Genomic Convergence to Identify Candidate Genes for Alzheimer Disease on Chromosome 10

A broad region of chromosome 10 (chr10) has engendered continued interest in the etiology of late-onset Alzheimer Disease (LOAD) from both linkage and candidate gene studies. However, there is a very extensive heterogeneity on chr10. We converged linkage analysis and gene expression data using the concept of genomic convergence that suggests that genes showing positive results across multiple different data types are more likely to be involved in AD. We identified and examined 28 genes on chr10 for association with AD in a Caucasian case-control dataset of 506 cases and 558 controls with substantial clinical information. The cases were all LOAD (minimum age at onset >= 60 years). Both single marker and haplotypic associations were tested in the overall dataset and eight subsets defined by age, gender, ApoE, and clinical status. PTPLA showed allelic, genotypic, and haplotypic association in the overall dataset. SORCS1 was significant in the overall data sets (p = 0.0025) and most significant in the female subset (allelic association p = 0.00002, a three-locus haplotype had p = 0.0005). Odds ratio of SORCS1 in the female subset was 1.7 (p < 0.0001). SORCS1 is an interesting candidate gene involved in the A(3 pathway. Therefore, genetic variations in PTPLA and SORCS1 may be associated and have modest effect to the risk of AD by affecting A beta pathway. The replication of the effect of these genes in different study populations and search for susceptible variants and functional studies of these genes are necessary to get a better understanding of the roles of the genes in Alzheimer disease. Hum Mutat 30, 463-471, 2009. (C) 2008 Wiley-Liss, Inc.