rs11836367 (PGAM1P5): Mammographic Density Locus

Key takeaways

• rs11836367 is one of 31 newly discovered genetic variants linked to mammographic density, found in a study of 24,192 women
• Women with 75% or more mammographic density face 4 to 5 times the breast cancer risk of low-density women
• 17 of the 46 total mapped density variants are independently linked to breast cancer risk
• One version of this variant is associated with increased NTN4 gene activity in breast tissue, brain, salivary gland, and prostate
• Evidence is based on a single meta-analysis; replication data specific to this locus are not yet available

What the research says A GWAS (genome-wide association study) meta-analysis of 24,192 non-Hispanic white women screened with full-field digital mammography identified 31 new loci for mammographic density (MD) phenotypes at genome-wide significance (P < 5 x 10^-8), tripling the total known to 46, with rs11836367 near the PGAM1P5 pseudogene (phosphoglycerate mutase 1 pseudogene 5, a stretch of DNA resembling a functional gene but not encoding a working protein) among the newly mapped signals PMID 32581249. Mendelian randomization analyses in the same study confirmed that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are each significantly associated with breast cancer risk (P < 0.05), and 17 of the 46 total loci were independently confirmed in a separate meta-analysis of over 200,000 breast cancer cases and controls PMID 32581249. GTEx v11 data show the ALT allele of this variant is associated with increased NTN4 expression in breast mammary tissue, minor salivary gland, brain caudate basal ganglia, and prostate, and with increased expression of the PGAM1P5 pseudogene in breast mammary tissue GTEx Portal.

Reported associations

• Mammographic density phenotypes (dense area, nondense area, and/or percent density): rs11836367 was among 31 newly identified genome-wide significant loci for MD phenotypes in a meta-analysis of 24,192 women (P < 5 x 10^-8); the specific phenotype subtype and effect size for this variant are not reported in the available study excerpt PMID 32581249
• Breast cancer risk (via mammographic density pathway): 17 of the 46 total MD loci were independently associated with breast cancer risk in a separate meta-analysis of over 200,000 cases and controls (P < 0.05); whether this locus is among those 17 is not specified in the available data PMID 32581249

Evidence quality The primary evidence comes from a single large GWAS meta-analysis of 24,192 non-Hispanic white women, conducted across two independent cohorts: a Hologic cohort (n = 20,311) and a GE cohort (n = 3,881) PMID 32581249. The study applied a genome-wide significance threshold (P < 5 x 10^-8), and genomic inflation factors ranged from 1.06 to 1.08, indicating little evidence of population substructure. The specific effect size and direction for rs11836367 are not available in the provided study excerpt, and no independent replication specific to this locus is included in the evidence base. The Mendelian randomization results support a causal link between MD phenotypes collectively and breast cancer risk, but do not isolate the contribution of this variant. The sample is restricted to non-Hispanic white women, limiting generalizability to other populations.

Tissue-specific expression effects

• NTN4: The ALT allele is associated with increased expression in breast mammary tissue, minor salivary gland, brain caudate basal ganglia, and prostate GTEx Portal
• PGAM1P5: The ALT allele is associated with increased expression of this pseudogene in breast mammary tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.