rs29941 — KCTD15

GWAS obesity locus near KCTD15

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KCTD15 — Linked to Obesity

KCTD15 (Potassium Channel Tetramerization Domain-Containing 15) was identified as an obesity-associated gene through large-scale genome-wide association studies. The rs29941 variant sits in an intergenic region on chromosome 19 near KCTD15, and the G allele has been consistently associated with modestly increased BMI and obesity risk across multiple populations.

The Mechanism

KCTD15 is a member of the KCTD protein family that shares a common BTB domain11 BTB domain
Bric-a-brac, Tramtrack, Broad complex domain — a protein-protein interaction motif at its N-terminal. The protein acts as a potent inhibitor of AP-2 transcription factors22 AP-2 transcription factors
Activating Protein 2, critical regulators of neural crest development and adipocyte differentiation. By binding directly to the activation domain of AP-2alpha, KCTD15 blocks its function in the neural crest induction hierarchy.

AP-2alpha regulates the activity of C/EBPalpha33 C/EBPalpha
CCAAT/enhancer-binding protein alpha, a master regulator of fat cell differentiation during adipogenesis.

Additionally, KCTD15 attenuates the Wnt/beta-catenin signaling pathway44 Wnt/beta-catenin signaling pathway
a key developmental pathway that also regulates adipocyte precursor commitment.

The Evidence

The GIANT consortium meta-analysis55 GIANT consortium meta-analysis
Willer et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics, 2009 of more than 32,000 individuals first identified KCTD15 as a genome-wide significant BMI locus (P < 5 x 10-8). This was confirmed in an expanded analysis of 249,796 individuals66 expanded analysis of 249,796 individuals
Speliotes et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genetics, 2010.

The association has been replicated in East Asian populations77 replicated in East Asian populations
Ng et al. Implication of genetic variants near obesity loci with obesity and type 2 diabetes in 7,705 Chinese. J Clin Endocrinol Metab, 2010, though allele frequencies differ substantially (G allele: ~82% in Africans, ~68% in Europeans, ~24% in East Asians).

Practical Actions

As a common GWAS hit with a modest per-allele effect, this variant represents one piece of a larger genetic obesity risk profile.

Interactions

KCTD15 rs29941 contributes to polygenic obesity risk alongside FTO rs9939609, MC4R rs17782313, MTCH2 rs10838738, and ETV5 rs7647305. Genetic risk score analyses show that carrying risk alleles at multiple loci has a cumulative effect on BMI.

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard Adipogenesis Normal

No increased obesity risk from this locus

You carry no copies of the G risk allele at the KCTD15 locus. About 9% of people of European descent share this genotype, though it is considerably more common in East Asian populations (~58%).

AG Mildly Increased Adipogenesis Intermediate

One risk allele — modestly increased obesity susceptibility

You carry one copy of the G allele at the KCTD15 locus. About 42% of Europeans share this genotype. The per-allele effect on BMI is approximately 0.06-0.07 kg/m2. This is a modest effect that becomes more meaningful if you also carry risk alleles at other obesity loci (FTO, MC4R, MTCH2).

GG Enhanced Adipogenesis High Risk

Two risk alleles — increased adipogenesis and obesity susceptibility

You carry two copies of the G allele at the KCTD15 locus. About 49% of Europeans share this genotype, making it the most common genotype in this population. The combined effect on BMI is approximately 0.12-0.14 kg/m2. While this effect is modest alone, it compounds significantly with risk alleles at other obesity loci.