Expressive

rs10034692 (AREG): Mammographic Dense Area

Key takeaways

  • rs10034692 sits near the AREG gene, which promotes growth of normal breast epithelial cells.
  • The variant is linked to mammographic dense area, a highly heritable tissue measure (heritability 0.6 to 0.7) and a known breast cancer risk factor.
  • In individual-level data from 6,624 women, the effect estimate was beta = -0.16 (P = 0.0002) for dense area.
  • A second nearby variant, rs12642133, also reached genome-wide significance for dense area and may be an independent signal.
  • Variants correlated with rs10034692 have also been linked to breast size in earlier research.

Key takeaways

  • rs10034692 sits near the AREG gene (amphiregulin, a member of the epidermal growth factor family), which promotes growth of normal breast epithelial cells.
  • The variant is linked to mammographic dense area, a highly heritable tissue measure (heritability 0.6 to 0.7) and a known breast cancer risk factor.
  • In individual-level data from 6,624 women, the effect estimate for dense area was beta = -0.16 (P = 0.0002).
  • A second nearby variant, rs12642133, also reached genome-wide significance for dense area and may represent an independent signal at the same locus.
  • Variants correlated with rs10034692 have also been linked to breast size in earlier research.

What the research says rs10034692 is located near the AREG gene (amphiregulin, a member of the epidermal growth factor family that promotes growth of normal epithelial cells). A two-stage GWAS meta-analysis covering up to 7,916 discovery-phase and 10,379 replication-phase women identified this locus as genome-wide significant (P < 5x10^-8) for mammographic dense area. In a subset of 6,624 women with individual-level genotype data, the effect estimate was beta = -0.16 (P = 0.0002); variants in strong linkage disequilibrium with rs10034692 had previously been associated with breast size, suggesting shared biology at this locus.

Reported associations

  • Mammographic dense area: genome-wide significant association (P < 5x10^-8) confirmed in two-stage meta-analysis (discovery n up to 7,916; replication n up to 10,379); effect estimate beta = -0.16 (P = 0.0002) in 6,624 women with individual-level data.
  • Dense area - secondary signal at the same locus: rs12642133, located 116 kb from rs10034692 in weak linkage disequilibrium (r-squared = 0.16, D' = 1.00), independently reached genome-wide significance (beta = 0.17, P = 9x10^-6); this second variant overlaps a weak enhancer region in human mammary epithelial cells.
  • Breast size: variants in strong linkage disequilibrium with rs10034692 have been previously associated with breast size.
  • Breast cancer: this locus showed a nominal association with breast cancer (P < 0.05) in a separate large meta-analysis, consistent with shared genetic architecture between mammographic density and breast cancer risk.

Evidence quality Evidence for this locus comes from a two-stage GWAS meta-analysis in predominantly post-menopausal women of European ancestry, with a discovery phase of up to 7,916 women and a replication phase of up to 10,379 women. The combined signal crossed the conventional genome-wide significance threshold (P < 5x10^-8). Mammographic density phenotypes are highly heritable (0.6 to 0.7), supporting a meaningful genetic contribution. A key unresolved question concerns the two signals at this locus: conditional analysis attenuated both rs10034692 (beta = -0.10, P = 0.04) and rs12642133 (beta = 0.13, P = 0.002) after mutual adjustment, leaving open whether they tag the same causal variant, represent two independent signals, or both serve as proxies for an unidentified causal SNP. Sample composition limits generalizability to other populations. The nominal breast cancer association at this locus requires validation in additional studies.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the AREG gene?

AREG stands for amphiregulin, a member of the epidermal growth factor family. It promotes the growth of normal epithelial cells, including those found in breast tissue.

What is mammographic density?

Mammographic density reflects the proportion of fibroglandular (dense) tissue versus fat visible on a mammogram. Higher density is a well-established risk factor for breast cancer and is highly heritable, with an estimated heritability of 0.6 to 0.7.

Is rs10034692 linked to breast cancer?

The variant is primarily associated with mammographic dense area rather than breast cancer directly. However, this locus showed a nominal association with breast cancer (P < 0.05) in a separate large meta-analysis, consistent with a shared genetic basis between breast density and breast cancer risk.

Are there two variants at the AREG locus affecting breast density?

Yes. Both rs10034692 and a second variant, rs12642133 (located 116 kb away in weak linkage disequilibrium), independently reached genome-wide significance for mammographic dense area. Whether they are two independent causal signals or proxies for the same underlying variant remains unresolved.

Is rs10034692 associated with breast size?

Variants in strong linkage disequilibrium with rs10034692 have been previously associated with breast size, suggesting shared biological pathways at this locus.