Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

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Int IBD Genetics Consortium , NIDDK IBD Genetics Consortium , T2D-Genes Consortium , Rivas , M A , Koskela , J , Pirinen , M , Kurki , M , Saavalainen , P , Farkkila , M , Kontula , K , Palotie , A & Daly , M J 2018 , ' Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population ' , PLoS Genetics , vol. 14 , no. 5 , 1007329 . https://doi.org/10.1371/journal.pgen.1007329

Title: Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population
Author: Int IBD Genetics Consortium; NIDDK IBD Genetics Consortium; T2D-Genes Consortium; Rivas, Manuel A.; Koskela, Jukka; Pirinen, Matti; Kurki, Mitja; Saavalainen, Paivi; Farkkila, Martti; Kontula, Kimmo; Palotie, Aarno; Daly, Mark J.
Other contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Mathematics and Statistics
University of Helsinki, Massachusetts General Hospital
University of Helsinki, Research Programs Unit
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Department of Medicine
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Centre of Excellence in Complex Disease Genetics



















Date: 2018-05
Language: eng
Number of pages: 25
Belongs to series: PLoS Genetics
ISSN: 1553-7404
DOI: https://doi.org/10.1371/journal.pgen.1007329
URI: http://hdl.handle.net/10138/245419
Abstract: 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 fourfold 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
Subject: INFLAMMATORY-BOWEL-DISEASE
SUSCEPTIBILITY LOCI
ULCERATIVE-COLITIS
STANDING VARIATION
ASSOCIATION
VARIANTS
MUTATION
SELECTION
LEPROSY
ARCHITECTURE
1184 Genetics, developmental biology, physiology
3121 General medicine, internal medicine and other clinical medicine
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