Expressive

rs1219651 (FGFR2): Gene Expression and Cancer Genetics

Key takeaways

  • rs1219651 sits within FGFR2, a gene studied in large-scale cancer genomics programs covering over 600,000 participants
  • The ALT allele increases FGFR2 expression specifically in sigmoid colon tissue, based on GTEx v11 eQTL data from 953 donors
  • The same allele reduces expression of a nearby gene in cervical spinal cord tissue, showing that regulatory effects differ by tissue type
  • A pan-cancer GWAS of 627,456 people found positive genetic correlations between breast and prostate cancer, with 91 new loci confirmed in a follow-up of over 1.1 million participants
  • Multi-population GWAS studies show thousands of genetic associations are only detectable when diverse ancestry groups are included

Key takeaways

  • rs1219651 falls within the FGFR2 gene (fibroblast growth factor receptor 2, chromosome 10q26), a locus actively studied in large-scale cancer genomics covering hundreds of thousands of participants
  • The ALT allele increases expression of this gene in sigmoid colon tissue, as detected in GTEx v11 eQTL data from 953 donors
  • The same allele reduces expression of ENSG00000223432 in cervical spinal cord tissue, illustrating that its regulatory effects are tissue-specific
  • A pan-cancer GWAS meta-analysis of 627,456 people across 13 cancer types found positive genetic correlations between breast and prostate cancer, with 91 new genome-wide significant loci identified in a combined analysis of over 1.1 million participants
  • Multi-population studies, including the VA Million Veteran Program with 635,969 participants across 2068 traits, show that thousands of genetic associations are only discoverable when diverse ancestry groups are included

What the research says A pan-cancer, cross-population GWAS meta-analysis examining 250,015 East Asians (BioBank Japan) and 377,441 Europeans (UK Biobank) across 13 cancer types detected significant positive genetic correlations between breast and prostate cancer; a large-scale follow-up meta-analysis of 277,896 cases and 901,858 controls identified 91 newly genome-wide significant loci PMID 37479680. The VA Million Veteran Program GWAS of 635,969 participants across 2068 traits identified 26,049 variant-trait associations including 9989 previously unreported, with 3477 associations only detectable when non-European ancestry participants were included PMID 38301026.

Reported associations

  • FGFR2 expression in sigmoid colon (eQTL): The ALT allele is associated with increased expression in sigmoid colon tissue (slope +0.12 on a log2-normalized scale, p=2.0e-5, FDR<0.05) GTEx Portal
  • ENSG00000223432 expression in cervical spinal cord (eQTL): The ALT allele is associated with reduced expression of ENSG00000223432 in cervical spinal cord (c-1 level) tissue (slope -0.33, p=2.8e-5, FDR<0.05) GTEx Portal
  • Breast and prostate cancer genetics (pan-cancer context): A pan-cancer GWAS meta-analysis of 250,015 East Asians and 377,441 Europeans across 13 cancer types found significant positive genetic correlations between breast and prostate cancer, validated in an independent Finnish cohort; a combined follow-up of 277,896 cases and 901,858 controls identified 91 newly genome-wide significant loci PMID 37479680
  • Diverse-population complex trait associations: The VA MVP GWAS identified 26,049 locus-trait associations across 2068 traits in 635,969 participants, with 1608 genomic risk loci reaching significance only after inclusion of non-European ancestry groups and fine-mapping identifying 57,601 independent signals PMID 38301026

Evidence quality The most direct variant-level evidence for rs1219651 comes from GTEx v11 eQTL data (953 donors, FDR<0.05); these are mechanistic regulatory signals characterizing gene expression, not disease-outcome associations. The pan-cancer GWAS PMID 37479680 is a large meta-analysis of 627,456 discovery-phase participants with cross-population replication and genome-wide significance thresholds (P<5.0x10-8), but the provided source text does not name rs1219651 or the FGFR2 locus among its explicitly reported findings. The MVP GWAS PMID 38301026 fine-mapped 635,969 participants and identified 15,045 high-confidence single-variant signals out of 57,601 independent signals; this study similarly does not name this specific variant in the available text. No conflicting findings were reported across the provided sources.

Tissue-specific expression effects

  • FGFR2: The ALT allele is associated with increased expression in sigmoid colon tissue (slope +0.12, p=2.0e-5, FDR<0.05) GTEx Portal
  • ENSG00000223432: The ALT allele is associated with reduced expression in cervical spinal cord (c-1 level) tissue (slope -0.33, p=2.8e-5, FDR<0.05) GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the FGFR2 gene and why is it studied in cancer research?

FGFR2 (fibroblast growth factor receptor 2) encodes a cell-surface receptor involved in cell growth and differentiation signaling. The locus is examined in large-scale pan-cancer genome-wide association studies, including a meta-analysis of 250,015 East Asians and 377,441 Europeans across 13 cancer types that found shared genetic backgrounds for breast and prostate cancer.

What does rs1219651 do to FGFR2 gene expression?

GTEx v11 eQTL data from 953 donors shows the ALT allele of rs1219651 is associated with increased FGFR2 expression in sigmoid colon tissue (slope +0.12, p=2.0e-5, FDR<0.05). This is a tissue-specific regulatory effect, not a direct disease outcome.

Does rs1219651 affect genes other than FGFR2?

Yes. GTEx v11 data shows the same ALT allele is associated with reduced expression of ENSG00000223432 in cervical spinal cord tissue (slope -0.33, p=2.8e-5, FDR<0.05). The direction and magnitude of effects differ between tissues, which is characteristic of regulatory variants.

Is rs1219651 associated with breast or prostate cancer?

The FGFR2 locus is within a region examined by pan-cancer GWAS studies. A large meta-analysis of 250,015 East Asians and 377,441 Europeans across 13 cancer types found positive genetic correlations between breast and prostate cancer and identified 91 new genome-wide significant loci in a follow-up. The provided sources do not report a specific effect size for rs1219651 by name.

Why does studying variants in diverse populations matter for rs1219651?

Research from the VA Million Veteran Program (635,969 participants, 2068 traits) found that 3477 out of 26,049 variant-trait associations were only detectable when non-European ancestry groups were included. Diverse populations improve variant discovery and ensure findings apply broadly across human groups.