rs1943226 — MC4R MC4R third tagSNP

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.