Blood Sugar & Diabetes

Intronic variant in WFS1 (wolframin) on chromosome 4q22, one of the earliest and most replicated common genetic risk factors for type 2 diabetes

Intergenic variant between GRB14 and COBLL1 that acts as an eQTL for GRB14 in adipose tissue, shifting body fat toward peripheral (hip and limb) versus central (visceral) deposition

Intronic variant in YKT6 immediately downstream of GCK; the A allele is a GWAS-identified common risk allele for type 2 diabetes with a modest additive effect on fasting glucose dysregulation

ENPP1 K121Q variant that increases ENPP1 binding affinity to the insulin receptor by 2–3 fold, blunting insulin signaling and raising insulin resistance risk.

Pathogenic glucokinase missense variant that nearly abolishes enzyme activity, causing autosomal dominant maturity-onset diabetes of the young type 2 (MODY2) in heterozygous carriers and permanent neonatal diabetes when homozygous

Pathogenic glucokinase missense variant causing MODY2 — mild, stable fasting hyperglycemia that typically requires no pharmacologic treatment

Regulatory variant upstream of CDKN2A/CDKN2B at the 9p21 locus; the T risk allele (major, ~83% globally) impairs cyclin-dependent kinase inhibitor expression and reduces beta-cell proliferative capacity, increasing type 2 diabetes risk by ~24% per allele

Intergenic variant near ADRA2A

Intronic TCF7L2 variant tagging the diabetes-risk haplotype and associated with elevated proinsulin/insulin ratio through impaired beta-cell insulin processing

Primary tag SNP at the HHEX/IDE locus on chromosome 10q23, one of the earliest and most replicated T2D GWAS hits, linked to reduced HHEX expression, impaired beta-cell development, and blunted first-phase insulin secretion

3-prime UTR variant in the SLC30A8 zinc transporter gene that alters ZnT8 mRNA expression via allele-specific mechanisms, providing additional signal on zinc-mediated insulin processing and type 2 diabetes susceptibility at this locus

Common coding variant in the HNF1A transcription factor dimerization domain that modestly reduces beta-cell function and transactivation activity, raising LDL cholesterol and lowering CRP, while increasing type 2 diabetes risk in normal-weight individuals and accelerating diabetes onset in MODY3 carriers

Upstream regulatory variant in IGF2BP2 that shifts mRNA isoform balance in adipose tissue and pancreatic islets, impairing insulin secretion and increasing insulin resistance risk, with moderate evidence for type 2 diabetes susceptibility

Intronic regulatory variant that reduces ADCY5 expression in pancreatic islets, impairing glucose-stimulated cAMP production and insulin secretion, and raising fasting glucose and type 2 diabetes risk

Intronic TCF7L2 depth variant replicated across multiple populations as a secondary type 2 diabetes risk signal, likely tagging a distinct regulatory element that modulates Wnt/TCF7L2-driven proglucagon expression and incretin signaling depth

Second TCF7L2 diabetes variant - compounds risk with rs7903146

Intronic INSR variant that may alter insulin receptor expression or isoform balance, linked to insulin signaling and psychiatric risk

Zinc transporter 8 variant affecting zinc loading into insulin granules, influencing insulin crystallization, secretion, and type 2 diabetes risk

Intronic GLIS3 variant in which the rare A allele modestly elevates TSH, reflecting reduced thyroid transcriptional activity; the same gene drives pancreatic beta cell development, linking thyroid-axis regulation to metabolic energy balance

Intronic tag SNP at the 12q24 locus, increasing risk for type 1 diabetes, juvenile idiopathic arthritis, and other autoimmune diseases; also associated with modest effects on lipid levels

Synonymous variant in the tyrosine kinase domain of the insulin receptor; the A risk allele (plus-strand) is associated with PCOS susceptibility and insulin resistance in lean women, possibly through altered mRNA processing near the ATP-binding site of the receptor kinase domain

Missense variant in the skeletal muscle glycogen-targeting subunit of protein phosphatase 1 (PP1)

Missense variant in HNF4A causing hepatocyte-specific loss of transcriptional activity; associated with early-onset type 2 diabetes and metabolic syndrome, particularly in Latino and Asian populations

Missense variant in insulin receptor substrate 1 that impairs tyrosine phosphorylation and PI3-kinase recruitment, reducing insulin signaling and increasing type 2 diabetes risk and oral antidiabetes drug failure

Intronic INSR variant associated with PCOS susceptibility and metabolic syndrome risk through altered insulin receptor signaling

Synonymous exon 13 variant in the insulin receptor gene; the A allele has been associated with schizoaffective disorder and modestly with body height in psychiatric cohort studies

Missense variant that impairs PAX4's ability to repress insulin and glucagon promoters, reducing beta-cell mass and insulin secretion capacity; strongly associated with type 2 diabetes and younger age of onset in East and Southeast Asian populations

Intronic GCK variant 38 bp downstream of exon 7; the A allele (GRCh38 reference, minor at ~43% globally) has been associated with gestational diabetes risk in some small studies, though evidence is limited and inconsistent across populations

TRIB3 pseudokinase missense variant that increases Akt inhibition, impairing insulin signaling across liver, muscle, and pancreatic beta cells, with associated risk for insulin resistance and type 2 diabetes

3'UTR variant in the zinc transporter ZnT8 gene that disrupts miRNA binding sites, altering ZnT8 expression in pancreatic beta cells and influencing type 2 diabetes, type 1 diabetes, and gestational diabetes risk

Regulatory tagging SNP near SGK1 (serum/glucocorticoid regulated kinase 1) — the major T allele is associated with salt-sensitive blood pressure, higher systolic BP on high-sodium diets, and attenuated plasma renin activity suppression on low-sodium diets; the minor C allele provides partial protection from salt-driven blood pressure excursions.

