Genome-wide association analysis identifies three new breast cancer susceptibility loci

Ghoussaini, Maya,Fletcher, Olivia,Michailidou, Kyriaki,Turnbull, Clare,Schmidt, Marjanka K,Dicks, Ed,Dennis, Joe,Wang, Qin,Humphreys, Manjeet K,Luccarini, Craig,Baynes, Caroline,Conroy, Don,Maranian, Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.3

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ??% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ??0,000 cases and ??8,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 ? 10<SUP>??35</SUP>), 12q24 (rs1292011; P = 4.3 ? 10<SUP>??19</SUP>) and 21q21 (rs2823093; P = 1.1 ? 10<SUP>??12</SUP>). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Ahmed, Shahana,Thomas, Gilles,Ghoussaini, Maya,Healey, Catherine S,Humphreys, Manjeet K,Platte, Radka,Morrison, Jonathan,Maranian, Melanie,Pooley, Karen A,Luben, Robert,Eccles, Diana,Evans, D Gareth,F Nature Publishing Group 2009 Nature genetics Vol.41 No.5

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10<SUP>−23</SUP>) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10<SUP>−8</SUP>). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Lin, Wei-Yu,Camp, Nicola J,Ghoussaini, Maya,Beesley, Jonathan,Michailidou, Kyriaki,Hopper, John L,Apicella, Carmel,Southey, Melissa C,Stone, Jennifer,Schmidt, Marjanka K,Broeks, Annegien,Van't Veer, L IRL Press 2015 Human molecular genetics Vol.24 No.1

<P>Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 ?? 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 ?? 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 ?? 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.</P>

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Orr, Nick,Dudbridge, Frank,Dryden, Nicola,Maguire, Sarah,Novo, Daniela,Perrakis, Eleni,Johnson, Nichola,Ghoussaini, Maya,Hopper, John L.,Southey, Melissa C.,Apicella, Carmel,Stone, Jennifer,Schmidt, M IRL Press 2015 Human molecular genetics Vol.24 No.10

<P>We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; <I>P</I>-value = 1.58 × 10<SUP>−25</SUP>). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; <I>P</I>-value = 7.89 × 10<SUP>−09</SUP>) and rs13294895 (OR = 1.09 [1.06–1.12]; <I>P</I>-value = 2.97 × 10<SUP>−11</SUP>). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; <I>P</I>-value = 2.77 × 10<SUP>−05</SUP>). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. <I>In vitro</I> analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the <I>KLF4</I> gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.</P>

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Zeng, Chenjie,Guo, Xingyi,Long, Jirong,Kuchenbaecker, Karoline B.,Droit, Arnaud,Michailidou, Kyriaki,Ghoussaini, Maya,Kar, Siddhartha,Freeman, Adam,Hopper, John L.,Milne, Roger L.,Bolla, Manjeet K.,Wa BioMed Central 2016 Breast cancer research Vol.18 No.-

<P><B>Background</B></P><P>Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.</P><P><B>Method</B></P><P>We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 <I>BRCA1</I> mutation carriers in the Consortium of Investigators of Modifiers of <I>BRCA1/2</I> (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.</P><P><B>Results</B></P><P>Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; <I>P</I> = 3 × 10<SUP>-9</SUP>), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, <I>P</I> = 2 × 10<SUP>-5</SUP>), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; <I>P</I> = 2 × 10<SUP>-4</SUP>) identified in the general populations, and rs113824616 (<I>P</I> = 7 × 10<SUP>-5</SUP>) identified in the meta-analysis of BCAC ER-negative cases and <I>BRCA1</I> mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at <I>P</I> < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that <I>PTHLH</I> was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of <I>PTHLH</I> and its nearby gene <I>CCDC91</I> at <I>P</I> < 0.05.</P><P><B>Conclusion</B></P><P>This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.</P>