Abstract
Tu1840 - Insights into the Genetic Epidemiology of Crohn's and Rare Diseases in the Ashkenazi Jewish Population
Highlights
Genetic population isolates like the Ashkenazim, Jews who trace their ancestry to eleventh century central European Jewish groups[1], have previously facilitated the mapping of alleles contributing to human disease predisposition[2,3,4,5]
Given the increased prevalence of Crohn’s disease in the Ashkenazi Jewish (AJ) population, our global sequencing efforts had included 5,652 individuals self-reporting as Jewish and, as we aimed to focus on variation observed in the AJ population in comparison to reference populations in ExAC[9,11] (including non-Finnish Europeans (NFE), Latino (AMR), and African/AfricanAmerican (AFR)) populations, we chose a model-based approach to estimate the ancestry of the study population using ADMIXTURE[12]
As we were interested in computing an enrichment statistic that would not be affected by possible admixture, we obtained alternate allele frequency estimates by restricting the enrichment analysis to the 2,178 non-Inflammatory Bowel Disease (IBD) Ashkenazi Jewish individuals that passed QC and relatedness filtering and had AJ ancestry fraction of > 0.9
Summary
Genetic population isolates like the Ashkenazim, Jews who trace their ancestry to eleventh century central European Jewish groups[1], have previously facilitated the mapping of alleles contributing to human disease predisposition[2,3,4,5]. The documented 2–4 fold enrichment of Crohn’s Disease (CD) prevalence in the Ashkenazi Jewish (AJ) population[6,7] motivated the use of exome sequencing and genome-wide array data to evaluate the degree to which bottleneck-enriched protein-altering alleles and unequivocally implicated common variants contribute an excess CD genetic risk to AJ[6]. We provide a frequency resource of protein-coding alleles from over 2,000 non-CD AJ individuals with low admixture that will serve to improve interpretation of rare disease risk alleles in the AJ population and which we employ to discover new Crohn’s risk alleles by comparison to 1855 AJ Crohn’s cases
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