Expressive

rs10401969 (SUGP1/TM6SF2): Fatty Acid and Lipid Variant

Key takeaways

  • rs10401969 in SUGP1 is one of the strongest genetic regulators of TM6SF2, increasing its expression in fat, heart, thyroid, and nerve tissue simultaneously.
  • Large studies covering up to 450,000 people link this locus to levels of circulating fatty acids and hundreds of metabolic biomarkers.
  • The alternative allele consistently increases TM6SF2 expression across four distinct tissues in GTEx v11 data from 953 donors.
  • Lower omega-3 fatty acid levels, which connect to the biology at this locus, show a potentially causal link to major depressive disorder based on Mendelian randomization.
  • The variant also reduces expression of MAU2 in skeletal muscle and affects several additional nearby genes, indicating broad regulatory reach.

Key takeaways

  • rs10401969 in SUGP1 (a splicing-factor protein on chromosome 19) is one of the strongest known genetic regulators of TM6SF2 expression, increasing it in fat, heart, thyroid, and peripheral nerve tissue simultaneously.
  • Large genomic studies covering up to 450,000 participants link this locus to levels of circulating fatty acids and hundreds of metabolic biomarkers.
  • The alternative allele consistently increases TM6SF2 expression across four distinct tissues in GTEx v11 data from 953 donors.
  • Lower omega-3 fatty acid levels, which connect to the biology at this locus, show a potentially causal link to major depressive disorder based on Mendelian randomization analyses.
  • The variant also reduces expression of MAU2 in skeletal muscle and affects several additional nearby genes, indicating broad regulatory reach.

What the research says

Genome-wide association studies (GWAS) of 19 circulating fatty acid (FA) traits, including polyunsaturated FA (PUFA), monounsaturated FA (MUFA), and saturated FA (SFA) measures, were performed in up to 239,268 UK Biobank participants of European ancestry and five additional ancestry groups, identifying 215 genome-wide significant loci for PUFA traits, 163 for MUFA traits, and 119 for SFA traits, with 35% of loci colocalized with quantitative trait loci (QTL) signals for at least one of six molecular phenotype layers including gene expression and splicing. A companion 33-cohort meta-analysis of 233 NMR-spectroscopy-measured circulating metabolic traits in up to 136,016 participants identified more than 400 independent loci, with probable causal genes assigned at two-thirds of these through manual curation PMID 38839900. GTEx v11 expression-QTL (eQTL) data from 953 tissue donors (FDR < 0.05) show that the alternative allele at rs10401969 is associated with increased TM6SF2 (transmembrane 6 superfamily member 2) expression in tibial nerve, heart atrial appendage, thyroid, and subcutaneous adipose tissue, and with reduced MAU2 expression in skeletal muscle GTEx Portal.

Reported associations

  • Circulating fatty acid traits (19 PUFA, MUFA, and SFA measures): GWAS across three primary models in up to 239,268 European-ancestry UK Biobank participants identified hundreds of genome-wide significant loci; 35% of loci colocalized with QTL signals across six molecular phenotype layers including gene expression, protein abundance, DNA methylation, splicing, histone modification, and chromatin accessibility.
  • Circulating metabolic biomarkers (233 NMR-measured traits): A 33-cohort meta-analysis in up to 136,016 participants identified more than 400 independent loci with extensive pleiotropy at lipid-associated regions, using detailed lipoprotein profiling to characterize effects at a granular level PMID 38839900.
  • Broad metabolic phenome (249 circulating traits): Trans-ancestral meta-analysis in approximately 450,000 UK Biobank participants (European, African, and South Asian ancestries) identified 29,824 locus-metabolite associations mapping to 753 genomic regions, with effector genes assigned at more than 100 loci via rare-to-common allelic series.
  • Omega-3 fatty acids and major depressive disorder (MDD): A metabolome-wide association study in 29,757 UK Biobank participants followed by bidirectional two-sample Mendelian randomization (a statistical method using genetic variants as causal anchors) found that lower omega-3 FA levels and a higher omega-6:omega-3 ratio showed potentially causal effects on MDD liability; colocalization between the FADS gene cluster and MDD loci was detected, though evidence did not confirm a single causal variant, suggesting two variants in linkage disequilibrium (LD, meaning co-inherited through genomic proximity) may both contribute PMID 37116553.
  • Serum lipid traits with gene-by-psychosocial interaction: Multi-ancestry GWAS in up to 133,157 individuals identified 10,230 variants at 120 loci significantly associated with serum lipids; nine novel loci were detected only when modeling interactions between genetic variants and psychosocial factors such as depressive symptoms and anxiety, with four lead variants absent or rare in European-ancestry populations.
  • Adiposity and body composition across the lifespan: A 4-factor genomic structural equation model applied to 18 anthropometric measures found that the genetic signal underlying adiposity is enriched specifically in neural tissue pathways, while that for adipose distribution is enriched more broadly across physiological systems.
  • Age-related disease pleiotropy: Pleiotropic meta-analyses across five longitudinal NIH-funded datasets identified seven novel genome-wide significant loci through joint analysis of endophenotypes (blood glucose, blood pressure, lipids, BMI) and time-to-event outcomes including age-at-onset of cardiovascular disease, diabetes, and neurodegenerative disease.

Evidence quality

The strongest evidence at this locus comes from some of the largest metabolic genomics datasets assembled: a trans-ancestral metabolomics meta-analysis covered approximately 450,000 UK Biobank participants across three ancestry groups, and a 33-cohort metabolic biomarker GWAS meta-analysis included up to 136,016 participants with 13.4 million variants PMID 38839900. Multi-ancestry representation across several analyses improves generalizability beyond European populations. The fatty acid GWAS integrated six molecular phenotype layers for colocalization, providing mechanistic triangulation. The Mendelian randomization analysis supporting the MDD-omega-3 link used bidirectional two-sample MR; the authors specifically characterize the association as "potentially causal" and note that FADS cluster colocalization with MDD does not confirm a single causal variant PMID 37116553. GTEx eQTL evidence for TM6SF2 at this variant is consistent across four tissues at FDR < 0.05 in 953 donors, providing robust directional support GTEx Portal. No conflicting evidence regarding the direction of the TM6SF2 expression effect was identified across the provided studies.

Tissue-specific expression effects

  • TM6SF2: Increased expression in tibial nerve, heart atrial appendage, thyroid, and subcutaneous adipose tissue; four tissues showing consistent positive effects with the alternative allele GTEx Portal
  • ATP13A1: Increased expression in aorta GTEx Portal
  • MAU2: Reduced expression in skeletal muscle GTEx Portal
  • BNIP3P9: Reduced expression in testicular tissue GTEx Portal
  • ENSG00000294647: Reduced expression in subcutaneous adipose tissue GTEx Portal

Lifestyle considerations

  • Omega-3 fatty acids (nutrition, mixed, low): Lower circulating omega-3 fatty acid levels showed potentially causal effects on major depressive disorder liability in Mendelian randomization analyses of UK Biobank metabolomics data, situating omega-3 fatty acid biology within the broader metabolic context of this locus.

Lifestyle context

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

Diet

  • Reduce refined carbohydrates and added sugars Moderate

    High glycemic index diet worsens insulin resistance and dyslipidemia; carriers of this variant show elevated triglycerides and fatty liver risk, making carbohydrate quality critical

    Limit sugar-sweetened beverages and refined grains; emphasize whole grains, legumes, non-starchy vegetables

Exercise

  • Aerobic exercise for metabolic health optimization Moderate

    Physical activity reduces type 2 diabetes risk and improves triglyceride and lipid profiles; particularly important to offset genetic metabolic risk from this variant

    150 minutes moderate-intensity aerobic exercise per week, or 75 minutes vigorous-intensity

Screening

  • Annual diabetes screening with fasting glucose and HbA1c High

    The C allele increases type 2 diabetes risk through metabolic dysfunction; early detection via annual screening enables preventive intervention before diagnosis

    Fasting glucose or HbA1c annually; oral glucose tolerance test if borderline

  • Annual lipid panel with focus on triglycerides High

    T allele carriers show elevated triglycerides and dyslipidemia; the variant increases CAD risk through lipid and fibrinogen pathways; regular monitoring enables early intervention

    Lipid panel (total cholesterol, LDL, HDL, triglycerides) annually; more frequently if elevated

  • Ultrasound screening for non-alcoholic fatty liver disease Moderate

    The C allele increases hepatic lipid accumulation; carriers show elevated hepatic lipid grade in proportion to allele dose; ultrasound or transient elastography detects steatosis and fibrosis early

    Baseline liver ultrasound or transient elastography; repeat every 2-3 years if abnormalities present

Frequently asked questions

What does the SUGP1 gene do?

SUGP1 encodes a splicing-factor protein that helps regulate how other genes' RNA transcripts are processed and assembled. At this locus, the most prominent downstream effect documented in tissue data is on TM6SF2, a gene involved in how the liver secretes fat-carrying lipoprotein particles.

What is TM6SF2 and why does rs10401969 affect it?

TM6SF2 (transmembrane 6 superfamily member 2) plays a role in VLDL particle secretion and lipid handling. GTEx v11 data from 953 tissue donors shows the alternative allele at rs10401969 is associated with increased TM6SF2 expression in subcutaneous fat, thyroid, heart, and peripheral nerve tissue.

Is rs10401969 linked to cholesterol or triglyceride levels?

Large-scale GWAS studies of hundreds of metabolic traits and fatty acid levels in up to 450,000 UK Biobank participants have identified this chromosomal region as a significant locus for circulating lipid and fatty acid traits, with documented mechanistic links to lipoprotein metabolism.

Does this variant have any connection to depression?

UK Biobank research found that lower circulating omega-3 fatty acid levels may have a potentially causal effect on major depressive disorder based on Mendelian randomization. Because this variant influences fatty acid metabolism, it sits within the same biological pathway, though a direct confirmed association between rs10401969 genotype and depression has not been established in the studies reviewed here.

What is an eQTL and what does one mean for this variant?

An eQTL (expression quantitative trait locus) is a genetic variant statistically associated with higher or lower expression of a nearby gene in a particular tissue. For rs10401969, GTEx v11 identifies it as an eQTL for TM6SF2 across four tissues and for four additional nearby genes, providing a potential molecular mechanism behind its associations with circulating lipid and metabolic traits.