rs7647305 — ETV5

GWAS obesity locus near ETV5

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ETV5 — The Hypothalamic Switch for Appetite and Reward

ETV5 (E-Twenty-Six Version 5) is an obesity-associated transcription factor expressed in key brain regions that regulate energy balance, appetite, and food reward. The rs7647305 variant sits in the regulatory region upstream of ETV5 on chromosome 3, and the C allele has been consistently associated with increased BMI and obesity risk across large GWAS.

The Mechanism

ETV5 is a member of the PEA3 group11 PEA3 group
a subfamily of ETS transcription factors involved in development and neural function of ETS transcription factors. In the brain, it is primarily expressed in the arcuate nucleus22 arcuate nucleus
a hypothalamic region containing hunger-sensing and satiety neurons (AGRP/NPY and POMC/CART), the ventromedial hypothalamus33 ventromedial hypothalamus
a brain region critical for energy homeostasis and satiety signaling, and the ventral tegmental area44 ventral tegmental area
the origin of dopaminergic reward neurons that project to the nucleus accumbens.

ETV5-deficient mice have reduced body weight, lower fat mass, and are resistant to diet-induced obesity. The gene's expression in hypothalamic nuclei changes with nutritional state — its transcription in the arcuate nucleus and VTA is altered by diet and food availability55 altered by diet and food availability
Gutierrez-Aguilar et al. Nutritional state affects the expression of the obesity-associated genes. Obesity, 2012, linking it directly to feeding behavior.

ETV5 also modulates the HPA axis66 HPA axis
hypothalamic-pituitary-adrenal axis, the body's central stress response system that regulates cortisol. ETV5-deficient animals show decreased expression of glucocorticoid receptors, mineralocorticoid receptors, and vasopressin receptors in the hypothalamus, resulting in elevated circulating glucocorticoids. This cortisol dysregulation promotes visceral fat deposition and insulin resistance.

The Evidence

In 18,014 Danish adults77 18,014 Danish adults
Haupt et al. Studies of metabolic phenotypic correlates of 15 obesity associated gene variants. PLoS ONE, 2011, the C allele at rs7647305 was associated with an obesity odds ratio of 1.18 (95% CI 1.08-1.29, P = 1.8 x 10-4) and a per-allele BMI increase of approximately 0.22 kg/m2.

The association extends beyond BMI: the variant has been independently linked to childhood hypertension88 independently linked to childhood hypertension
Wang et al. Two obesity susceptibility loci in LYPLAL1 and ETV5 independently associated with childhood hypertension in Chinese population. Gene, 2017 in a Chinese population.

Interactions

ETV5 rs7647305 contributes to polygenic obesity risk alongside FTO rs9939609, MC4R rs17782313, KCTD15 rs29941, and MTCH2 rs10838738.

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Appetite Regulation Normal

Protective genotype — standard hypothalamic appetite signaling

You carry two copies of the protective T allele at the ETV5 locus. Only about 8% of Europeans share this genotype, though it is more common in African populations (~21%).

CT Moderate Obesity Risk Intermediate

One risk allele — slightly higher BMI and obesity risk

You carry one copy of the C risk allele and one protective T allele at the ETV5 locus. About 38% of Europeans share this genotype. Your per-allele increase in BMI is approximately 0.22 kg/m2 — a modest effect that becomes more meaningful in the context of your overall genetic risk profile.

CC Increased Obesity Risk High Risk

Two risk alleles — higher BMI and obesity risk at this locus

You carry two copies of the C allele at the ETV5 locus. About 54% of Europeans share this genotype, making it the most common. The C allele is even more prevalent in East Asian populations (~93%).