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

International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1007329
JournalPLoS Genetics
Volume14
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Molecular Epidemiology
epidemiology
Rare Diseases
Crohn Disease
Alleles
allele
alleles
Exome
fold
Population
Founder Effect
Crohn disease
founder effect
Canavan Disease
Tay-Sachs Disease
protein
Gaucher Disease
Proteins
proteins
Genome-Wide Association Study

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, & T2D-GENES Consortium (2018). Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genetics, 14(5), [e1007329]. https://doi.org/10.1371/journal.pgen.1007329

Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. / International IBD Genetics Consortium; NIDDK IBD Genetics Consortium; T2D-GENES Consortium.

In: PLoS Genetics, Vol. 14, No. 5, e1007329, 01.05.2018.

Research output: Contribution to journalArticle

International IBD Genetics Consortium, NIDDK IBD Genetics Consortium & T2D-GENES Consortium 2018, 'Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population', PLoS Genetics, vol. 14, no. 5, e1007329. https://doi.org/10.1371/journal.pgen.1007329
International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genetics. 2018 May 1;14(5). e1007329. https://doi.org/10.1371/journal.pgen.1007329
International IBD Genetics Consortium ; NIDDK IBD Genetics Consortium ; T2D-GENES Consortium. / Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. In: PLoS Genetics. 2018 ; Vol. 14, No. 5.
@article{8862c529e552409dbfea96eb9019ce76,
title = "Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population",
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.",
author = "{International IBD Genetics Consortium} and {NIDDK IBD Genetics Consortium} and {T2D-GENES Consortium} and Rivas, {Manuel A.} and Avila, {Brandon E.} and Jukka Koskela and Hailiang Huang and Christine Stevens and Matti Pirinen and Talin Haritunians and Neale, {Benjamin M.} and Mitja Kurki and Andrea Ganna and Daniel Graham and Benjamin Glaser and Inga Peter and Gil Atzmon and Nir Barzilai and Levine, {Adam P.} and Elena Schiff and Nikolas Pontikos and Ben Weisburd and Monkol Lek and Karczewski, {Konrad J.} and Jonathan Bloom and Minikel, {Eric V.} and Petersen, {Britt Sabina} and Laurent Beaugerie and Philippe Seksik and Jacques Cosnes and Stefan Schreiber and Bernd Bokemeyer and Johannes Bethge and Graham Heap and Tariq Ahmad and Vincent Plagnol and Segal, {Anthony W.} and Stephan Targan and Dan Turner and Paivi Saavalainen and Martti Farkkila and Kimmo Kontula and Aarno Palotie and Brant, {Steven R.} and Duerr, {Richard H.} and Silverberg, {Mark S.} and Rioux, {John D.} and Weersma, {Rinse K.} and Andre Franke and Luke Jostins and Anderson, {Carl A.} and Barrett, {Jeffrey C.} and MacArthur, {Daniel G.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1371/journal.pgen.1007329",
language = "English (US)",
volume = "14",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

AU - International IBD Genetics Consortium

AU - NIDDK IBD Genetics Consortium

AU - T2D-GENES Consortium

AU - Rivas, Manuel A.

AU - Avila, Brandon E.

AU - Koskela, Jukka

AU - Huang, Hailiang

AU - Stevens, Christine

AU - Pirinen, Matti

AU - Haritunians, Talin

AU - Neale, Benjamin M.

AU - Kurki, Mitja

AU - Ganna, Andrea

AU - Graham, Daniel

AU - Glaser, Benjamin

AU - Peter, Inga

AU - Atzmon, Gil

AU - Barzilai, Nir

AU - Levine, Adam P.

AU - Schiff, Elena

AU - Pontikos, Nikolas

AU - Weisburd, Ben

AU - Lek, Monkol

AU - Karczewski, Konrad J.

AU - Bloom, Jonathan

AU - Minikel, Eric V.

AU - Petersen, Britt Sabina

AU - Beaugerie, Laurent

AU - Seksik, Philippe

AU - Cosnes, Jacques

AU - Schreiber, Stefan

AU - Bokemeyer, Bernd

AU - Bethge, Johannes

AU - Heap, Graham

AU - Ahmad, Tariq

AU - Plagnol, Vincent

AU - Segal, Anthony W.

AU - Targan, Stephan

AU - Turner, Dan

AU - Saavalainen, Paivi

AU - Farkkila, Martti

AU - Kontula, Kimmo

AU - Palotie, Aarno

AU - Brant, Steven R.

AU - Duerr, Richard H.

AU - Silverberg, Mark S.

AU - Rioux, John D.

AU - Weersma, Rinse K.

AU - Franke, Andre

AU - Jostins, Luke

AU - Anderson, Carl A.

AU - Barrett, Jeffrey C.

AU - MacArthur, Daniel G.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

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 (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.

UR - http://www.scopus.com/inward/record.url?scp=85048235952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048235952&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1007329

DO - 10.1371/journal.pgen.1007329

M3 - Article

VL - 14

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 5

M1 - e1007329

ER -