Identification of Novel Candidate Genes for Alzheimer's Disease by Autozygosity Mapping using Genome Wide SNP Data

Article type: Research Article

Authors: Sherva, Richard^a | Baldwin, Clinton T.^{a; c} | Inzelberg, Rivka^d | Vardarajan, Badri^a | Cupples, L. Adrienne^e | Lunetta, Kathryn^e | Bowirrat, Abdalla^g | Naj, Adam^h | Pericak-Vance, Margaret^h | Friedland, Robert P.ⁱ | Farrer, Lindsay A.^{a; b; e; f; *}

Affiliations: [a] Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA | [b] Departments of Neurology, Ophthalmology, and Genetics & Genomics, Boston University School of Medicine, Boston, MA, USA | [c] Center for Human Genetics, Boston University School of Medicine, Boston, MA, USA | [d] Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer and Sackler, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel | [e] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [f] Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA | [g] Department of Neurology and Neurophysiology, Ziv Medical Center, Safed, Israel | [h] John P. Hussman Institute for Human Genomics, University of Miami Milller School of Medicine, Miami, FL, USA | [i] Department of Neurology, University of Louisville, Louisville, KY, USA

Correspondence: [*] Correspondence to: Lindsay A. Farrer, Boston University School of Medicine, Genetics L-320, 72 East Concord Street, Boston, MA 02118, USA. Tel.: +1 617 638 5393; Fax: +1 617 638 4275; Email farrer@bu.edu.

Abstract: Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E ε4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nucleotides polymorphisms (SNPs) which were used to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although a high degree of relatedness was evident in both AD cases and controls, controls were significantly more related and contained more autozygous regions than AD cases (p = 0.004). Eight autozygous regions on seven different chromosomes were more frequent in controls than the AD cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD. The association with rs3130283 in AGPAT1 on chromosome 6 was observed in a meta-analysis of seven genome-wide association study (GWAS) datasets. Analysis of the full Wadi Ara GWAS dataset revealed 220 SNP associations with AD at p ≤ 10 −5, and seven of these were confirmed in the replication GWAS datasets (p < 0.05). The unique population structure of Wadi Ara enhanced efforts to identify genetic variants that might partially explain the high prevalence of AD in the region. Several of these variants show modest evidence for association in other Caucasian populations.

Keywords: Alzheimer's disease, genome-wide association study, meta-analysis, population groups

DOI: 10.3233/JAD-2010-100714

Journal: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 349-359, 2011