Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population
Authors: Rivas Manuel A. , Koskela Jukka , Huang Hailiang , Stevens Christine , Avila Brandon E. , Haritunians Talin , Neale Benjamin M. , Kurki Mitja , Ganna Andrea , Graham Daniel , Glaser Benjamin , Peter Inga , Atzmon Gil , Barzilai Nir , Levine Adam P. , Schiff Elena , Pontikos Nikolas , Weisburd Ben , Karczewski Konrad J. , Minikel Eric V. , Petersen Britt-Sabina , Beaugerie Laurent , Seksik Philippe , Cosnes Jacques , Schreiber Stefan , Bokemeyer Bernd , Bethge Johannes ,   NIDDK IBD Genetics consortium,   T2D-GENES consortium, Heap Graham , Ahmad Tariq , Plagnol Vincent , Segal Anthony W. , Targan Stephan , Turner Dan , Saavalainen Paivi , Farkkila Martti , Kontula Kimmo , Pirinen Matti , Palotie Aarno , Brant Steven R. , Duerr Richard H. , Silverberg Mark S. , Rioux John D. , Weersma Rinse K. , Franke Andre , MacArthur Daniel G. , Jalas Chaim , Sokol Harry , Xavier Ramnik J. , Pulver Ann , Cho Judy H. , McGovern Dermot P.B. , Daly Mark J. 
Published: September 2016

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim. We estimate that 30% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 7.6-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 151 AJ enriched protein-altering alleles that overlap with “pathogenic” ClinVar alleles, including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn’s disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically evaluate whether strong acting rare alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn’s disease in AJ, and find that ten rare genetic risk factors inNOD2andLRRK2are strongly enriched in AJ, including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10−16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC to pinpoint genetic variation that contributes to variable disease predisposition across populations.