Expressive

rs11627032 (RIN3): Breast Cancer and Brain Morphology

Key takeaways

  • Multiple breast cancer GWAS drawing on over 100,000 cases have linked this locus to susceptibility
  • rs11627032 reduces expression of the RIN3 gene in the gut, esophagus, lung, and skeletal muscle
  • A brain imaging genetics study of 35,657 UK Biobank participants identified this locus among 780 variants shaping cortical surface area and thickness
  • Associations have been studied in both European and Asian populations across multiple meta-analyses
  • Per-variant effect sizes are modest, as expected for common susceptibility variants found by GWAS

Key takeaways

  • Multiple breast cancer GWAS drawing on over 100,000 cases have linked this locus to susceptibility.
  • rs11627032 reduces expression of the RIN3 gene (Ras and Rab Interactor 3) in the gut, esophagus, lung, and skeletal muscle.
  • A brain imaging genetics study of 35,657 UK Biobank participants identified this locus among 780 variants shaping cortical surface area and thickness.
  • Associations have been studied in both European and Asian populations across multiple meta-analyses.
  • Per-variant effect sizes are modest, as expected for common susceptibility variants found by GWAS.

What the research says rs11627032 functions as an expression quantitative trait locus (eQTL) for RIN3, meaning the alternate allele is linked to reduced RIN3 messenger RNA levels in seven tissues, most markedly in the sigmoid colon and small intestine terminal ileum GTEx Portal. Multiple large-scale breast cancer GWAS identified the region around this variant as a susceptibility locus at genome-wide significance (P < 5x10-8), including a combined analysis of 122,977 European-ancestry cases, 105,974 controls, and 14,068 East Asian cases PMID 29059683. A vertex-wise multivariate GWAS of cortical brain morphology in 35,657 UK Biobank participants placed this locus among 780 unique associations with cortical surface area and/or thickness, with replication in 8,060 children from the Adolescent Brain Cognitive Development (ABCD) Study PMID 35248748.

Reported associations

  • Breast cancer risk (overall): Identified at genome-wide significance in a combined analysis of 122,977 European-ancestry cases, 105,974 controls, and 14,068 East Asian cases PMID 29059683
  • Breast cancer risk (overall): Identified in a meta-analysis of breast cancer GWAS and iCOGS array data totaling over 120,000 women of European ancestry, among 15 novel susceptibility loci reported PMID 26323059
  • ER-negative breast cancer: Associated in a GWAS of 21,468 estrogen-receptor-negative cases and 100,594 controls combined with BRCA1 mutation carrier cohorts; 125 variants at identified loci collectively explained approximately 14% of familial risk for this subtype PMID 28920502
  • Breast cancer risk (cross-ancestry): Examined in a meta-analysis combining Asian GWAS data (24,206 cases, 24,775 controls) with European data (122,977 cases, 105,974 controls), with 10 of 31 novel loci replicated in an independent Asian cohort of 16,787 cases and 16,680 controls PMID 32066765
  • Cortical surface area and/or cortical thickness: Among 780 unique loci from vertex-wise multivariate GWAS in 35,657 UK Biobank participants, replicated in 8,060 children in the ABCD Study PMID 35248748

Evidence quality Breast cancer associations come from consortium meta-analyses exceeding 100,000 cases and controls, providing robust statistical power at the genome-wide significance threshold PMID 29059683 PMID 26323059. The ER-negative subtype analysis drew on 21,468 ER-negative cases, 100,594 controls, and over 18,000 BRCA1 mutation carriers, achieving genome-wide significant associations at nine new loci; 125 variants across those loci explain approximately 14% of ER-negative familial breast cancer risk PMID 28920502. The 2020 cross-ancestry study expanded findings to approximately 82,000 Asian and 228,000 European women, with 10 of 31 novel loci replicated in an additional Asian cohort PMID 32066765. The cortical morphology association used MOSTest, a multivariate method the authors estimated triples effective sample size versus standard univariate approaches, with findings replicated in an independent pediatric cohort PMID 35248748. Per-allele effect sizes for common GWAS variants are modest, and no individual locus explains a large share of familial risk. No direct conflicts between the breast cancer and cortical morphology associations are noted in the provided studies, as they reflect distinct trait categories in different cohorts.

Tissue-specific expression effects

  • RIN3: Reduced expression in seven tissues, most strongly in the sigmoid colon and small intestine terminal ileum; also reduced in esophageal muscularis, the esophageal gastroesophageal junction, lung, esophageal mucosa, and skeletal muscle GTEx Portal
  • ENSG00000308283: Reduced expression in the sigmoid colon GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What does the RIN3 gene do?

RIN3 (Ras and Rab Interactor 3) encodes a protein involved in intracellular protein transport. This variant is associated with reduced RIN3 expression particularly in the colon, small intestine, esophagus, and lung.

Is rs11627032 linked to breast cancer?

Multiple large genome-wide association studies have identified the region around rs11627032 as associated with breast cancer risk, including studies of over 100,000 cases of European ancestry and cross-ancestry analyses including Asian women.

Does rs11627032 affect brain structure?

A large multivariate imaging genetics study of over 35,000 UK Biobank participants identified this locus among 780 variants associated with cortical surface area and thickness, with results replicated in a separate pediatric cohort.

Which tissues does rs11627032 affect gene expression in?

GTEx data links this variant to reduced RIN3 expression in the sigmoid colon, small intestine terminal ileum, multiple esophageal segments, lung, and skeletal muscle. A neighboring gene (ENSG00000308283) is also affected in the sigmoid colon.

Has rs11627032 been studied in non-European populations?

Yes, a 2020 cross-ancestry meta-analysis combined data from approximately 82,000 Asian and 228,000 European women to study breast cancer associations, with 10 novel loci independently replicated in an additional Asian cohort.