Monkol Lek, Inga Peter, Steven R. Brant, Harry Sokol, Jonathan M. Bloom, Konrad J. Karczewski, Ann E. Pulver, Benjamin Glaser, Gil Atzmon, Stefan Schreiber, Chaim Jalas, Christine Stevens, Mark S. Silverberg, Richard H. Duerr, Tariq Ahmad, Carl A. Anderson, Dermot P.B. McGovern, Jeffrey C. Barrett, Jacques Cosnes, Daniel B. Graham, Elena R. Schiff, Eric Vallabh Minikel, Mark J. Daly, Andre Franke, Talin Haritunians, Brandon E Avila, Nir Barzilai, Andrea Ganna, Benjamin M. Neale, Martti Färkkilä, Philippe Seksik, Rinse K. Weersma, Daniel G. MacArthur, Mitja I. Kurki, Ben Weisburd, Aarno Palotie, Hailiang Huang, Kimmo Kontula, Jukka Koskela, Päivi Saavalainen, Stephan R. Targan, Ramnik J. Xavier, Luke Jostins, Graham A. Heap, Dan Turner, Bernd Bokemeyer, Britt-Sabina Petersen, Nikolas Pontikos, John D. Rioux, Laurent Beaugerie, Matti Pirinen, Adam P. Levine, Vincent Plagnol, Judy H. Cho, Anthony W. Segal, Manuel A. Rivas, Johannes Bethge, Institute for Molecular Medicine Finland, Doctoral Programme in Population Health, Department of Mathematics and Statistics, Biostatistics Helsinki, Centre of Excellence in Complex Disease Genetics, Doctoral Programme in Mathematics and Statistics, Research Programs Unit, Immunomics, Immunobiology Research Program, Department of Medical and Clinical Genetics, Medicum, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Aarno Palotie / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Statistical and population genetics, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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 (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, 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 attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size 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 enriched in AJ (p < 0.005), 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, Author summary The Ashkenazim are a people with ancestry in northern-European Jewish groups. A founder effect caused a bottleneck in this population approximately one thousand years ago, resulting in a group of enriched alleles in their genetic makeup. A higher documented prevalence of Crohn’s Disease in the Ashkenazim indicates that some enriched alleles may confer risk of having this disease. By studying which genes are enriched, and which of these contribute to Crohn’s Disease risk, we are better able to understand the genetic architecture of the affected population, and of the disease itself. Further, we are able to develop a resource containing tables of significantly enriched alleles that are known or suspected to contribute to other disease.