rs1943226 — MC4R MC4R third tagSNP

Upstream regulatory tag variant ~3 kb proximal to MC4R, included in MC4R haplotype studies; appears in a large BMI GWAS at p=1×10⁻²⁶ through LD with the MC4R locus, with no independent obesity association established in direct association studies

See your personal result for MC4R

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.

MC4R Third TagSNP — Haplotype Depth Marker at the Brain's Appetite Locus

The melanocortin-4 receptor (MC4R) gene is the best-characterized monogenic and polygenic obesity locus known. Hypothalamic MC4R neurons sit at the convergence of leptin and melanocortin signaling: when fat stores are adequate, POMC neurons release alpha-MSH, which binds MC4R to suppress appetite and raise energy expenditure. Disrupting this pathway — by coding mutations, copy-number variants, or regulatory variants that reduce receptor expression — leads to increased food intake and fat deposition. rs1943226 sits approximately 3 kilobases upstream of the MC4R transcription start site11 3 kilobases upstream of the MC4R transcription start site
at chr18:60,367,971 GRCh38, with MC4R running from 60,371,062 to 60,372,775 on the minus strand.

This is a haplotype depth variant. GeneOps already covers rs1778231322 rs17782313
the primary MC4R-region obesity GWAS signal (~188kb downstream), replicated across >100,000 participants and rs1297013433 rs12970134
the discovery-paper waist circumference signal, p=1.7×10⁻⁹ in Indian Asians and Europeans. rs1943226 was included as a third MC4R tagSNP in a Belgian association study alongside those two, and appears in the GWAS Catalog with a BMI association at p=1×10⁻²⁶ — a large signal driven by its position in the same extended MC4R haplotype block.

The Mechanism

The MC4R gene is transcribed on the minus strand; the region just upstream on the plus strand contains regulatory DNA including the proximal promoter and early enhancer elements. rs1943226 (T>G substitution, plus strand) lies approximately 3kb upstream of the MC4R start codon, within the zone where transcription factor binding and chromatin accessibility directly influence receptor expression in hypothalamic neurons.

No functional molecular study has been published specifically for rs1943226. No electrophoretic mobility-shift assay, luciferase reporter, chromatin immunoprecipitation, or eQTL data has been reported for this variant. It is classified as a regulatory or intronic variant44 classified as a regulatory or intronic variant
Ensembl VEP classifies it as affecting a nearby transcript at position n.156+38626, with low CADD scores of 0.42 (C) and 0.38 (G), indicating minimal predicted functional impact rather than a functionally characterized regulatory element. It is more accurately understood as a genomic marker that co-segregates with the MC4R haplotype block than as a variant with established independent molecular function.

The Evidence

The most direct evidence comes from Beckers et al. (2011)55 Beckers et al. (2011)
Association study of MC4R with complex obesity in 1,049 obese Belgians vs. 312 lean controls. The authors selected rs1943226 as one of three MC4R tagSNPs (alongside rs8087522 and rs11872992) to fully capture haplotype diversity at the MC4R locus. Their results were unambiguous: "No associations with obesity could be found for rs8087522 and rs1943226." At the same time, rs17782313 replicated strongly (OR=1.42, 95% CI 1.14–1.77, p=0.002), confirming the study had adequate power to detect real MC4R-region effects. The negative result for rs1943226 indicates it does not carry independent disease-mapping information beyond what rs17782313 already captures in European ancestry.

The large GWAS signal (p=1×10⁻²⁶ for BMI) recorded in the GWAS Catalog from Zhu et al. (2020)66 Zhu et al. (2020)
UK Biobank cross-trait analysis of obesity-asthma shared genetics is almost certainly a tag signal77 tag signal
a statistical association inherited from nearby causal variants through linkage disequilibrium rather than evidence that rs1943226 is itself causal. The effect size was not separately reported for this SNP, and the paper identified the MC4R locus collectively as a shared obesity-asthma locus without attributing causality to this specific marker.

Practical Implications

For individuals carrying the G allele at rs1943226, the main value is as a haplotype indicator. A G allele at this position marks co-occurrence with the same extended MC4R regulatory region that overlaps rs17782313 and rs12970134. If those primary variants are also present, their associated advice (waist circumference monitoring, insulin resistance awareness, structured meal timing) applies. The rs1943226 G allele adds depth to the haplotype picture but does not independently change the clinical recommendation set beyond what the primary MC4R variants already indicate.

The South Asian population carries the highest G-allele frequency at ~13.6% (vs. ~8.9% European, ~1.5% African, ~0% East Asian), consistent with the broader MC4R locus showing stronger signals for central adiposity in South Asian populations, where waist circumference risk is often more clinically relevant than BMI alone.

Interactions

rs17782313 and rs12970134: These are the primary functional signals at the MC4R locus. rs1943226 was explicitly tested in studies alongside them and found to carry no independent association. The three variants tag different aspects of the same haplotype block; if rs17782313 or rs12970134 risk alleles are present, those entries contain the actionable recommendations for MC4R-related adiposity and insulin resistance.

rs8087522: The Beckers 2011 study found no obesity association for rs8087522 and rs1943226 in the same analysis, suggesting they tag similar null-effect haplotypes at the proximal MC4R upstream region. rs8087522 has a separate signal in antipsychotic-induced weight gain through proposed transcription factor binding site creation; whether rs1943226 shares that pharmacogenomic signal has not been studied.

Genotype Interpretations

What each possible genotype means for this variant.

TT Common Haplotype Normal

Common TT genotype — reference sequence at the MC4R upstream locus

You carry two copies of the T reference allele at rs1943226, the most common configuration at this MC4R upstream locus. About 84–85% of people globally share this genotype (approximately 83% of Europeans). Direct association studies have found no obesity risk attributable to the T allele, and this genotype does not add independent information about MC4R-mediated appetite regulation beyond your results at the primary MC4R variants rs17782313 and rs12970134.

GT G-Allele Carrier Normal

One G allele — MC4R upstream haplotype marker, no established independent obesity risk

The Beckers 2011 study genotyped rs1943226 specifically to determine whether it tagged an independent MC4R haplotype associated with obesity in 1,049 obese and 312 lean Belgian adults. Unlike rs17782313 (which replicated at OR=1.42, p=0.002), rs1943226 showed no association. This design — a well-powered direct test — establishes that any BMI signal at rs1943226 in genome-wide association scans reflects LD with the established MC4R causal variants rather than an independent effect of this SNP.

The South Asian population carries the highest G-allele frequency at ~13.6%, which aligns with the MC4R locus showing particularly strong central adiposity signals in South Asian cohorts.

GG Homozygous G Allele Normal

Two G alleles — rare homozygous configuration; MC4R haplotype marker with no established independent obesity effect

The rarity of GG (under 1% globally) means it was unlikely to have been separately analyzed in the Beckers 2011 study, where even the full G-allele carrier group showed no obesity association. The absence of an independent signal for this variant means homozygosity does not confer an established additional metabolic risk layer beyond what the primary MC4R haplotype variants indicate.

Given the very low East Asian frequency (~0%) and modest South Asian frequency (~1.8%), finding GG is most likely in European or South Asian individuals with a strong co-inheritance of the extended MC4R haplotype region.