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Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

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Chen, Hongjie 
Fan, Shaoqi 
Stone, Jennifer 
Thompson, Deborah J 
Douglas, Julie 


BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.



Breast cancer, Genome-wide association study (GWAS), Mammographic density, Transcriptome-wide association study (TWAS), Breast Density, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Transcriptome

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Breast Cancer Res

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Springer Science and Business Media LLC
NIH HHS (CA194393)
NCI NIH HHS (CA244670, U01 CA194393, R01 CA244670, R01 CA194393)