wide association study (Affymetrix Human SNP Array 6.0) on 830 successfully genotyped Amish individuals (125 with LOAD). We also genotyped APOE in 823 individuals (127 with LOAD). Analyses were performed using the MQLS test, a novel test of association, which uses kinship coefficients to correct for relatedness (Thornton & McPeek). LOAD was significantly associated with APOE (p < 9.0x10) in our Amish population except for the Adams County, Indiana, community (p < 0.55). For the GWAS, 614,957 SNPs were analyzed following extensive QC procedures. Using the MQLS test, our most significant association (p < 1.7 x 10) was at rs1236195 on chromosome 13 in SPATA13, a spermatogenesis gene. Fourteen additional SNPs had p-values <1x10, but none are near known or strongly suspected AD loci (APP, PS1, PS2, PICALM, CLU, CR1). APOE seems to be a genetic risk factor for LOAD in some of the Amish communities, but also suggests genetic heterogeneity. The GWAS results suggest novel non-APOE genetic effects for LOAD in our Amish dataset, identifying multiple loci for further detailed analysis. We have also done linkage analysis in this dataset, which indicates additional regions of interest, to complement the association results.

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