Expressive

rs115458560 (AMIGO1/GPR61): Biomarker Variant

Key takeaways

  • The alternative allele reduces GSTM1 (a detoxification enzyme) in the brain's caudate region while increasing GSTM4 in skin and colon - opposite directions from the same allele.
  • This variant was identified in a UK Biobank GWAS of 35 blood and urine biomarkers across 363,228 individuals.
  • GSTM1 and GSTM4 are glutathione S-transferase enzymes that help cells process and neutralize potentially harmful compounds.
  • Evidence is preliminary; the specific blood biomarker trait linked to this locus and its effect size are not reported in available study text.
  • A large lipoprotein lipid study of up to 441,016 UK Biobank participants provides genetic context for the broader chromosomal region.

Key takeaways

  • The alternative allele reduces GSTM1 (glutathione S-transferase mu 1, a cellular detoxification enzyme) expression in the brain's caudate region (part of the basal ganglia, involved in motor control and learning) while increasing GSTM4 (a closely related detoxification enzyme) in skin and colon - opposite directions from the same allele across tissues.
  • This variant was identified in a UK Biobank GWAS of 35 blood and urine biomarkers across 363,228 individuals.
  • GSTM1 and GSTM4 are glutathione S-transferase enzymes that help cells neutralize potentially harmful compounds.
  • Evidence is preliminary; the specific blood biomarker trait(s) linked to this locus and their effect sizes are not detailed in the available study text.
  • A large lipoprotein lipid study of up to 441,016 UK Biobank participants provides additional genetic context for the chromosomal region around this locus.

What the research says A genome-wide association study (GWAS, a population-scale scan linking genetic variants to measurable traits) of 35 blood and urine laboratory measurements in the UK Biobank (n=363,228) identified 1,857 associated loci spanning 3,374 fine-mapped associations, with the AMIGO1 (Adhesion Molecule with Ig-Like Domain 1) and GPR61 (an orphan G protein-coupled receptor whose natural activating molecule is not yet identified) locus among those examined. A companion study of up to 441,016 UK Biobank participants used Mendelian randomization (a method using genetic variants as natural experiments to infer causal relationships) to evaluate lipoprotein lipid traits - LDL cholesterol (low-density lipoprotein cholesterol), apolipoprotein B, triglycerides (blood fats), HDL cholesterol (high-density lipoprotein cholesterol), and apolipoprotein A-I - in relation to coronary heart disease risk. GTEx tissue expression data from 953 donors (cis-window, FDR less than 0.05) shows this variant has opposing directional effects on two related detoxification genes across tissue types GTEx Portal.

Reported associations

  • Blood and urine biomarker traits: A UK Biobank GWAS of 363,228 individuals identified 3,374 fine-mapped associations at 1,857 loci across 35 laboratory measurements; the specific biomarker(s) and effect sizes for this locus are not described in the available study text.
  • Lipoprotein lipid traits: A UK Biobank GWAS of up to 441,016 individuals identified 220 independent variants for LDL cholesterol, 255 for apolipoprotein B, 440 for triglycerides, 534 for HDL cholesterol, and 440 for apolipoprotein A-I; the role of this specific variant in those findings is not described in the text provided.
  • GSTM1 expression in the brain caudate: The alternative allele is associated with reduced GSTM1 expression in the caudate (beta = -1.31 in log2-scale normalized units, where a 1-unit difference corresponds roughly to a 2-fold change in gene activity; p=8.3e-5; n=953 donors) GTEx Portal.
  • GSTM4 expression in skin and colon: The same allele is associated with increased GSTM4 expression in non-sun-exposed skin (beta = +0.73, p=9.9e-6), sun-exposed lower-leg skin (beta = +0.62, p=7.4e-5), and the transverse colon (beta = +0.51, p=2.6e-5) GTEx Portal.

Evidence quality The most specific evidence for rs115458560 comes from GTEx eQTL (expression quantitative trait locus, meaning a genetic variant that influences how much RNA a gene produces in a given tissue) data from 953 donors, with p-values ranging from 9.9e-6 to 8.3e-5 across four tissue-gene associations, all at FDR less than 0.05 GTEx Portal. The population-level GWAS studies are large and well-powered (n=363,228 for biomarkers; up to n=441,016 for lipoprotein lipid traits), but the available text does not report a specific trait, effect size, or significance level for this variant individually. No replication in independent cohorts or functional validation studies are described. Overall, evidence is preliminary and largely confined to gene expression associations.

Tissue-specific expression effects

  • GSTM1: The alternative allele is associated with reduced expression in the brain's caudate (beta = -1.31, p=8.3e-5), indicating decreased activity of this detoxification enzyme in a brain region involved in motor control and learning GTEx Portal.
  • GSTM4: The same allele is associated with increased expression in non-sun-exposed skin (beta = +0.73, p=9.9e-6), sun-exposed lower-leg skin (+0.62, p=7.4e-5), and the transverse colon (+0.51, p=2.6e-5), indicating higher activity of this detoxification enzyme in peripheral tissues, a directional contrast with the GSTM1 brain effect from the same allele GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What genes are near rs115458560?

rs115458560 is annotated to the AMIGO1 (Adhesion Molecule with Ig-Like Domain 1) and GPR61 (an orphan G protein-coupled receptor) locus. GTEx expression data also links this variant to GSTM1 and GSTM4, two glutathione S-transferase detoxification genes in the same chromosomal region.

What do GSTM1 and GSTM4 do?

GSTM1 and GSTM4 are glutathione S-transferase enzymes that help cells break down and remove potentially harmful compounds, including environmental chemicals and byproducts of normal metabolism. They are expressed across many tissues but differ in where in the body they are most active.

Is rs115458560 linked to any specific disease?

The variant was captured in large population-level studies of blood biomarkers and lipoprotein lipid traits in the UK Biobank, but no specific disease association is described in the available evidence. The tissue gene expression effects on GSTM1 and GSTM4 suggest a biological role but do not establish any clinical outcome.

What is an eQTL and how does it apply here?

An eQTL (expression quantitative trait locus) is a genetic variant that influences how much of a gene's RNA is produced in a given tissue. GTEx data from 953 donors shows rs115458560 acts as an eQTL for GSTM1 in brain caudate and for GSTM4 in skin and colon, with p-values ranging from 9.9e-6 to 8.3e-5 across those tissue associations.

What is GPR61?

GPR61 is an orphan G protein-coupled receptor, a cell-surface signaling protein whose natural activating molecule has not been definitively identified. It is one of the nearest genes to rs115458560 and is thought to play a role in neurological or metabolic signaling, though its precise biological function is still being studied.