25 research outputs found
Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
No full textGenome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al
Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts
No full textBackground: DLG5 p. R30Q has been reported to be associated with Crohn disease ( CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD.
Methods: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women.
Results: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p= 0.049, OR= 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR= 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p= 0.010, OR= 0.86, 95% CI 0.76 to 0.97), but not in men.
Conclusion: DLG5 30Q is associated with a small reduction in risk of CD in women
Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population
No full textAs 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 fourfold 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, pPeer reviewe
Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
No full textUsing the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
Migraine, inflammatory bowel disease and celiac disease: a Mendelian randomization study
No full textObjectiveTo assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BackgroundMigraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.MethodsLinkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.ResultsMigraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99–1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99–1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96–1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79–1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00–1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92–0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02–1.29, p = 0.025). However, the results were not significant after multiple testing correction.ConclusionsWe found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.Genetics of disease, diagnosis and treatmen
The impact of different DNA extraction kits and laboratories upon the assessment of human gut microbiota composition by 16S rRNA gene sequencing
No full textPeer reviewe
Genetic risk variants in intestinal inflammatory disorders
No full textPhDThis thesis includes work on the genetics of intestinal inflammatory disorders, concentrating
on coeliac disease and Crohn’s disease. It explores how common genetic variants influence
risk of complex phenotypes including immunological intolerance to gluten (coeliac disease)
and intolerance to therapeutic agents (azathioprine and mercaptopurine) used in the
treatment of intestinal inflammatory diseases. Finally it presents work aiming to move from
genetic associations with complex phenotypes to understanding of how these variants
modulate immunological processes.
Results of a large genome wide association study that identified more than 13 new genetic risk
regions influencing susceptibility to coeliac disease are presented. Results of a genome wide
association study of azathioprine and 6-mercaptopurine-induced pancreatitis in inflammatory
bowel disease-affected individuals are presented. Finally, a cell cytokine release assay for the
prostaglandin EP4 receptor was developed, with a view to investigating how SNPs associated
with Crohn’s disease in the 5p13.1 region influence EP4 receptor signalling and contribute to
disease pathogenesis. This work highlights some of the challenges in moving from SNP-disease
associations identified in GWASs to understanding how genetic variants change biological
processes
Multiple Epistasis Interactions Within MHC Are Associated With Ulcerative Colitis
No full textpeer reviewedSuccessful searching for epistasis is much challenging, which generally requires very large sample sizes and/or very dense marker information. We exploited the largest Crohn's disease (CD) dataset (18,000 cases + 34,000 controls) and ulcerative colitis (UC) dataset (14,000 cases + 34,000 controls) to date. Leveraging its dense marker information and the large sample size of this IBD dataset, we employed a two-step approach to exhaustively search for epistasis. We detected abundant genome-wide significant (p < 1 x 10(-13)) epistatic signals, all within the MHC region. These signals were reduced substantially when conditional on the additive background, but still nine pairs remained significant at the lmmunochip-wide level (P < 1.1 x 10(-8)) in conditional tests for UC. All these nine epistatic interactions come from the MHC region, and each explains on average 0.15 of the phenotypic variance. Eight of them were replicated in a replication cohort. There are multiple but relatively weak interactions independent of the additive effects within the MHC region for UC. Our promising results warrant the search for epistasis in large data sets with dense markers, exploiting dependencies between markers
Genomic selection in dairy cattle
No full textThe objectives of this Ph.D. thesis were (1) to optimise genomic selection in dairy cattle with respect to the accuracy of predicting total genetic merit and (2) to optimise a dairy cattle breeding program using genomic selection. The study was performed using a combination of real data sets and simulations. Real data sets consisted of dense marker genotypes of progeny tested bulls that had accurate phenotypes derived from their daughters’ performance records. Through cross-validation, the reliability of genomic predictions was assessed for Bayesian models that fitted either marker genotypes, ancestral haplotypes or genomic relationships. Haplotype-based methods gave the most reliable predictions and provided opportunities to limit computer requirements for analysing very large data sets. The reliability of genomic predictions across breeds was studied using simulated marker data. The data was simulated such that it showed the same the patterns of linkage disequilibrium (LD) as observed within and between Holstein, Angus, and Jersey cattle from the Netherlands, Australia, and New Zealand. It was concluded that the most reliable genomic predictions can be obtained when the reference populations of each breed are combined, whereas for diverged breeds at least 300,000 markers are required to ensure that the LD between markers and QTL persists across breeds. Using a simulated genomic selection scheme, it was shown that the annual rate of genetic gain in dairy cattle may double compared to current progeny test schemes, without compromising the rate of inbreeding. To achieve such a high rate of genetic gain, the generation interval needs to be reduced significantly, as young bulls will prove to be superior to progeny tested bulls. It is expected that in the near future many animals will be genotyped and very high marker densities will be inferred by imputation techniques. This may result in genomic predictions that are persistent across breeds and generations. Large scale genotyping of cows may enable genomic selection for novel traits and the integration of genomic information in herd management processes
