TY - JOUR

T1 - Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

AU - Orr, Nick

AU - Dudbridge, Frank

AU - Dryden, Nicola

AU - Maguire, Sarah

AU - Novo, Daniela

AU - Perrakis, Eleni

AU - Johnson, Nichola

AU - Ghoussaini, Maya

AU - Hopper, John L

AU - Southey, Melissa C

AU - Apicella, Carmel

AU - Stone, Jennifer

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Van't Veer, Laura J

AU - Hogervorst, Frans B

AU - Fasching, Peter A

AU - Haeberle, Lothar

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Gibson, Lorna

AU - Aitken, Zoe

AU - Warren, Helen

AU - Sawyer, Elinor

AU - Tomlinson, Ian

AU - Kerin, Michael J

AU - Miller, Nicola

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Schneeweiss, Andreas

AU - Sohn, Chistof

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Cordina-Duverger, Emilie

AU - Sanchez, Marie

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Benitez, Javier

AU - Zamora, Maria Pilar

AU - Arias Perez, Jose Ignacio

AU - Menéndez, Primitiva

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Gao, Yu-Tang

AU - GENICA Network

N1 - © The Author 2015. Published by Oxford University Press.

PY - 2015

Y1 - 2015

N2 - 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]; P-value = 1.58 × 10(-25)). 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]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). 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. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 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.

AB - 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]; P-value = 1.58 × 10(-25)). 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]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). 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. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 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.

KW - Adult

KW - Aged

KW - Asian Continental Ancestry Group

KW - Breast Neoplasms

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 9

KW - Enhancer Elements, Genetic

KW - Estrogen Receptor alpha

KW - European Continental Ancestry Group

KW - Female

KW - GATA3 Transcription Factor

KW - Genetic Association Studies

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Hepatocyte Nuclear Factor 3-alpha

KW - Humans

KW - Kruppel-Like Transcription Factors

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Risk

U2 - 10.1093/hmg/ddv035

DO - 10.1093/hmg/ddv035

M3 - Journal article

C2 - 25652398

VL - 24

SP - 2966

EP - 2984

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -