Abstract
BackgroundMammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained.MethodsWe conducted a genetic association study of volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability [h2SNP]) in 4948 participants of the cohort.ResultsIn total, three novel MD loci were identified (at P < 5 × 10− 8): one for percent dense volume (HABP2) and two for the absolute dense volume (INHBB, LINC01483). INHBB is an established locus for ER-negative breast cancer, and HABP2 and LINC01483 represent putative new breast cancer susceptibility loci, because both loci were associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h2SNP (SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h2SNP to previously observed narrow-sense h2 estimates in the same cohort were 0.46, 0.72, and 0.41, respectively.ConclusionsThese findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h2SNP/h2 ratios varying between dense and nondense MD components.
Highlights
Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained
Family-based studies have estimated that approximately 60–70% of the variance in MD is explained by additive genetic effects, which is considerably higher than the narrow-sense heritability estimate reported for breast cancer (h2 = 30–40%)
Additive effects of these genomewide significant Single-nucleotide polymorphism (SNP) explain only a small fraction of the total MD variance (< 5%). This discrepancy in explained variance or “missing heritability” has been attributed to various factors, including the presence of large numbers of common variants with small effects, rare variants with large effects not tagged by common SNPs on genotyping arrays and possible inflation of narrow-sense h2 estimates if family resemblance is influenced by nonadditive effects, shared environmental effects, and/or gene-environment interactions
Summary
Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained. Despite being an important determinant of breast cancer risk, the biological mechanisms determining tumor development in women with highly dense breasts are not Family-based studies have estimated that approximately 60–70% of the variance in MD is explained by additive genetic effects, which is considerably higher than the narrow-sense heritability estimate reported for breast cancer (h2 = 30–40%). Additive effects of these genomewide significant SNPs explain only a small fraction of the total MD variance (< 5%). The exact contribution of each of these possible explanations is difficult to determine, the contribution of common genetic variation to MD variance (SNP-based heritability or [h2SNP]) can be assessed rather in genome-wide association data and can provide insights into the heritability fraction that remains to be identified in future larger-scale GWAS
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