Genetic Studies of Alzheimer's Disease in Jewish and Arab Populations

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Most discoveries of the genetic basis of Alzheimer disease (AD) were made in Caucasians of European ancestry (EAs) and required samples between 10,000 and 150,000 subjects to detect them. We and others have demonstrated that discovery of AD risk variants can be accomplished in more genetically homogeneous cohorts comprising several thousand or fewer subjects. Studies of non-EA populations also afford the opportunity to discover variants that are relatively rare or absent in EAs and that display a smaller effect size in EAs due to modification by other genes and environmental factors. We will focus on Jews and Arabs currently living in Israel who are descended from the Middle East and North Africa (MENA). Although MENA Jews assimilated to some extent with their non-Jewish neighbors, they have maintained a distinctive genetic profile that reflects some admixture with non-Jews, ancient Jewish background, and a unique component reflecting genetic drift and new mutations during the last two millennia. Our previous studies of Arabs living in the Israeli village called Wadi Ara revealed a genome-wide significant association for AD with ACE, were central to the establishment of SORL1 as an AD gene, and contributed to a trans-ethnic GWAS leading to the discovery of several novel AD genes. In this project, we will leverage the genetic architecture of MENA Jews and Israeli-Arabs, as well as their distinctive environmental exposures and lifestyles, to promote discovery of AD-related genes and variants. Specifically, we will recruit 3,000 MENA Jews at three sites in Israel, as well as 1,000 Israeli-Arabs located in multiple villages (equal numbers of AD cases and controls in the total sample). We will obtain from each participant a blood specimen for DNA and biomarker studies, and phenotypic data including clinical, cognitive test, medical history and lifestyle information, as well as brain MRI data for a portion of the sample. DNA specimens will be whole genome sequenced (WGS). WGS data will be processed using pipelines established by the Alzheimer Disease Sequencing Project (ADSP). We will conduct a GWAS for AD using admixture mapping and methods for single variant and gene-based tests. Top-findings will be replicated in Ashkenazi Jewish and non-Jewish datasets assembled by the Alzheimer Disease Genetics Consortium and ADSP using trans-ethnic analysis and approaches that focus on variants affecting protein structure, transcription, and gene expression. We will also conduct GWAS for age at onset and AD biomarkers using single outcome and pleiotropy models. Next, we will identify gene targets of the top-ranked SNPs by performing expression quantitative trait locus analysis using locally derived and publicly available data containing genotype and gene expression data in brain and other tissues, and establish functional connections among the top-ranked SNPs and genes using pathway, co- expression network, and Mendelian randomization analysis. Finally, we will evaluate the association of viruses detected in WGS data with AD using machine learning methods and regression models. We expect that this project will identify novel targets for development of effective drugs to treat or retard processes leading to AD.