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

View ORCID ProfileManuel A. Rivas, Jukka Koskela, Hailiang Huang, Christine Stevens, Brandon E. Avila, Talin Haritunians, Benjamin M. Neale, Mitja Kurki, Andrea Ganna, Daniel Graham, Benjamin Glaser, Inga Peter, Gil Atzmon, Nir Barzilai, Adam P. Levine, Elena Schiff, Nikolas Pontikos, Ben Weisburd, Konrad J. Karczewski, Eric V. Minikel, Britt-Sabina Petersen, Laurent Beaugerie, Philippe Seksik, Jacques Cosnes, Stefan Schreiber, Bernd Bokemeyer, Johannes Bethge, NIDDK IBD Genetics consortium, T2D-GENES consortium, Graham Heap, Tariq Ahmad, Vincent Plagnol, Anthony W. Segal, Stephan Targan, Dan Turner, Paivi Saavalainen, Martti Farkkila, Kimmo Kontula, Matti Pirinen, Aarno Palotie, Steven R. Brant, Richard H. Duerr, Mark S. Silverberg, John D. Rioux, Rinse K. Weersma, Andre Franke, Daniel G. MacArthur, Chaim Jalas, Harry Sokol, Ramnik J. Xavier, Ann Pulver, Judy H. Cho, Dermot P.B. McGovern, Mark J. Daly
doi: https://doi.org/10.1101/077180
Manuel A. Rivas
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
2Department of Biomedical Data Science, Stanford, CA, USA
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  • ORCID record for Manuel A. Rivas
Jukka Koskela
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Hailiang Huang
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Christine Stevens
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
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Brandon E. Avila
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Talin Haritunians
4F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Benjamin M. Neale
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Mitja Kurki
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Andrea Ganna
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Daniel Graham
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
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Benjamin Glaser
5Hadassah-Hebrew University Medical Center, Endocrinology and Metabolism Service Department of Internal Medicine, Jerusalem, Israel
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Inga Peter
6Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Gil Atzmon
7Department of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
8Faculty of Natural Sciences, University of Haifa, Haifa, Israel
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Nir Barzilai
7Department of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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Adam P. Levine
9Division of Medicine, University College London, London, UK
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Elena Schiff
9Division of Medicine, University College London, London, UK
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Nikolas Pontikos
9Division of Medicine, University College London, London, UK
10UCL Genetics Institute, University College London, London, UK
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Ben Weisburd
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Konrad J. Karczewski
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Eric V. Minikel
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Britt-Sabina Petersen
11Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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Laurent Beaugerie
12Gastroenterology Department, Saint-Antoine Hospital, AP-HP, UPMC Univ Paris 06, Paris, France
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Philippe Seksik
12Gastroenterology Department, Saint-Antoine Hospital, AP-HP, UPMC Univ Paris 06, Paris, France
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Jacques Cosnes
12Gastroenterology Department, Saint-Antoine Hospital, AP-HP, UPMC Univ Paris 06, Paris, France
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Stefan Schreiber
13Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
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Bernd Bokemeyer
14Gastroenterology Practice, Minden, Germany
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Johannes Bethge
13Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
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Graham Heap
15IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter, UK
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Tariq Ahmad
16Peninsula College of Medicine and Dentistry, Exeter, UK
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Vincent Plagnol
10UCL Genetics Institute, University College London, London, UK
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Anthony W. Segal
9Division of Medicine, University College London, London, UK
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Stephan Targan
4F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Dan Turner
17Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
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Paivi Saavalainen
18Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
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Martti Farkkila
19Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
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Kimmo Kontula
20Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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Matti Pirinen
21Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
22Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland
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Aarno Palotie
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
21Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
23Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
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Steven R. Brant
24Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
25Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
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Richard H. Duerr
26Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
27Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
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Mark S. Silverberg
28Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
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John D. Rioux
29Research Center, Montreal Heart Institute, Montréal, Québec, Canada
30Department of Medicine, Université de Montréal, Montréal, Québec, Canada
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Rinse K. Weersma
31Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
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Andre Franke
11Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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Daniel G. MacArthur
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Chaim Jalas
32Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, USA.
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Harry Sokol
12Gastroenterology Department, Saint-Antoine Hospital, AP-HP, UPMC Univ Paris 06, Paris, France
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Ramnik J. Xavier
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
33Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Ann Pulver
34Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Judy H. Cho
35Icahn School of Medicine at Mount Sinai, Dr Henry D. Janowitz Division of Gastroenterology, New York, New York, USA
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Dermot P.B. McGovern
4F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Mark J. Daly
1Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
3Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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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. 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.

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

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