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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
Nat Genet. 2020 Jan;52(1) :56-73
PMID: 31911677    PMCID: PMC6974400    URL: https://www.ncbi.nlm.nih.gov/pubmed/31911677
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Abstract
Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Notes
Fachal, Laura Aschard, Hugues Beesley, Jonathan Barnes, Daniel R. Allen, Jamie Kar, Siddhartha Pooley, Karen A. Dennis, Joe Michailidou, Kyriaki Turman, Constance Soucy, Penny Lemacon, Audrey Lush, Michael Tyrer, Jonathan P. Ghoussaini, Maya Marjaneh, Mahdi Moradi Jiang, Xia Agata, Simona Aittomaki, Kristiina Rosario Alonso, M. Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arason, Adalgeir Arndt, Volker Aronson, Kristan J. Arun, Banu K. Auber, Bernd Auer, Paul L. Azzollini, Jacopo Balmana, Judith Barkardottir, Rosa B. Barrowdale, Daniel Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina Bialkowska, Katarzyna Blanco, Amie M. Blomqvist, Carl Blot, William Bogdanova, Natalia, V Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Borg, Ake Bosse, Kristin Brauch, Hiltrud Brenner, Hermann Briceno, Ignacio Brock, Ian W. Brooks-Wilson, Angela Bruening, Thomas Burwinkel, Barbara Buys, Saundra S. Cai, Qiuyin Caldes, Trinidad Caligo, Maria A. Camp, Nicola J. 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