Appetite & Obesity

Obesity and waist circumference GWAS hit in NRXN3 — links reward-circuit synaptic function to appetite dysregulation and addictive eating patterns

Intronic variant in PCSK1 that tags the Q665E-S690T functional haplotype

Intronic GWAS obesity variant in MTCH2 — affects mitochondrial energy balance, adipogenesis, and fatty acid oxidation

GIANT consortium GWAS obesity locus near GNPDA2

Intronic variant in CLECL1, a dendritic-cell costimulatory C-type lectin, associated with elevated type 1 diabetes risk

Intergenic variant in the proximal 3' regulatory block near MC4R associated with increased BMI, body fat percentage, elevated leptin, and severe obesity risk

Near-gene variant ~188kb downstream of MC4R associated with increased waist circumference, insulin resistance, and obesity risk through the same regulatory block as rs17782313

Intergenic variant 188kb downstream of MC4R affecting appetite regulation, meal size, and obesity risk

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

Missense variant in MC4R converting valine to isoleucine at position 103; the I103 allele confers modest but replicable protection against obesity and improves metabolic syndrome components

Top obesity GWAS variant near NEGR1

Regulatory variant at the TMEM18 locus on chromosome 2p25.3 — one of the most replicated obesity GWAS signals — modulating hypothalamic appetite suppression via the paraventricular nucleus

GWAS obesity locus near KCTD15

Common MC3R missense variant that reduces receptor expression and shifts nutrient partitioning toward fat storage, particularly when co-inherited with the Thr6Lys variant (rs3746619)

Intergenic variant in the MC4R regulatory haplotype block, tagging the same appetite-suppression pathway as rs17782313 and associated with increased BMI, fat mass, and obesity risk

Intronic variant at the SH2B1 locus on chromosome 16p11.2 — a key adaptor protein in hypothalamic leptin and insulin signaling; A allele is associated with increased BMI and metabolic risk in large GWAS studies

Intergenic variant near MC4R with genome-wide significant association with antipsychotic-induced weight gain, particularly olanzapine and clozapine; also tags the MC4R locus for general BMI effects

Regulatory variant upstream of MC4R associated with increased caloric intake, elevated BMI, and obesity risk through reduced MC4R satiety signaling

Missense variant in PCSK1 encoding an Asn221Asp substitution near the Ca-1 calcium binding site of prohormone convertase 1/3 (PC1/3); impairs catalytic activity by approximately 10%, reducing cleavage of proinsulin to insulin, POMC to alpha-MSH, and proglucagon to GLP-1; the strongest functionally-characterized common PCSK1 coding variant, with OR 1.15 for obesity in meta-analysis of over 331,000 individuals across multiple ethnic groups

Intergenic regulatory variant near NCK1 at 3q22.3; in strong linkage disequilibrium (r²=0.95) with rs1866813, a remote cis-regulatory variant that increases NCK1 expression in glomerular podocytes, elevating risk of diabetic nephropathy in type 1 diabetes patients

Second strongest obesity GWAS locus after FTO

Missense variant in the ghrelin prepropeptide that impairs postprandial ghrelin suppression, increasing appetite, sugar intake, and metabolic syndrome susceptibility

Obesity GWAS missense variant in SH2B1 that impairs leptin signaling and increases visceral fat and type 2 diabetes risk

GWAS obesity locus near ETV5

Promoter variant that increases leptin gene expression in adipose tissue, elevating circulating leptin and raising obesity, insulin resistance, and metabolic syndrome risk

Upstream regulatory variant near MC4R that may create a transcription factor binding site, with emerging evidence linking the A allele to greater weight gain during clozapine treatment

Adipocyte transcription factor variant influencing central fat distribution and modifying weight-loss response to dietary fat