Biology subjects

Miles Parkes

Publications and source records attributed to Miles Parkes.

3 recordsLinked to original sources

bioRxiv2016

Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association at ADCY7

In order to further resolve the genetic architecture of the inflammatory bowel diseases, ulcerative colitis and Crohns disease, we sequenced the whole genomes of 4,280 patients at low coverage, and compared them to 3,652 previously sequenced population controls across 73.5 million variants. To increase power we imputed from these sequences into new and existing GWAS cohorts, and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles risk of ulcerative colitis, and offers insight into a new aspect of disease biology. Despite good statistical power, we did not identify any other new low-frequency risk variants, and found that such variants as a class explained little heritability. We did detect a burden of very rare, damaging missense variants in known Crohns disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve our understanding of the biology of complex diseases.

Genetics↗

bioRxiv2016

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Genetic association studies have identified 210 risk loci for inflammatory bowel disease, which have revealed fundamental aspects of the molecular biology of the disease, including the roles of autophagy and Th17 cell signaling and development. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 26 new genome-wide significant loci, three of which contain integrin genes that encode molecules in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are also correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at two previously implicated integrin loci (ITGAL, ICAM1). In all four cases, the stimulus-dependent expression increasing allele also increases disease risk. We applied summary statistic fine-mapping and identified likely causal missense variants in the primary immune deficiency gene PLCG2 and the negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes and pathways of relevance to therapeutic target identification and prioritization.

Genomics↗

bioRxiv2015

Association mapping of inflammatory bowel disease loci to single variant resolution

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder that affects millions worldwide. Genome-wide association studies (GWAS) have identified 200 IBD-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 IBD loci using high-density genotyping in 67,852 individuals. Of the 139 independent associations identified in these regions, 18 were pinpointed to a single causal variant with >95% certainty, and an additional 27 associations to a single variant with >50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription factor binding sites (n=3) and tissue specific epigenetic marks (n=10), with the latter category showing enrichment in specific immune cells among associations stronger in CD and gut mucosa among associations stronger in UC. The results of this study suggest that high-resolution, fine-mapping in large samples can convert many GWAS discoveries into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Genetics↗