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PLoS Genet. 2018 May 24;14(5):e1007329. doi: 10.1371/journal.pgen.1007329. eCollection 2018 May.

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

Author information

1
Medical and Population Genetics, Broad Institute, Cambridge, MA, United States of America.
2
Department of Biomedical Data Science, Stanford University, Stanford, CA, United States of America.
3
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States of America.
4
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
5
Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
6
Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
7
Hadassah-Hebrew University Medical Center, Endocrinology and Metabolism Service Department of Internal Medicine, Jerusalem, Israel.
8
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
9
Department of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY, United States of America.
10
Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
11
Division of Medicine, University College London, London, United Kingdom.
12
UCL Genetics Institute, University College London, London, United Kingdom.
13
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
14
Gastroenterology Department, Saint-Antoine Hospital, AP-HP, UPMC Univ Paris, Paris, France.
15
Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany.
16
Gastroenterology Practice, Minden, Germany.
17
IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter, United Kingdom.
18
Peninsula College of Medicine and Dentistry, Exeter, United Kingdom.
19
Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
20
Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
21
Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
22
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
23
Department of Neurology, Massachusetts General Hospital, Boston, MA, United States of America.
24
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America.
25
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America.
26
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
27
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States of America.
28
Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada.
29
Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
30
Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
31
Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
32
Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom.
33
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
34
Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, United States of America.
35
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
36
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
37
Icahn School of Medicine at Mount Sinai, Dr Henry D. Janowitz Division of Gastroenterology, New York, NY, United States of America.

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 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<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 (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.

PMID:
29795570
PMCID:
PMC5967709
DOI:
10.1371/journal.pgen.1007329
[Indexed for MEDLINE]
Free PMC Article

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