Diabetic neuropathy

Summary

Diabetic neuropathy (MONDO:0006626) is a disease with 1 cohort gene (126 GWAS associations across 13 studies) and 245 clinical trials. Top therapeutic interventions include duloxetine, gabapentin, and lacosamide.

At a glance

• Cohort genes: 1
• GWAS associations: 126
• Clinical trials: 245

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetic neuropathy
Mondo ID	MONDO:0006626
EFO	EFO:1000783
MeSH	D003929
DOID	DOID:9743
NCIT	C26748
SNOMED CT	230572002
UMLS	C0011882
MedGen	8353
Is cancer (heuristic)	no

Data availability: 126 GWAS associations (13 studies).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › diabetic neuropathy

Related subtypes (29): autoimmune neuropathy, autonomic neuropathy, mononeuropathy, ischemic neuropathy, polyneuropathy, neuritis, motor peripheral neuropathy, sensory peripheral neuropathy, uremic neuropathy, nerve compression syndrome, axonal neuropathy, acquired peripheral neuropathy, hereditary peripheral neuropathy, neuralgia, peripheral nerve lesion, nerve plexus disorder, traumatic neuropathy, radiation-induced neuropathy, vasculitic neuropathy, chronic idiopathic neuropathy, chemotherapy-induced neuropathy, infectious neuropathy, vitamin deficiency related neuropathy, paraproteinemia-associated neuropathy, neuropathy in cryoglobulinemia, neuropathy in endocrine disorder, sarcoid neuropathy, neuropathy, small fiber, idiopathic small fibers neuropathy

Subtypes (2): diabetic autonomic neuropathy, diabetic polyneuropathy

Genetics & variants

GWAS landscape

126 GWAS associations across 13 studies. Top hits map to 20 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7903146	8e-236	TCF7L2	C	0.2
rs1421085	5e-116	FTO	T	0.13
rs13092876	2e-70	IGF2BP2	G	0.11
rs10811662	7e-57	CDKN2B-AS1	G	0.12
rs9859406	3e-44	IGF2BP2	G	0.1
rs7766070	2e-42	CDKAL1	C	0.09
rs1801214	5e-41	WFS1	C	0.08
rs1708302	1e-40	JAZF1	C	0.07
rs10811660	3e-37	CDKN2B-AS1	G	0.12
chr2:227156662	3e-36		C	0.08
rs11558471	2e-33	SLC30A8	A	0.08
chr10:94466439	7e-30		A	0.07
rs10195252	3e-29	COBLL1	T	0.07
rs182533474	1e-27	JAZF1	C	0.07
rs13266634	2e-27	SLC30A8	C	0.08
rs2237897	5e-25	KCNQ1	C	0.14
rs2203452	1e-24	NYAP2 - MIR5702	A	0.07
chr1:214156514	4e-24		T	0.06
rs734312	5e-24	WFS1	G	0.07
rs2185756	2e-23	EIF2S2P3 - HHEX	A	0.06
rs76895963	3e-23	CCND2-AS1, CCND2	T	0.29
rs9368222	4e-23	CDKAL1	C	0.07
rs13389219	7e-23	COBLL1	C	0.06
rs697239	8e-23	ZMIZ1	T	0.06
chr15:90449523	2e-21		T	0.06
chr11:2857194	9e-20		A	0.05
chr13:80705315	9e-20		G	0.06
chr1:120254506	3e-18		A	0.05
chr10:12245520	5e-18		G	0.07
chr11:17408404	6e-18		C	0.05

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475676	Verma A	2024	59,205	375,439	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475675	Verma A	2024	16,638	99,303	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479883	Verma A	2024	16,638	99,303	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475674	Verma A	2024	7,320	50,236	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651451	Liu TY	2025	1,146	196,787	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90129436	Zorina-Lichtenwalter K	2023	772	435,199	Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling.
GCST90081515	Backman JD	2021	751	25,077	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90085501	Backman JD	2021	751	25,077	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90435708	Zhou W	2018	575	388,756	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90481584	Verma A	2024	443	6,209	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	43

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
unknown	17
intron_variant	15
intergenic_variant	10
missense_variant	3
3_prime_UTR_variant	2
regulatory_region_variant	2
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7903146	10	112998590	C>G,T	0.295	intron_variant	TCF7L2	8e-236	Tier 4: intronic/intergenic
rs1421085	16	53767042	T>C	0.407	intron_variant	FTO	5e-116	Tier 4: intronic/intergenic
rs13092876	3	185777532	G>A,T	0.312	intron_variant	IGF2BP2	2e-70	Tier 4: intronic/intergenic
rs10811662	9	22134254	G>A,C	0.173	intergenic_variant	CDKN2B-AS1	7e-57	Tier 4: intronic/intergenic
rs9859406	3	185816694	G>A	0.397	intron_variant	IGF2BP2	3e-44	Tier 4: intronic/intergenic
rs7766070	6	20686342	C>A,G,T	0.266	intron_variant	CDKAL1	2e-42	Tier 4: intronic/intergenic
rs1801214	4	6301295	C>A,G,T	0.397	missense_variant	WFS1	5e-41	Tier 1: coding
rs1708302	7	28159058	C>T	0.491	intron_variant	JAZF1	1e-40	Tier 4: intronic/intergenic
rs10811660	9	22134069	G>A,C,T	0.15	intergenic_variant	CDKN2B-AS1	3e-37	Tier 4: intronic/intergenic
chr2:227156662				0.376			3e-36	Tier 4: intronic/intergenic
rs11558471	8	117173494	A>G	0.312	3_prime_UTR_variant	SLC30A8	2e-33	Tier 2: splice/UTR
chr10:94466439				0.424			7e-30	Tier 4: intronic/intergenic
rs10195252	2	164656581	T>C	0.405	intergenic_variant	COBLL1	3e-29	Tier 4: intronic/intergenic
rs182533474	7	28175045	C>A	0.41	intron_variant	JAZF1	1e-27	Tier 4: intronic/intergenic
rs13266634	8	117172544	C>A,T	0.261	missense_variant	SLC30A8	2e-27	Tier 1: coding
rs2237897	11	2837316	C>T	0.071	intron_variant	KCNQ1	5e-25	Tier 4: intronic/intergenic
rs2203452	2	226230042	A>C,G	0.352	intergenic_variant	NYAP2 - MIR5702	1e-24	Tier 4: intronic/intergenic
chr1:214156514				0.387			4e-24	Tier 4: intronic/intergenic
rs734312	4	6301627	G>A,C	0.466	missense_variant	WFS1	5e-24	Tier 1: coding
rs2185756	10	92670740	A>C,G,T	0.392	intergenic_variant	EIF2S2P3 - HHEX	2e-23	Tier 4: intronic/intergenic
rs76895963	12	4275678	T>C,G	0.017	non_coding_transcript_exon_variant	CCND2-AS1, CCND2	3e-23	Tier 4: intronic/intergenic
rs9368222	6	20686765	C>A,T	0.252	intron_variant	CDKAL1	4e-23	Tier 4: intronic/intergenic
rs13389219	2	164672366	C>T	0.445	intergenic_variant	COBLL1	7e-23	Tier 4: intronic/intergenic
rs697239	10	79187681	T>C	0.446	intron_variant	ZMIZ1	8e-23	Tier 4: intronic/intergenic
chr15:90449523				0.288			2e-21	Tier 4: intronic/intergenic
chr11:2857194				0.417			9e-20	Tier 4: intronic/intergenic
chr13:80705315				0.278			9e-20	Tier 4: intronic/intergenic
chr1:120254506				0.42			3e-18	Tier 4: intronic/intergenic
chr10:12245520				0.191			5e-18	Tier 4: intronic/intergenic
chr11:17408404				0.358			6e-18	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GYPA	HGNC:4702	ENSG00000170180	P02724	Glycophorin-A	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GYPA	Glycophorin-A	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GYPA	Other/Unknown	no		Glycophorin, Glycophorin_CS, GYPA_B

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GYPA	158	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GYPA	1,537

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GYPA	P02724	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cell surface interactions at the vascular wall	1	95.2×	0.011	GYPA

Therapeutics

Drugs indicated for this disease

0 approved, 23 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetaminophen	Phase 3 (in late-stage trials)
Actovegin	Phase 3 (in late-stage trials)
Benfotiamine	Phase 3 (in late-stage trials)
Capsaicin	Phase 3 (in late-stage trials)
Donaperminogene Seltoplasmid	Phase 3 (in late-stage trials)
Duloxetine	Phase 3 (in late-stage trials)
Eslicarbazepine Acetate	Phase 3 (in late-stage trials)
Fentanyl	Phase 3 (in late-stage trials)
Gabapentin	Phase 3 (in late-stage trials)
Inosine	Phase 3 (in late-stage trials)
Lacosamide	Phase 3 (in late-stage trials)
Lipoic Acid, Alpha	Phase 3 (in late-stage trials)
Nabilone	Phase 3 (in late-stage trials)
Niacinamide	Phase 3 (in late-stage trials)
Oxycodone	Phase 3 (in late-stage trials)
Pregabalin	Phase 3 (in late-stage trials)
Ranirestat	Phase 3 (in late-stage trials)
Riboflavin	Phase 3 (in late-stage trials)
Rosiglitazone	Phase 3 (in late-stage trials)
Ruboxistaurin	Phase 3 (in late-stage trials)
Succinic Acid	Phase 3 (in late-stage trials)
Tapentadol	Phase 3 (in late-stage trials)
Tramadol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Astaxanthin, Bicifadine, Cannabidiol, Carisbamate, Cebranopadol, Centella Asiatica Extract, Clonidine, Cyanocobalamin, Dapagliflozin, Dextromethorphan, Eptinezumab, Ergocalciferol, Esreboxetine, Fulranumab, Gabapentin Enacarbil, Incobotulinumtoxina, Insulin Human, Lidocaine, Mirogabalin, Naloxone, Naltrexone, Nitroglycerin, Perampanel, Pirenzepine, Reboxetine, Resveratrol, Rituximab, Rosuvastatin, Sodium Chloride, Suzetrigine, Tanezumab, Testosterone Cypionate, Trazodone.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GYPA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GYPA	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GYPA

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GYPA	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 245.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	132
PHASE2	36
PHASE3	32
PHASE4	21
PHASE1	13
PHASE1/PHASE2	6
PHASE2/PHASE3	4
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00123136	PHASE4	UNKNOWN	Bi-Axial Rotating Magnetic Field Therapy in Refractory Neuropathic Foot Pain Secondary to Diabetic Peripheral Neuropathy
NCT00194909	PHASE4	COMPLETED	An Open Label, Dose Finding Trial of Viagra for the Treatment of Neuropathic Pain (in Diabetes Mellitus)
NCT00322621	PHASE4	COMPLETED	Maintenance of Effect of Duloxetine in Patients With Diabetic Peripheral Neuropathic Pain (DPNP)
NCT00380913	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Diabetic Peripheral Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00573261	PHASE4	COMPLETED	A Randomized Double-Blind Study Testing the Effects of Pregabalin on Diabetic Neuropathy
NCT00634543	PHASE4	COMPLETED	A Study to Compare Safety and Efficacy of Tramadol Hydrochloride/Acetaminophen With Gabapentin in Participants With Diabetic Neuropathy
NCT00644748	PHASE4	COMPLETED	A Study on the Efficacy and Safety of Gabapentin in the Treatment of Patients With Painful Diabetic Neuropathy
NCT00844194	PHASE4	COMPLETED	Duloxetine in Patients With Diabetic in Peripheral Neuropathic Pain With or Without Co-morbid Major Depressive Disorder
NCT00904020	PHASE4	COMPLETED	A Study of the Effectiveness And Safety Of Lidoderm® As Add-On Treatment in Patients With Postherpetic Neuralgia, Diabetic Neuropathy, or Low Back Pain
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT00931879	PHASE4	COMPLETED	Lovaza® and Microvascular Function in Type 2 Diabetes
NCT02249897	PHASE4	COMPLETED	PRELIMINARY EVALUATION OF PHARMACOLOGICAL LOWERING OF AGEs
NCT02439879	PHASE4	COMPLETED	Alpha Lipoic Acid for Treatment of Diabetic Neuropathy
NCT02891928	PHASE4	COMPLETED	Evaluation of Rocker sOles in Diabetis
NCT03914404	PHASE4	COMPLETED	Efficacy of γ-linolenic Acid and Thioctic Acid in Patients With Diabetic Neuropathy
NCT04238208	PHASE4	COMPLETED	The Efficacy and Safety Profile of Capsaicin 8% Patch Versus 5% Lidocaine Patch in Males With Diabetic Neuropathy
NCT04377399	PHASE4	COMPLETED	High vs Low Dose Vitamin D in Patients With Diabetic Peripheral Neuropathy
NCT04766450	PHASE4	UNKNOWN	Effect of High-Dose NAC on Patients With DPN
NCT05296759	PHASE4	COMPLETED	Botulinum Toxin Type A in Diabetic Peripheral Neuropathy
NCT00004647	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Mexiletine for Painful Diabetic Neuropathy
NCT00034788	PHASE3	TERMINATED	A Study on the Efficacy and Safety of Long-Term Treatment and Re-Treatment of Lower Extremity Diabetic Ulcers With REGRANEX
NCT00044395	PHASE3	COMPLETED	Treatment for Symptomatic Peripheral Neuropathy in Patients With Diabetes
NCT00044408	PHASE3	COMPLETED	Treatment for Symptomatic Peripheral Neuropathy in Patients With Diabetes
NCT00044421	PHASE3	COMPLETED	Treatment of Peripheral Neuropathy in Patients With Diabetes
NCT00101426	PHASE3	COMPLETED	Safety and Efficacy of AS-3201 in the Treatment of Diabetic Sensorimotor Polyneuropathy
NCT00113620	PHASE3	COMPLETED	Safety and Efficacy of Dextromethorphan and Quinidine in the Treatment of the Pain of Diabetic Neuropathy
NCT00134524	PHASE3	UNKNOWN	The Effects of the Magnetic Molecular Energizer (MME) on Diabetic Peripheral Neuropathy
NCT00135109	PHASE3	COMPLETED	Trial to Assess the Efficacy and Safety of SPM 927 (200, 400, and 600mg/Day) in Subjects With Painful Distal Diabetic Neuropathy
NCT00141219	PHASE3	COMPLETED	Pregabalin Peripheral Neuropathic Pain Study
NCT00143156	PHASE3	COMPLETED	Pregabalin vs Placebo in Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy
NCT00210847	PHASE3	COMPLETED	A Study Comparing the Effectiveness and Safety of Tramadol HCl/Acetaminophen Versus Placebo for the Treatment of Painful Neuropathy in Diabetic Patients
NCT00228605	PHASE3	COMPLETED	Evaluating the Safety and Tolerability of OraVescent Fentanyl for Opioid Tolerant Patients With Noncancer Related Breakthrough Pain
NCT00228904	PHASE2/PHASE3	WITHDRAWN	Effects of Pulsatile Intravenous Insulin Delivery on Diabetic Neuropathy in pATIENTS (Pts) With Type 1 and Type 2 Diabetes
NCT00235443	PHASE2/PHASE3	COMPLETED	A Follow-On Trial to Assess the Long Term Safety and Efficacy of SPM 927 in Painful Distal Diabetic Neuropathy
NCT00235469	PHASE2/PHASE3	COMPLETED	A Trial to Assess the Efficacy and Safety of SPM 927 in Subjects With Painful Distal Diabetic Neuropathy
NCT00238524	PHASE3	COMPLETED	A Trial to Assess the Efficacy and Safety of SPM 927 (Lacosamide) in Subjects With Painful Distal Diabetic Neuropathy
NCT00283842	PHASE3	TERMINATED	Study Evaluating Desvenlafaxine Succinate Sustained-release (DVS SR) in Adult Outpatients With Pain Associated With Diabetic Peripheral Neuropathy
NCT00408993	PHASE3	COMPLETED	Duloxetine Versus Placebo in the Treatment of Patients With Diabetic Peripheral Neuropathic Pain in China

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DULOXETINE	4	4
GABAPENTIN	4	4
LACOSAMIDE	4	4
DEXTROMETHORPHAN	4	3
SILDENAFIL	4	3
TRAMADOL	4	3
BECAPLERMIN	4	2
CLONIDINE	4	2
PAROXETINE	4	2
TAPENTADOL	4	2
ACARBOSE	4	1
ACETAMINOPHEN	4	1
ACETYLCYSTEINE	4	1
CAPSAICIN	4	1
CHOLESTYRAMINE	4	1
CODEINE	4	1
ERGOCALCIFEROL	4	1
GABAPENTIN ENACARBIL	4	1
IBUDILAST	4	1
LIDOCAINE	4	1
MELATONIN	4	1
MEXILETINE	4	1
NABILONE	4	1
NIACINAMIDE	4	1
PERAMPANEL	4	1
PREGABALIN	4	1
RIBOFLAVIN	4	1
ROFLUMILAST	4	1
RUBOXISTAURIN	3	4
LIPOIC ACID, ALPHA	3	3