Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
Lawrenson, Kate Kar, Siddhartha McCue, Karen Kuchenbaeker, Karoline Michailidou, Kyriaki Tyrer, Jonathan Beesley, Jonathan Ramus, Susan J Li, Qiyuan Delgado, Melissa K
Lawrenson, Kate
Kar, Siddhartha
McCue, Karen
Kuchenbaeker, Karoline
Michailidou, Kyriaki
Tyrer, Jonathan
Beesley, Jonathan
Ramus, Susan J
Li, Qiyuan
Delgado, Melissa K
Citations
Altmetric:
Alternative Title
Abstract
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Keywords
Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, GENOME-WIDE ASSOCIATION, BRCA2 MUTATION CARRIERS, EPITHELIAL-CELLS, COMMON VARIANTS, IDENTIFIES 3, MODIFIERS, REVEALS, GWAS, GENE, INVESTIGATORS
Source Title
NATURE COMMUNICATIONS
Publisher
NATURE PUBLISHING GROUP
Series/Report No.
Collections
Rights
Date
2016-09-01
DOI
10.1038/ncomms12675
Type
Article