Abstract
Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
Highlights
Ashkenazi Jews (AJs) comprise a single genetic community of individuals of Eastern and Central European descent
Higher frequencies of particular mutations strongly associated with common diseases, such as breast cancer (BRCA1 185delAG) [7] and Parkinson’s disease (LRRK2 G2019S) [8] have been detected in AJ compared to nonJewish peoples of Europe (NJ)
We showed that genetic risks associated with Crohn’s disease (CD) in the AJ population for the 22 most frequently replicated variants were similar to those reported in NJ populations [19] and, are unlikely to explain the excess disease prevalence in individuals of AJ descent
Summary
Ashkenazi Jews (AJs) comprise a single genetic community of individuals of Eastern and Central European descent. It has been demonstrated that the genomes of individuals with one to four grandparents of Jewish descent carry an unambiguous signature of their heritage allowing a perfect inference of their Jewish ancestry [1]. Jewish populations represent a series of geographical clusters with each group demonstrating Middle Eastern ancestry and variable admixture with European populations [2,3]. Higher frequencies of particular mutations strongly associated with common diseases, such as breast cancer (BRCA1 185delAG) [7] and Parkinson’s disease (LRRK2 G2019S) [8] have been detected in AJ compared to NJ. A three-phase genome-wide association study (GWAS) conducted in an AJ population has identified a novel region on 6q22.33 associated with familial breast cancer risk [9]
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