当前位置： SCI文献检索 > PLoS Genetics期刊下所有文献 > Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

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.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Rivas MA,Avila BE,Koskela J,Huang H,Stevens C,Pirinen M,Haritunians T,Neale BM,Kurki M,Ganna A,Graham D,Glaser B,Peter I,Atzmon G,Barzilai N,Levine AP,Schiff E,Pontikos N,Weisburd B,Lek M,Karczewski KJ,Bloom J,

doi

10.1371/journal.pgen.1007329

subject

Has Abstract

pub_date

2018-05-24 00:00:00

pages

e1007329

issue

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-17-02189

journal_volume

pub_type

杂志文章

在线工具

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