rs6548238 — TMEM18

Second strongest obesity GWAS locus after FTO - influences hypothalamic appetite regulation

See your personal result for TMEM18

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Brain's Hidden Weight Controller

TMEM18 (Transmembrane Protein 18) sits at the second strongest obesity locus ever discovered by genome-wide association studies, trailing only FTO. The variant rs6548238 lies 23 kilobases upstream of TMEM18 on chromosome 2p25.3, in a regulatory region that influences how much TMEM18 protein the brain produces. What makes this gene remarkable is where it acts: deep within the hypothalamus11 hypothalamus
The brain region that controls hunger, thirst, body temperature, and energy balance, specifically the paraventricular nucleus (PVN)22 paraventricular nucleus (PVN)
A cluster of neurons in the hypothalamus that integrates hunger and satiety signals and regulates energy expenditure, the brain's central command for appetite and energy expenditure.

The Mechanism

TMEM18 encodes a protein with four transmembrane domains that localizes to the nuclear membrane, where it physically interacts with components of the nuclear pore complex33 nuclear pore complex
The channel through which molecules pass between the cell nucleus and cytoplasm. Its expression in the PVN is nutritionally regulated -- it responds to feeding state and leptin44 leptin
The "satiety hormone" produced by fat cells that signals the brain to reduce appetite signaling. In functional studies, mice lacking TMEM1855 mice lacking TMEM18
Larder et al. TMEM18 has a role in the central control of appetite and body weight regulation. PNAS, 2017 showed increased body weight driven by hyperphagia (overeating), particularly on a high-fat diet. Conversely, overexpressing TMEM18 in the PVN reduced food intake, increased energy expenditure, and decreased both total body mass and fat mass. This demonstrates that TMEM18 acts as a brake on appetite: less TMEM18 means more eating.

The Evidence

The GIANT consortium GWAS66 GIANT consortium GWAS
Willer et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics, 2009 first identified this locus in a meta-analysis of over 32,000 individuals, with replication in 59,000 more, reaching genome-wide significance (p = 3.2 x 10-26) with a per-allele BMI increase of 0.26 kg/m2 for the C allele.

A comprehensive meta-analysis77 comprehensive meta-analysis
Li et al. The association between polymorphisms near TMEM18 and the risk of obesity: a meta-analysis. BMC Medical Genomics, 2021 pooling 27 studies with 53,395 obesity cases and 123,972 controls confirmed the association with an overall odds ratio of 1.25 (95% CI: 1.08-1.45). The effect was strongest in Europeans (OR 1.32) and Mexicans (OR 1.39). Notably, the association was more robust in children (OR 1.28, 95% CI: 1.18-1.39) than in adults, and one study found TMEM18 variants conferred the strongest effect on pediatric BMI88 strongest effect on pediatric BMI
Almen et al. TMEM18 variants associated with BMI and waist circumference in children. European Journal of Human Genetics, 2012 out of 25 obesity-associated variants tested in 6,078 children.

The C allele is very common -- around 83-91% frequency depending on ancestry -- meaning most people carry the risk version. The protective T allele is found in only about 9-17% of chromosomes. Because the risk allele is the major allele, the CC genotype (highest risk) is also the most common genotype (~70% of people).

Practical Implications

Because the C risk allele is so prevalent, carrying CC does not mean inevitable obesity -- it means your hypothalamic appetite signaling provides less restraint than the uncommon TT genotype. The effect is modest per allele (0.26 kg/m2 BMI), but it compounds across the many obesity-risk loci each person carries. For CC homozygotes, proactive appetite management strategies -- particularly protein-first meals and structured eating patterns -- can counteract the reduced hypothalamic brake on hunger.

Interactions

TMEM18 acts independently of FTO (rs9939609) and MC4R (rs17782313) -- the three loci are in linkage equilibrium and their effects on BMI are additive. A person carrying risk alleles at all three loci faces a meaningfully higher cumulative genetic load for obesity than someone with risk alleles at only one. While no synergistic gene-gene interaction has been documented (each adds its own effect independently), the combined burden of risk alleles across FTO, TMEM18, and MC4R creates a significantly higher baseline appetite drive that warrants proactive management strategies.

Genotype Interpretations

What each possible genotype means for this variant.

TT Lower Appetite Drive Normal

Two protective alleles - optimal hypothalamic appetite regulation

You carry two copies of the protective T allele at the TMEM18 locus, found in only about 4% of the global population. This is the most favorable genotype for TMEM18-mediated appetite control. Functional studies show that higher TMEM18 activity in the hypothalamic paraventricular nucleus reduces food intake and increases energy expenditure.

Your per-allele BMI advantage of 0.52 kg/m2 (two copies at 0.26 each) compared to CC homozygotes translates to naturally better appetite regulation from this brain region.

CT Moderate Appetite Drive Intermediate

One risk allele - intermediate appetite regulation

You carry one copy each of the C (risk) and T (protective) allele at the TMEM18 locus. About 26% of people share this genotype. Your hypothalamic appetite suppression from TMEM18 is intermediate -- better than CC homozygotes but not as effective as the rare TT genotype.

Each T allele is associated with 0.26 kg/m2 lower BMI, so your single protective copy provides a modest advantage compared to the 70% of people who carry CC.

CC Higher Appetite Drive High Risk

Two risk alleles - reduced hypothalamic appetite suppression

Functional studies in mice demonstrate that loss of TMEM18 function leads to increased body weight driven by hyperphagia (overeating), particularly on a high-fat diet. The CC genotype is associated with the lowest level of TMEM18-mediated appetite suppression. TMEM18 expression in the PVN is nutritionally regulated and responds to leptin, suggesting the C allele variant may impair the brain's response to satiety signals.

The association with increased waist circumference, fasting glucose, HbA1c, triglycerides, and LDL cholesterol suggests effects beyond appetite alone, potentially contributing to metabolic syndrome risk.