Expressive

rs11039165 (MADD): Metabolic Biomarker Variant

Key takeaways

  • rs11039165 near MADD was identified in large-scale genome-wide studies of metabolic traits and diverse human phenotypes
  • The alternate allele reduces MADD expression in the pituitary gland and esophagus
  • The same allele increases C1QTNF4 expression in skin and subcutaneous fat
  • NR1H3 expression is reduced specifically in ovarian tissue
  • This variant affects four genes across at least six tissue types, suggesting broad regulatory influence

Key takeaways

  • rs11039165 near MADD was identified in large-scale genome-wide studies of metabolic traits and diverse human phenotypes
  • The alternate allele reduces MADD expression in the pituitary gland and esophagus
  • The same allele increases C1QTNF4 expression in skin and subcutaneous fat
  • NR1H3 expression is reduced specifically in ovarian tissue
  • This variant affects four genes across at least six tissue types, suggesting broad regulatory influence

What the research says

This locus appears in a genome-wide meta-analysis of 233 circulating metabolic traits measured by nuclear magnetic resonance (NMR) spectroscopy - a technique that simultaneously quantifies hundreds of metabolic molecules in blood - across up to 136,016 participants from 33 cohorts, which identified more than 400 independent genomic loci and assigned probable causal genes at roughly two-thirds of them. It also appears in a cross-population association atlas covering 220 deep-phenotype genome-wide association studies in BioBank Japan (179,000 participants) combined with UK Biobank and FinnGen for a total of approximately 628,000 participants, which identified around 5,000 new loci spanning diseases, biomarkers, and medication usage. Tissue-level expression-QTL (eQTL - a type of genetic association that quantifies how a variant changes the activity level of a nearby gene) data from GTEx v11 across 953 donors shows the alternate allele at this locus reduces MADD and NR1H3 expression in specific tissues while increasing C1QTNF4 expression in skin and subcutaneous fat GTEx Portal.

Reported associations

  • MADD expression, pituitary (eQTL): Reduced MADD expression in pituitary gland tissue with the alternate allele GTEx Portal
  • MADD expression, esophagus (eQTL): Reduced MADD expression in esophagus mucosa and esophagus muscularis (the muscular layer of the esophagus wall) with the alternate allele GTEx Portal
  • C1QTNF4 expression, skin and adipose (eQTL): Increased C1QTNF4 expression in sun-exposed lower-leg skin, subcutaneous adipose tissue (fat just beneath the skin), and non-sun-exposed skin with the alternate allele GTEx Portal
  • NR1H3 expression, ovary (eQTL): Reduced NR1H3 expression in ovarian tissue with the alternate allele GTEx Portal
  • ENSG00000303744 expression, testis (eQTL): Increased expression of this currently uncharacterized gene in testicular tissue with the alternate allele GTEx Portal
  • Circulating metabolic traits (GWAS): This locus was detected in a large NMR metabolomics GWAS of 233 metabolic traits across up to 136,016 participants; specific trait associations and effect sizes for rs11039165 are not provided in the available study text
  • Diverse human phenotypes (GWAS): This locus was detected in a cross-population GWAS atlas of 220 phenotypes across approximately 628,000 participants; specific associations are not provided in the available study text

Evidence quality

The eQTL evidence from GTEx v11 is based on 953 donors with FDR correction applied across all tested tissues. Signal strength varies considerably: MADD in the pituitary is the strongest association (p=4.3e-28), esophageal and skin/adipose associations range from p=2.2e-10 to p=2.3e-9, NR1H3 in ovary reaches p=5.0e-7, and ENSG00000303744 in testis carries the weakest signal at p=1.8e-6, all passing FDR correction. The two GWAS studies represent very large sample sizes (up to 136,016 and approximately 628,000 participants respectively), providing substantial statistical power for discovery; however, specific p-values, odds ratios, or beta coefficients for rs11039165 are not provided in the available study excerpts. No conflicting findings were identified in the provided materials.

Tissue-specific expression effects

  • MADD: Reduced expression in pituitary gland (strongest signal, p=4.3e-28), esophagus mucosa, and esophagus muscularis in carriers of the alternate allele GTEx Portal
  • C1QTNF4: Increased expression in sun-exposed lower-leg skin, subcutaneous adipose tissue, and non-sun-exposed skin in carriers of the alternate allele GTEx Portal
  • NR1H3: Reduced expression specifically in ovary in carriers of the alternate allele GTEx Portal
  • ENSG00000303744: Increased expression in testis in carriers of the alternate allele GTEx Portal

Lifestyle considerations

No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Diet

  • prioritize low glycemic index foods High

    MADD rs11039165 variant affects glucose homeostasis; low-GI diet reduces postprandial glucose excursions.

    Emphasize whole grains, legumes, and non-starchy vegetables; limit refined carbohydrates

Exercise

  • regular aerobic and resistance training High

    Physical activity improves insulin sensitivity and glucose clearance, mitigating genetic predisposition to hyperglycemia.

    150 minutes per week moderate-intensity aerobic exercise plus 2+ days resistance training

Screening

  • blood glucose and HbA1c testing High

    rs11039165 risk alleles are associated with elevated fasting glucose; regular monitoring enables early detection of dysglycemia.

    Annually or every 2 years starting at age 30

Frequently asked questions

What is rs11039165?

rs11039165 is a genetic variant located in the MADD gene region. It has been detected in large-scale genome-wide association studies of circulating metabolic biomarkers and diverse human phenotypes, and it functions as an expression-QTL for multiple nearby genes across several tissues.

What does the MADD gene do?

MADD is the gene nearest to rs11039165. GTEx eQTL data shows that the alternate allele of rs11039165 is linked to reduced MADD expression in pituitary gland and esophageal tissues. The available study materials do not describe MADD protein function in detail.

What traits is rs11039165 associated with?

This variant was identified in a genome-wide study of 233 NMR-measured metabolic traits across more than 136,000 participants, and in a cross-population atlas of 220 human phenotypes across approximately 628,000 participants. Specific trait associations and effect sizes for this individual variant are not detailed in the available study materials.

What does the C1QTNF4 eQTL signal mean for rs11039165?

GTEx data shows the alternate allele of rs11039165 increases C1QTNF4 expression in sun-exposed and non-sun-exposed skin, as well as subcutaneous fat. This is a regulatory effect: the variant influences how much C1QTNF4 is produced in those tissues rather than changing the gene sequence itself.

Is rs11039165 linked to reproductive or hormonal traits?

GTEx data shows the alternate allele reduces NR1H3 expression specifically in ovary and increases expression of an uncharacterized gene in testis, both tissue-specific effects. Whether these expression changes connect to reproductive or hormonal outcomes is not established in the provided study materials.