Appetite & Obesity

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

3'UTR variant in the appetite-suppression gene POMC that disrupts miRNA binding sites, altering mRNA stability and melanocortin satiety signaling

Intronic variant in PCSK1 that tags the Q665E-S690T functional haplotype, reducing prohormone convertase 1/3 activity and impairing processing of proinsulin to insulin and POMC to satiety peptides

Obesity GWAS locus in a conserved BDNF enhancer - reduces hypothalamic BDNF expression and satiety signaling, increasing caloric intake and BMI

Intronic GWAS obesity variant in MTCH2 — affects mitochondrial energy balance, adipogenesis, and fatty acid oxidation through CPT1 regulation

GIANT consortium GWAS obesity locus near GNPDA2 — affects hexosamine-pathway-mediated glucose homeostasis and adipogenesis, increasing BMI risk

Intronic EXT2 variant associated with a modest increase in type 2 diabetes susceptibility; the C allele impairs heparan sulfate-mediated insulin signaling in adipose tissue and pancreatic beta-cells.

Intronic variant in CLECL1, a dendritic-cell costimulatory C-type lectin, associated with elevated type 1 diabetes risk via modulation of T-cell immune responses

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

An intronic FTO variant outside the well-known intron-1 obesity cluster; the T allele (GRCh38 reference, ~77% globally) is associated with increased obesity risk in Asian populations, while the protective A allele reduces obesity susceptibility. Not in linkage disequilibrium with the primary FTO obesity signals (rs9939609, rs1421085).

Intergenic variant on chromosome 11q13.4 associated with circulating vitamin B12 levels in genome-wide association studies; the A allele is linked to higher serum B12 concentrations

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

Intronic variant in FSTL4 (Follistatin-Like 4) on chromosome 5q31; heterozygous GC carriers show a ~23% reduction in type 1 diabetes risk in the WTCCC genome-wide association study, though the 5q31 causal gene remains disputed due to extensive regional linkage disequilibrium

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

Promoter variant that alters alpha-2A adrenergic receptor expression, affecting adrenergic suppression of insulin secretion and lipolysis; C allele carriers show greater susceptibility to antipsychotic- and antidepressant-induced weight gain

Hypothalamic appetite regulator variant linking obesity susceptibility to migraine risk via shared neural pathways

Rare intronic variant near a DENND2C splice site associated with an 8-fold increase in type 2 diabetes risk in carriers of European ancestry.

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

MAPK signaling variant in MAP2K5 associated with BMI through altered adipogenesis via the MEK5-ERK5 pathway

Top obesity GWAS variant near NEGR1 — affects hypothalamic appetite regulation and neuronal growth

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

Upstream regulatory variant near the ghrelin receptor gene; the A allele is associated with abdominal adiposity and metabolic syndrome risk in women through altered GHSR expression

GWAS obesity locus near KCTD15 — modulates adipogenesis through AP-2 transcription factor regulation

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

Promoter variant in the ghrelin receptor gene that disrupts NF-1 transcription factor binding; the G allele preserves the binding site and elevates GHSR expression, increasing appetite drive and resistance to dietary weight loss intervention

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

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

Missense variant in PCSK1 that causes a Gln665Glu substitution in the C-terminal domain of prohormone convertase 1/3 (PC1/3), reducing enzyme activity and impairing cleavage of proinsulin to insulin, POMC to alpha-MSH, and proglucagon to GLP-1; the first of a near-obligate coding haplotype (Q665E/S690T, rs6234/rs6235) associated with modest but well-replicated obesity risk across European populations

Missense variant encoding the Ser690Thr substitution in the C-terminal domain of prohormone convertase 1/3 (PC1/3); paired with rs6234 (Q665E) in near-complete LD to form the Q665E-S690T haplotype that reduces PC1/3 enzymatic efficiency, impairing proinsulin-to-insulin conversion and POMC processing to satiety peptides, and conferring modest obesity risk

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 - influences hypothalamic appetite regulation

Activin A signaling variant near INHBA linking adipocyte dysfunction to shared migraine and type 2 diabetes risk

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

Regulatory CpG-SNP downstream of SH2B1 that reduces gene expression via allele-specific methylation, impairing leptin and insulin signaling and increasing NAFLD severity and insulin resistance risk

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

Upstream regulatory variant near INSIG2 that influences lipogenesis control and has been associated with BMI, subcutaneous fat accumulation, and obesity risk in multiple populations

GWAS obesity locus near ETV5 — affects hypothalamic appetite regulation and food reward circuitry via glucocorticoid signaling

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

Promoter-region tag SNP in the ghrelin receptor gene associated with body weight and dietary weight loss response; the T allele is linked to lower body weight and greater weight loss after both dietary intervention and bariatric surgery, likely through LD with nearby functional GHSR promoter variants

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

The most strongly replicated obesity-associated variant, affecting body weight through reduced adipocyte thermogenesis