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.

Fig 1. Enrichment of alleles discovered in AJ exome sequencing project.

A) Histogram of estimated log enrichment statistic, defined as the log of the bias corrected odds ratio comparing the allele frequency in AJ population to the maximum allele frequency estimated from NFE, AFR, and AMR populations in ExAC. For each histogram bin we show a bar plot of the expected number of alleles belonging to the two groups we analyzed: 1) enriched (green) and 2) not enriched (white). B) Bar plots of estimated percentage of alleles belonging to the two groups we analyzed for all protein-coding (ALL), synonymous (SYN), protein-altering (PRA), and protein-truncating variants (PTV). An estimate of 34% of protein-coding alleles observed in AJ have a mean shift of 15-fold increased odds of the alternate allele compared to other reference populations. This observation is supported by the property that compared to intergenic variants, coding variants tend to be younger for a given frequency and the more pathogenic a variant, the younger it is, therefore tending to be population specific[13].

Fig 2. Q-Q plots of enriched alleles.

Q-Q plots of Crohn’s disease association for AJ enriched A) protein-altering (protein-truncating and missense) and B) synonymous alleles in GWAS regions; and AJ enriched C) protein-altering and D) synonymous alleles outside of GWAS regions. For each Q-Q plot variants with a corresponding p-value less than or equal to a threshold where expected number of false discoveries is equal to one are annotated. The black dashed line is y = x, and the grey shapes show 95% confidence interval under the null.

Fig 3. AJ individuals have higher CD polygenic risk score than NJ controls.

NJ: non-Jewish; AJ: Ashkenazi Jewish; CD: Crohn’s disease; PRS: polygenic risk score. A) Density plot of CD polygenic risk scores in 454 AJ (green) and 35,007 NJ(purple)controls. AJ controls have higher CD polygenic risk score than NJ controls (0.97 s.d. higher, p<10⁻¹⁶). B) Density plot of CD polygenic risk scores in 1,938 AJ (green) and 20,652 NJ CD (purple) cases (0.54 s.d. higher, p<10⁻¹⁶). For both density plots the scores have been scaled to NJ controls, thus resulting in an NJ control PRS density of mean equal to 0 and variance equal to 1 (see Online Methods). C) Ranked (decreasing order) CD associated variants by estimated contribution to the differences in genetic risk between AJ and NJ. Associated variants with estimated contribution greater than or equal to 0.01, computed as 2 log(odds ratio) (AJ frequency—NJ frequency), assuming additive effects on the log scale, are highlighted in green. Associated variants with estimated contribution less than or equal to -0.01 are highlighted in purple. Forward slashes represent a break in variants highlighted.