PT - JOURNAL ARTICLE AU - Manuel A. Rivas AU - Jukka Koskela AU - Hailiang Huang AU - Christine Stevens AU - Brandon E. Avila AU - Talin Haritunians AU - Benjamin M. Neale AU - Mitja Kurki AU - Andrea Ganna AU - Daniel Graham AU - Benjamin Glaser AU - Inga Peter AU - Gil Atzmon AU - Nir Barzilai AU - Adam P. Levine AU - Elena Schiff AU - Nikolas Pontikos AU - Ben Weisburd AU - Konrad J. Karczewski AU - Eric V. Minikel AU - Britt-Sabina Petersen AU - Laurent Beaugerie AU - Philippe Seksik AU - Jacques Cosnes AU - Stefan Schreiber AU - Bernd Bokemeyer AU - Johannes Bethge AU - NIDDK IBD Genetics consortium AU - T2D-GENES consortium AU - Graham Heap AU - Tariq Ahmad AU - Vincent Plagnol AU - Anthony W. Segal AU - Stephan Targan AU - Dan Turner AU - Paivi Saavalainen AU - Martti Farkkila AU - Kimmo Kontula AU - Matti Pirinen AU - Aarno Palotie AU - Steven R. Brant AU - Richard H. Duerr AU - Mark S. Silverberg AU - John D. Rioux AU - Rinse K. Weersma AU - Andre Franke AU - Daniel G. MacArthur AU - Chaim Jalas AU - Harry Sokol AU - Ramnik J. Xavier AU - Ann Pulver AU - Judy H. Cho AU - Dermot P.B. McGovern AU - Mark J. Daly TI - Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population AID - 10.1101/077180 DP - 2016 Jan 01 TA - bioRxiv PG - 077180 4099 - http://biorxiv.org/content/early/2016/09/25/077180.short 4100 - http://biorxiv.org/content/early/2016/09/25/077180.full AB - 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 in NOD2 and LRRK2 are 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.