rs509035 — GHSR GHSR Metabolic Syndrome Variant

Intronic variant in the ghrelin receptor gene; the A allele is associated with higher fat-free mass, greater stature, and elevated serum IGF-1, reflecting enhanced GHSR-driven growth hormone pulsatility and its downstream anabolic effects on body composition

See your personal result for GHSR

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 Ghrelin Receptor Variant That Shapes Lean Body Mass and IGF-1

Ghrelin does far more than signal hunger. When it docks onto GHSR-1a (growth hormone secretagogue receptor)11 GHSR-1a (growth hormone secretagogue receptor)
The canonical ghrelin receptor, expressed in the pituitary gland, hypothalamus, and across peripheral tissues. Named for its original discovery as the receptor mediating growth hormone secretion in response to synthetic GH secretagogues., it triggers a powerful pulse of growth hormone release from the pituitary. That GH pulse drives the liver to secrete IGF-1 (insulin-like growth factor 1)22 IGF-1 (insulin-like growth factor 1)
The primary mediator of GH's anabolic effects: stimulates muscle protein synthesis, promotes linear bone growth, and regulates fat metabolism. Circulating IGF-1 levels closely track GH secretion patterns over hours to days., and IGF-1 is the hormone that actually builds lean tissue — muscle, bone, connective tissue. rs509035 is an intronic variant within the GHSR gene itself, sitting at chromosome 3:172,445,659 (GRCh38). It does not change the receptor's amino acid sequence, but GWAS data from populations totalling hundreds of thousands of individuals shows that the A allele is associated with higher fat-free mass, greater adult stature, and elevated serum IGF-1 — the three expected downstream consequences of enhanced GHSR-mediated GH pulsatility.

The Mechanism

rs509035 sits within an intron of GHSR, likely in a regulatory element that influences how efficiently the gene is transcribed or the mRNA is processed. The exact molecular function has not been characterized by gel-shift or reporter assays (unlike the functionally annotated nearby promoter variant rs490683), so the mechanism is inferred from the downstream phenotype pattern rather than direct biochemical evidence. The convergence of three independent large GWAS signals — lean body mass, height, and IGF-1 — pointing to the same A allele strongly implies that A tracks with modestly elevated GHSR expression or activity, producing more frequent or larger GH pulses, more IGF-1, and consequently more lean tissue accretion over a lifetime.

Animal model support comes from studies of GHSR knockout mice33 GHSR knockout mice
Labarthe et al. 2022 (PMID 33774644): GHS-R1a deletion reduced pulsatile GH secretion, decreased linear growth, and reduced hypothalamic GHRH mRNA expression in males — demonstrating that GHSR is causally required for normal GH pulsatility and growth., which show reduced GH pulsatility and impaired linear growth when the receptor is absent. If loss of GHSR reduces lean mass and growth, it follows that variants that enhance GHSR signaling would move these phenotypes in the opposite direction — and rs509035-A appears to do exactly that at the population level.

The Evidence

The strongest evidence comes from a sex-stratified GWAS in the UK Biobank by Hübel et al. 201944 Hübel et al. 2019
Genomics of body fat percentage may contribute to sex bias in anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet. 2019;180(3):222-235. N=155,961 healthy UK Biobank participants., which identified rs509035 as a genome-wide significant hit for fat-free mass (overall beta = 0.188, p = 2×10⁻¹⁵; males beta = 0.214, p = 1×10⁻⁸; females beta = 0.151, p = 5×10⁻⁹). The effect is present in both sexes but is modestly larger in men, consistent with the testosterone–GH axis interaction in lean mass regulation.

Height GWAS results from Wood et al. 201455 Wood et al. 2014
Nature Genetics, N=253,288 adults; the A allele (frequency 0.316) shows beta = 0.031 SD per allele, p = 3×10⁻²³. confirm that the lean mass signal has a growth axis explanation — the same allele that promotes lean tissue accretion also produces slightly greater adult height.

The CHARGE Consortium IGF-1 meta-analysis by Teumer et al. 201666 Teumer et al. 2016
Aging Cell, N=30,884 European adults; rs509035 A allele associated with higher serum IGF-1, p = 2×10⁻⁸. provides the mechanistic link: the A allele is associated with higher circulating IGF-1, which is the molecular effector translating GH pulsatility into lean tissue construction. Together, these three GWAS signals (fat-free mass, height, IGF-1) form a coherent picture of enhanced GHSR-to-GH-to-IGF-1 anabolic signaling in A allele carriers.

