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.
- MeSH
- Bayesova věta MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- lokus kvantitativního znaku * MeSH
- mapování chromozomů metody MeSH
- nádorové biomarkery genetika MeSH
- nádory prsu genetika MeSH
- regulační oblasti nukleových kyselin MeSH
- rizikové faktory MeSH
- vazebná nerovnováha MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
- MeSH
- adenokarcinom genetika MeSH
- běloši genetika MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- homeostáza telomer genetika MeSH
- jednonukleotidový polymorfismus MeSH
- kouření epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokus kvantitativního znaku MeSH
- mapování chromozomů MeSH
- nádory plic epidemiologie etnologie genetika MeSH
- senioři MeSH
- zdraví rodiny MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
- MeSH
- alfa receptor estrogenů genetika metabolismus MeSH
- exprese genu MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- lidské chromozomy, pár 6 genetika MeSH
- nádory prsu genetika metabolismus MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- rizikové faktory MeSH
- sekvence nukleotidů MeSH
- transportní proteiny genetika metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH