Type 2 Diabetes

2026-04-29 · Mass General Brigham Heart and Vascular Institute & Broad Institute of MIT and Harvard, published in JACC (245,394 All of Us participants; validated in a separate 53,306-person biobank cohort)

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions

Researchers combined publicly available polygenic risk scores for 8 cardiovascular conditions (coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism, thoracic aortic aneurysm, extreme hypertension, severe hypercholesterolemia, elevated Lp(a)) into one integrated report, trained on 245,394 All of Us participants and validated in a separate 53,306-person biobank. People in the top 10% of genetic risk were 3.7x more likely to develop coronary artery disease and 3.1x more likely to develop type 2 diabetes than those at average risk. The test is now clinically available through Mass General Brigham's Laboratory for Molecular Medicine and Broad Clinical Labs -- a risk score, not a diagnosis or treatment.

2026-09-08 · Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D. Diabetes, Obesity and Metabolism. 2026. DOI:10.1111/dom.71302

Type 2 diabetes diagnosed before 55 and after 70 look genetically different, not just clinically different

Using 74,795 UK Biobank participants, this study ran separate GWAS for type 2 diabetes diagnosed before age 55 (early-onset) versus at or after age 70 (late-onset) rather than treating T2D as one uniform trait. SNP-based heritability was nearly double for early-onset disease (11.2% vs 6.4%), and the two subtypes pointed to different biology: early-onset T2D was driven by beta-cell function and insulin-regulation genes, including SLC30A8 and IRS1 -- both already on this site's own type 2 diabetes page -- while late-onset T2D showed a more lipid-related genetic profile centered on APOE-associated signals and immune-cell expression patterns, a gene not previously linked to T2D on this site. Mendelian randomization found early-onset disease shared broader genetic overlap with cardiometabolic traits generally, while late-onset disease tracked more closely with classic metabolic risk factors -- evidence that age at diagnosis is not just a clinical detail but marks a real difference in underlying genetic architecture. This site's type 2 diabetes page carries 138 variants including SLC30A8 and IRS1; the study's specific SNPs were not yet indexed in GWAS Catalog with p-values at the time of writing, so this entry adds context rather than a new variant page.

2026-02-25 · A genome-wide association study identifies EYA2 as a contributing gene for diabetic retinopathy in type 2 diabetes. Communications Medicine. 2026. DOI:10.1038/s43856-026-01465-1

A gene-level study finds type 2 diabetes causally drives diabetic retinopathy risk, via EYA2 and proinsulin

Diabetic retinopathy (DR) is a well-known complication of type 2 diabetes (T2D), but it was unclear how much of that connection is truly causal at the genetic level versus simply co-occurring. Using 16,988 T2D patients from UK Biobank, this study found a genome-wide significant lead SNP, rs6066146 in EYA2 (P=4.21x10^-8), associated with DR risk and replicated in three independent cohorts -- SNP-based heritability for DR was estimated at 14.6%. Colocalization analysis found moderate but distinct overlap between the DR and T2D signals at this locus, and critically, cis-Mendelian randomization provided gene-centric evidence that T2D itself exerts a causal effect on DR risk -- not just a shared risk factor coincidentally affecting both. A follow-up multivariable MR analysis identified proinsulin specifically as a significant mediator of that T2D-to-DR causal pathway. Tissue and pathway analyses pointed toward the spleen and B-cell biology as relevant, suggesting splenic B-cell abundance could eventually serve as a predictive marker for DR risk. This site's type 2 diabetes page carries 138 variants; EYA2 is not currently among them, and this finding is specifically about the diabetic retinopathy complication rather than T2D risk itself, so it is recorded as complication-specific context on the page rather than a general T2D variant.

2026-04-23 · PLOS Medicine

Largest-ever lipid metabolite GWAS in South Asians finds a diabetes-linked and a heart-protective variant

A metabolite GWAS of 516 lipid species in 3,000 Punjabi Sikhs (validated in 1.13M Europeans and 15,000 additional Asian Indians) found 609 SNP-metabolite associations, 33 of them never reported before. Mendelian randomization pointed at two variants with likely causal roles: a PTPRC (CD45) variant near LPC O-16:0 tied to type 2 diabetes risk, and a FADS1 3' UTR variant (rs174544) tied to a lipid that appears protective against coronary artery disease (OR 1.36 for the risk allele). PMID:42024661.

2026-04-15 · Bandesh K, Motakis E, Nargund S, et al. (The Jackson Laboratory), The EMBO Journal

Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects

A single-cell atlas of nearly 250,000 pancreatic islet cells from 48 donors (non-diabetic, prediabetic, and diabetic) found 511 genes with altered activity in type 2 diabetes beta cells, narrowed to 58 genes likely contributing to beta cell dysfunction -- centered on cell death and vitamin A metabolism pathways. This is an expression-atlas study, not a GWAS: its specific genes (including newly flagged GRAMD2B and PDZK1) are not among the 273 type 2 diabetes variants already in this catalogue, but it is a real mechanistic companion to why those variants matter. PMID:41986506.

2026-05-22 · Sinnott-Armstrong N, et al., Nature Communications 2026, PMID:42173832

Genetic variants affect diurnal glucose levels throughout the day

Circadian rhythms regulate glucose metabolism as well as sleep, but which genetic variants govern the timing of glucose had not been examined. Using the time of day each blood sample was taken, this study of about 420,000 UK Biobank participants — replicated in the Estonian Biobank, FinnGen, the VA Million Veteran Program and the MGB Biobank — shows that glucose levels are under diurnal genetic control. The two robust time-dependent signals are at MTNR1B, the melatonin receptor (rs10830963), and at CRY2, a core circadian clock gene (rs12419690). Sleep modulated glucose levels, the variants acted independently of sleep, they independently changed the risk of type 2 diabetes, and sleep medications including melatonin were associated with type 2 diabetes. Those two headline positions are not on this site yet; 21 other positions from the study are, among them rs560887 (G6PC2), rs34872471 (TCF7L2), rs3802177 (SLC30A8) and rs11708067 (ADCY5). PMID:42173832.

2026-06-01 · Brito Nunes C, et al., Nature Communications 2026, PMID:42225636

Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects

Gestational diabetes affects about 14% of pregnancies and raises the mother's later risk of type 2 diabetes. The GenDiP Consortium's meta-analysis covers up to 38,305 women with gestational diabetes and 776,145 controls and finds 37 associated loci, 7 of them new, plus five new loci for blood sugar traits in pregnancy — all acting through the mother's genome rather than the baby's. Every locus overlaps type 2 diabetes or glycaemic traits outside pregnancy, which is the 'limited evidence' of the title; but 12 variants have stronger effects in gestational diabetes than in type 2 diabetes, four loci (G6PC2, CAST-PCSK1, HKDC1, FOXA2) have no genome-wide-significant type 2 diabetes association, GCK shows distinct causal variants, and MTNR1B's effect is amplified in pregnancy. Seven of the study's positions are on this site under other traits, including rs560887 (G6PC2), rs11558471 (SLC30A8), rs849134 (JAZF1) and rs4665972 (GCKR). It sits beside this site's gestational diabetes page, which is built on a separate 2026 study. PMID:42225636.

Definition and diagnosis. Type 2 diabetes is a chronic disorder of glucose homeostasis characterised by insulin resistance with progressive beta-cell dysfunction. Diagnosis rests on fasting plasma glucose, HbA1c or a two-hour value on an oral glucose tolerance test, confirmed on a second occasion unless the patient is symptomatically hyperglycaemic. Genotype has no diagnostic role.

KCNQ1 rs2237892. Intronic in KCNQ1 (11p15.4), which encodes a voltage-gated potassium channel subunit. The GWAS Catalog records the C allele as the risk allele across multiple studies with odds ratios of 1.30 (p = 4 x 10^-29), 1.33 (p = 1 x 10^-26) and 1.45 (p = 2 x 10^-42), at risk allele frequencies around 0.59 to 0.61. The locus was identified in Japanese cohorts and the effect estimates are correspondingly weighted toward East Asian ancestry. Checked directly against the GWAS Catalog (15 Sep 2026): every study of this exact position is East Asian or Hispanic ancestry (Japanese OR 1.30-1.45, Han Chinese OR 1.32, Korean OR 1.20, Hispanic OR 1.20) -- there is no comparably powered European-ancestry study of this position in the catalogue to compare against, so a claim that the European-ancestry effect is smaller cannot currently be sourced and has been removed rather than repeated unverified. Note that loss-of-function coding variants in the same gene cause long QT syndrome, an unrelated cardiac phenotype — the diabetes association is a separate, non-coding signal.

ARAP1 rs1552224. At 11q13.4, near ARAP1; reported as CENTD2 in earlier literature including the DIAGRAM meta-analyses. The A allele is the risk allele, odds ratio 1.11 to 1.14 (p = 1 x 10^-22 in the largest reported analysis) at a risk allele frequency of roughly 0.81 to 0.83. The high frequency of the risk allele is worth noting when interpreting an individual result: most people carry it.

DUSP9 rs5945326. At Xq28, near DUSP9, encoding a MAP kinase phosphatase. Odds ratios of 1.14 (p = 2 x 10^-12), 1.18 (p = 7 x 10^-16) and 1.27 (p = 3 x 10^-10) are recorded for the A allele. X-linked loci are uncommon among established type 2 diabetes signals, and the hemizygosity of male carriers complicates direct comparison of effect estimates between sexes.

Genetic architecture. Highly polygenic. Hundreds of common loci of small effect are established, and together they account for a modest fraction of heritability; polygenic scores built from them stratify populations but perform poorly as individual predictors relative to conventional risk factors. The secular rise in incidence within genetically stable populations establishes the dominant contribution of environment and lifestyle.

Pharmacogenomics. See the pgx note below. Briefly: CYP2C9 reduced-function alleles decrease clearance of several sulfonylureas, and the Dutch Pharmacogenetics Working Group nonetheless recommends no dose adjustment, a position supported by meta-analysis showing no significant excess of sulfonylurea-induced hypoglycaemia for CYP2C9*3. Metformin response has been associated with variation in SLC22A1 and ATM in some studies without reaching clinical actionability. No diabetes drug currently carries a genotype-guided dosing recommendation in routine practice.