Glucose and insulin metabolism may also be modified. In the Finnish Diabetes Prevention Study (Mager et al. 2008, N=507), rs509035 was associated with several glucose and insulin measures during 3-year follow-up77 rs509035 was associated with several glucose and insulin measures during 3-year follow-up
Mager U et al. PLoS One. 2008;3(8):e2941. The paper studied 7 GHSR SNPs in overweight adults with impaired glucose tolerance; rs509035 and rs490683 were the two variants showing significant metabolic associations., though the specific direction and magnitude of the effect for rs509035 were not separately published in the abstract. IGF-1 itself has insulin-sensitizing effects at the receptor level, so the higher IGF-1 in A allele carriers may partially explain glucose metabolism differences.

Practical Actions

For GG individuals (the majority), the GHSR intronic variant confers typical lean mass accrual potential without the enhanced GH-axis signaling that A allele carriers appear to have. For those pursuing body composition goals, the GG genotype means that lean mass gains depend primarily on training stimulus and protein adequacy rather than a genetically elevated IGF-1 floor. Monitoring IGF-1 levels is more informative for AA individuals than GG individuals, as the GG baseline is uncharacterized relative to the A allele effect.

For A allele carriers (AG and AA), enhanced GHSR-mediated GH pulsatility confers a measurable lean mass and IGF-1 advantage. This is actionable in resistance training contexts: a higher IGF-1 floor generally means faster muscle protein synthesis recovery and potentially better hypertrophic response to resistance training. Adequate protein intake (1.6–2.2 g/kg body weight daily) is necessary to fully leverage the elevated anabolic signaling environment.

Interactions

rs509035 is an intronic variant in the same GHSR gene as the promoter variants rs490683 and rs9819506, which have independent associations with appetite drive and body weight change during dietary intervention. The functional NF-1 binding site variant rs490683 (promoter) affects ghrelin receptor expression level; rs509035 (intronic) appears to operate through a downstream mechanism influencing the GH/IGF-1 anabolic axis more than appetite per se. Individuals carrying rs490683-GG (elevated appetite drive) combined with rs509035-AA (elevated IGF-1) may have a phenotype characterized by both high appetite and efficient lean tissue accretion — the genetic profile of a mesomorphic body type that gains muscle readily but also experiences strong hunger during caloric restriction.

Genotype Interpretations

What each possible genotype means for this variant.

GG Reference Genotype Normal

Reference GHSR genotype — typical GH pulsatility and IGF-1 levels

You carry two copies of the G allele, the reference sequence at this GHSR intronic position. Globally, approximately 56% of people share this genotype; in African-ancestry populations the frequency is higher (~84% GG) while in East Asian populations it is lower (~31% GG). There is no documented elevated disease risk from this genotype — your GHSR intronic variant follows the common regulatory pattern without the enhanced GH-axis signal associated with the A allele. Lean mass accrual and IGF-1 levels reflect typical population averages.

AG One A Allele Intermediate

One copy of the GHSR A allele — modestly enhanced GH pulsatility and lean mass potential

The A allele effect on fat-free mass (beta = 0.188 per allele in Hübel et al. 2019) means AG carriers carry approximately half this effect size, putting their genetically-influenced lean mass potential modestly above the population average. The height signal (Wood et al. 2014, beta = 0.031 SD per allele) and IGF-1 signal (Teumer et al. 2016, p = 2×10⁻⁸) both point to the same mechanism: slightly enhanced GHSR-mediated GH secretion driving more IGF-1 production. This is a body composition advantage, not a disease risk — AG carriers are not at elevated metabolic risk from this variant.

AA Two A Alleles High Risk

Two copies of the GHSR A allele — enhanced GH axis activity, elevated IGF-1, and above-average lean body mass potential

The full AA effect on fat-free mass corresponds to approximately 2× the per-allele beta from Hübel et al. 2019 (overall beta = 0.188 per allele in SD units). For context, a 0.376 SD difference in fat-free mass represents a clinically meaningful lean mass difference between AA individuals and the GG average. The height signal (beta ≈ 0.031 SD per allele in Wood et al. 2014; ≈0.023 SD in Yengo et al. 2022) similarly implies that AA individuals are typically slightly taller than GG individuals from the population average.

The Mager et al. 2008 Finnish Diabetes Prevention Study (N=507 adults with impaired glucose tolerance) found rs509035 associated with glucose and insulin metabolism measures, though AA-specific effect sizes were not published in the abstract. IGF-1 itself has biphasic effects on insulin sensitivity — acutely insulin-sensitizing at physiological levels, but with complex interactions at elevated levels. AA carriers may benefit from monitoring fasting glucose and IGF-1 levels periodically, particularly if metabolic risk factors are present.

The Luglio et al. 2014 study (N=78 Indonesian obese adolescents) found no association with dietary intake, suggesting rs509035 does not primarily influence appetite or food choice — the effect is concentrated in the GH/IGF-1 anabolic axis rather than the orexigenic ghrelin pathway.