Expressive

rs10104063 (TUSC3): Metabolic Syndrome Risk Locus

Key takeaways

  • rs10104063 is one of 1,307 genetic loci tied to metabolic syndrome, identified in the largest such GWAS to date spanning nearly 5 million people
  • The variant lies near TUSC3 (Tumor Suppressor Candidate 3)
  • GTEx data shows the alternate allele reduces TUSC3 expression in at least 8 tissues including heart, skeletal muscle, and both visceral and subcutaneous fat
  • Metabolic syndrome loci from this study as a group were enriched in brain tissues, pointing to possible nervous system involvement in metabolic risk

Key takeaways

  • rs10104063 is one of 1,307 genetic loci tied to metabolic syndrome, identified in the largest such GWAS to date spanning nearly 5 million people
  • The variant lies near TUSC3 (Tumor Suppressor Candidate 3)
  • GTEx data shows the alternate allele reduces TUSC3 expression in at least 8 tissues including heart, skeletal muscle, and both visceral and subcutaneous fat
  • Metabolic syndrome loci from this study as a group were enriched in brain tissues, pointing to possible nervous system involvement in metabolic risk

What the research says A multivariate GWAS (genome-wide association study) of metabolic syndrome (MetS) - a cluster of conditions including central obesity, dyslipidemia, hypertension, and impaired glucose tolerance - covering nearly 5 million European-ancestry individuals identified 1,307 associated genetic loci using Genomic SEM, a statistical method that models shared genetic architecture across multiple correlated traits simultaneously. GTEx eQTL (expression quantitative trait locus) data from 953 donors shows the alternate allele at rs10104063 is associated with reduced TUSC3 expression across 8 tissues, with slopes ranging from -0.13 to -0.19 on a log2-normalized scale, all at FDR < 0.05 GTEx Portal.

Reported associations

  • Metabolic syndrome: Identified among 1,307 loci associated with the shared genetic liability for MetS components - including BMI, waist circumference, type 2 diabetes, fasting glucose, hypertension, HDL cholesterol, and triglycerides - in the largest multivariate MetS GWAS conducted to date
  • TUSC3 expression reduction (multiple tissues): The alternate allele is associated with reduced TUSC3 expression across 8 tissues - esophagus muscularis (slope -0.19), heart atrial appendage (-0.18), skeletal muscle (-0.16), cultured fibroblasts (-0.15), visceral adipose/omentum (-0.15), heart left ventricle (-0.14), subcutaneous adipose (-0.14), and transverse colon (-0.13) - all reaching FDR < 0.05 GTEx Portal

Evidence quality The MetS association derives from a large-scale multivariate GWAS (observed n = 4,947,860, European ancestry) using Genomic SEM, representing the largest MetS genetic study reported to date. No variant-specific effect sizes or p-values for rs10104063 are available in the summary materials for this entry. The enrichment of MetS loci in brain tissues is a study-wide pattern across all 1,307 loci and is not a finding specific to this variant. The GTEx eQTL evidence (v11, 953 donors, FDR < 0.05) is consistent across 8 distinct tissues with slopes between -0.13 and -0.19, suggesting a reproducible effect on TUSC3 expression levels. eQTL associations reflect changes in gene expression and do not directly imply clinical outcomes.

Tissue-specific expression effects

  • TUSC3: The alternate allele is associated with reduced expression across 8 tissues - esophagus muscularis, heart atrial appendage, skeletal muscle, cultured fibroblasts, visceral adipose (omentum), left ventricle, subcutaneous adipose, and transverse colon - with all effect slopes in the range of -0.13 to -0.19 on a log2-normalized scale GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the TUSC3 gene?

TUSC3 (Tumor Suppressor Candidate 3) is a gene near rs10104063. GTEx data shows the alternate allele at this variant reduces TUSC3 expression across 8 tissues. The biological mechanisms linking TUSC3 to metabolic syndrome are not described in the available research for this entry.

What is metabolic syndrome?

Metabolic syndrome is a cluster of interrelated conditions - including central obesity, abnormal blood fats (dyslipidemia), high blood pressure (hypertension), and impaired blood sugar control - that together raise the risk of cardiovascular disease and type 2 diabetes.

Is rs10104063 linked to metabolic syndrome?

A multivariate GWAS of nearly 5 million European-ancestry individuals identified rs10104063 as one of 1,307 loci associated with the shared genetic liability for metabolic syndrome components, including BMI, triglycerides, HDL cholesterol, hypertension, and type 2 diabetes.

What does rs10104063 do to TUSC3 expression?

According to GTEx data, the alternate allele at rs10104063 is associated with reduced TUSC3 expression across 8 tissues including heart (both atrial appendage and left ventricle), skeletal muscle, visceral and subcutaneous fat, cultured fibroblasts, and transverse colon, with effect slopes ranging from -0.13 to -0.19.

How large was the study that identified this variant?

The study applied a multivariate method called Genomic SEM to European-ancestry GWAS data with a combined observed sample size of approximately 4.9 million individuals, making it the largest metabolic syndrome genetic study to date.