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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

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  1. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

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  2. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

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  3. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

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  4. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

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  5. The genetic evolution of metastatic uveal melanoma

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  1. Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status

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  2. Induction of PIK3CA alterations during neoadjuvant letrozole may improve outcome in postmenopausal breast cancer patients

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  3. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

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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.

Original languageEnglish
JournalNature Genetics
Volume52
Issue number1
Pages (from-to)56-73
Number of pages18
ISSN1061-4036
DOIs
Publication statusPublished - Jan 2020

ID: 59351842