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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, TN, Nashville, United States.
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, TN, Nashville, United States; Department of Biomedical Informatics, Vanderbilt University School of Medicine, TN, Nashville, United States.
Department of Biostatistics, Vanderbilt University Medical Center, TN, Nashville, United States; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, TN, Nashville, United States.
Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 3557Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Place, publisher, year, edition, pages
Springer Nature, 2024. Vol. 15, no 1, article id 3557
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Medical Genetics and Genomics
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URN: urn:nbn:se:umu:diva-224181DOI: 10.1038/s41467-024-47399-xISI: 001210969800022PubMedID: 38670944Scopus ID: 2-s2.0-85191635301OAI: oai:DiVA.org:umu-224181DiVA, id: diva2:1858507
Funder
NIH (National Institutes of Health), R01CA188214NIH (National Institutes of Health), R37CA227130NIH (National Institutes of Health), R01CA269589Available from: 2024-05-17 Created: 2024-05-17 Last updated: 2025-04-24Bibliographically approved

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van Guelpen, Bethany

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