7 research outputs found
Discovery of common and rare genetic risk variants for colorectal cancer.
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest
Insurance Rating of Patients with Inflammatory Bowel Disease: Report of a Conference on Morbidity and Mortality
Patient members reported to the Crohn’s and Colitis Foundation of Canada (CCFC) about their difficulties to obtain insurance. In 1991, the Lay Board of the CCFC requested its Medical Advisory Board (MAB) to investigate this problem. At that time, insurance ratings could be illustrated by the 1985 edition of Brackenridge’s monograph on life risks. The MAB found that data on mortality were outdated. A conference on morbidity and mortality of inflammatory bowel disease (IBD) was organized by the authors and held in May 1992. Based on questionnaires to patients, evidence provided by invited speakers and the results of small group conferences, it was concluded that patients with IBD have difficulties in obtaining insurance, even though the quality of life and mortality of IBD patients is not very different from that of the general population. However, the mortality rate of the healthy insured population is lower than that of the general population, and thus much lower than that of IBD patients. Patients have a better chance to obtain insurance if there is a close cooperation between the treating physician and the medical officer of the insurance company. Changes have occurred since the conference held in May 1992. The recent edition of Brackenridge’s text (1992) provides a better prognosis but unfortunately unchanged rating for patients with IBD than did the 1985 edition. Close cooperation between the Patient Advisory Committee of the CCFC and the Executives of the Canadian Life Insurance Medical Officers Association may further improve the insurance rating of patients with IBD
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Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data
Background: The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues. Methods: Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE. Results: ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 × 10−4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029). Conclusions: Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future association studies would likely benefit from joint analysis of transcriptomes and epigenomes to better link regulatory variation with target genes
Analysis approaches for assessing ARE enrichment of stronger CRC associations with common and less frequent variants.
<p>ARE, Active Regulatory Elements; CR, Colorectal; ND, Non-digestive; Fig 1 describes the series of analyses performed examining the enrichment of ARE for more significant <i>common single</i> variant CRC associations from GWAS and <i>less frequent variant</i> set associations from an integrative epigenomic RVAM.</p
CR-specific ARE enrichment of stronger GWAS CRC p-values.
<p>Each point in this scatter plot corresponds to an enrichment result comparing CR ARE (n = 108,297) to ARE in one of the 124 non-colorectal tissues and cell-types tested. The x-axis shows the number of variants in ARE examined for the corresponding non-colorectal tissue or cell-type (n = 270,030 CR ARE variants). The y-axis is the–log 10 × the p-value from the KS test comparing the distribution of CRC association p-values for variants inside CR ARE versus those inside ARE of a non-colorectal tissue and cell-type. The size of the point corresponds to the number of ARE in the tissue or cell-type. The color of the point represents membership to an epigenomic group, based on a hierarchal clustering of the AREs. In comparison to ARE of digestive tissues (in light purple) and immune cell types (in two shades of green), CR-specific ARE did not exhibit additional enrichment. The strongest enrichment was observed for induced pluripotent stem cells (iPSCs), embryonic stem cells (ESC), and ESC-derived cells, and Brain cell-types. The red dash line corresponds to the Bonferroni p-value threshold correcting for 124 comparisons (0.05/124 = 4 × 10<sup>−4</sup>). The red solid line corresponds to the Bonferroni p-value threshold correcting for 19 epigenomic group comparisons (0.05/19 = 3 × 10<sup>−3</sup>).</p
ARE enrichment of stronger GWAS CRC p-values.
<p>Each point in this scatter plot corresponds to one of the 127 tissues and cell-types examined for ARE enrichment of more significant single common variant association p-values with CRC. The x-axis shows the number of variants in ARE examined for the corresponding tissue or cell-type. The y-axis scale is the–log 10 × the p-value from the KS test comparing the distribution of CRC-variant association p-values for variants inside and outside of ARE. The size of the point corresponds to the number of ARE in the tissue or cell-type. The color of the point represents membership to an epigenomic group, based on a hierarchal clustering of the AREs. ARE of digestive tissues (in light purple) and immune cell types (in two shades of green) were more significantly enriched (lower KS test p-values). The range of ARE and ARE variants spreads across the high and low KS P-values, suggesting that the difference in number of ARE across tissues is not biasing the enrichment results. The red dash line corresponds to the Bonferroni p-value threshold correcting for 127 comparisons (0.05/127 = 4 × 10<sup>−4</sup>).</p
Rare variant test set.
<p>Variant sets were anchored on Transcription Start Sites (TSS) as defined by protein coding gene transcripts with validated RefSeq records. If a gene had multiple TSS, the 5'-most and 3'-most TSS were used as anchors. Accordingly, variants overlapping ARE within 200Kb of a TSS were pooled into a test set.</p