RT Journal Article SR Electronic T1 Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population JF bioRxiv FD Cold Spring Harbor Laboratory SP 077180 DO 10.1101/077180 A1 Manuel A. Rivas A1 Jukka Koskela A1 Hailiang Huang A1 Christine Stevens A1 Brandon E. Avila A1 Talin Haritunians A1 Benjamin M. Neale A1 Mitja Kurki A1 Andrea Ganna A1 Daniel Graham A1 Benjamin Glaser A1 Inga Peter A1 Gil Atzmon A1 Nir Barzilai A1 Adam P. Levine A1 Elena Schiff A1 Nikolas Pontikos A1 Ben Weisburd A1 Konrad J. Karczewski A1 Eric V. Minikel A1 Britt-Sabina Petersen A1 Laurent Beaugerie A1 Philippe Seksik A1 Jacques Cosnes A1 Stefan Schreiber A1 Bernd Bokemeyer A1 Johannes Bethge A1 NIDDK IBD Genetics consortium A1 T2D-GENES consortium A1 Graham Heap A1 Tariq Ahmad A1 Vincent Plagnol A1 Anthony W. Segal A1 Stephan Targan A1 Dan Turner A1 Paivi Saavalainen A1 Martti Farkkila A1 Kimmo Kontula A1 Matti Pirinen A1 Aarno Palotie A1 Steven R. Brant A1 Richard H. Duerr A1 Mark S. Silverberg A1 John D. Rioux A1 Rinse K. Weersma A1 Andre Franke A1 Daniel G. MacArthur A1 Chaim Jalas A1 Harry Sokol A1 Ramnik J. Xavier A1 Ann Pulver A1 Judy H. Cho A1 Dermot P.B. McGovern A1 Mark J. Daly YR 2016 UL http://biorxiv.org/content/early/2016/09/25/077180.abstract 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.