Regulates insulin signaling efficiency and cellular glucose uptake

Rare gain-of-function variant causing autosomal dominant metabolic syndrome (AOMS3) — early-onset central obesity, insulin resistance, hypertriglyceridemia, and type 2 diabetes

Intronic PTPN1 tag SNP within the 100-kb PTP1B insulin-resistance haplotype block; the minor C allele co-segregates with the risk haplotype associated with elevated PTP1B expression and impaired insulin signaling

Intronic PTPN1 tag SNP within the 100-kb insulin-resistance haplotype block; carriers of the T allele show reduced weight loss response to lifestyle intervention and blunted leptin reduction

Intronic variant in serine racemase that alters D-serine production in pancreatic beta cells, modulating NMDA receptor signaling and glucose-stimulated insulin secretion; C allele associated with increased type 2 diabetes risk, particularly in East Asian populations

Pathogenic glucokinase missense variant causing maturity-onset diabetes of the young type 2 (MODY2) — lifelong mild fasting hyperglycemia that rarely requires treatment and is frequently misdiagnosed as type 1 or type 2 diabetes

Common variant near glucokinase that raises fasting glucose by impairing the pancreatic glucose-sensing threshold; each A allele adds ~0.062 mmol/L to fasting glucose and modestly reduces beta-cell function

Intronic PTPRS variant that tags elevated type 2 diabetes risk in both sexes through increased receptor protein tyrosine phosphatase sigma activity, which dephosphorylates insulin-signalling substrates and attenuates both pancreatic insulin secretion and peripheral insulin sensitivity

Common intronic variant in HNF4A associated with modestly elevated type 2 diabetes risk via reduced pancreatic beta-cell function; identified through GWAS in South Asian and European populations

Severe Class II G6PD deficiency variant (c.563C>T, p.Ser188Phe) causing less than 10% residual enzyme activity and high risk of acute hemolytic anemia from drugs, fava beans, and infections; prevalent across Mediterranean, Middle Eastern, and South Asian populations

A regulatory 3' UTR variant in KCNJ11 that modulates KATP channel expression via microRNA binding, influencing insulin secretion and sulfonylurea drug response

Secondary T2D risk variant at the 9p21 CDKN2A/B locus within ANRIL (CDKN2B-AS1); the T risk allele impairs glucose-stimulated pancreatic beta-cell proliferation, conferring a modest but independently replicated ~8% increased type 2 diabetes risk per allele

Multi-allelic pathogenic locus — both H90P (T>G) and H90R (T>C) disrupt the DYRK1B DH box, causing AOMS3 (early-onset central obesity, type 2 diabetes, hypertension, coronary artery disease) via impaired kinase maturation

Intronic HNF4A tag SNP associated with altered bile acid synthesis regulation through modified HNF4A-driven CYP7A1 expression; linked to primary biliary cholangitis progression in a single Japanese cohort study

Intronic PTPN1 tag SNP in the PTP1B regulatory LD block; the minor A allele is associated with elevated total and LDL cholesterol in lean men

Intronic PTPN1 tag SNP raising LDL cholesterol risk in lean individuals

Pleiotropic 12q24 locus variant in SH2B3 (LNK) modulating JAK-STAT cytokine signaling, with associations spanning blood pressure, celiac disease, and coronary artery disease

Intergenic variant near CTRB1/CTRB2 that regulates chymotrypsinogen expression and GLP-1-stimulated insulin secretion; T allele carriers have mildly impaired incretin-driven beta-cell response and modestly elevated type 2 diabetes risk

Missense variant in glucose-6-phosphate dehydrogenase causing Class III G6PD deficiency (~50% residual enzyme activity), associated with hemolytic anemia triggered by fava beans, infections, and specific drugs

Intronic GCKR enhancer variant on the CGG regulatory haplotype; the G allele increases FOXA2-driven GCKR expression in the liver, boosting GKRP protein levels and glucokinase inhibition, resulting in elevated fasting glucose and the characteristic GCKR metabolic trade-off

Main type 2 diabetes risk variant - strongly modulated by dietary fat

Regulatory variant in SGK1 (serum/glucocorticoid regulated kinase 1) — the minor G allele is associated with improved insulin secretion in lean individuals and a modest reduction in type 2 diabetes prevalence, while also modifying blood pressure response to high dietary salt intake.

Intronic PTPN1 variant tagging a haplotype block associated with reduced insulin sensitivity, higher fasting insulin, and elevated lipids through altered PTP1B expression