Transcriptome-wide Association Study Identifies Genetically Dysregulated Genes in Diabetic Neuropathy

Area of Science:

• Genetics
• Neuroscience
• Endocrinology

Background:

• Diabetic complications significantly contribute to disease burden.
• Diabetic neuropathy, affecting nerves in legs and feet, is the most common and debilitating complication.
• Identifying genes involved in diabetic neuropathy progression is crucial.

Purpose of the Study:

• To identify genes specifically associated with diabetic neuropathy.
• To leverage genome-wide association studies (GWASs) for diabetes.
• To find potential biomarkers for early detection.

Main Methods:

• Utilized the functional summary-based imputation (FUSION) algorithm to convert GWAS signals to transcriptomic profiles.
• Analyzed gene expression in the sciatic nerve of mouse models with diabetic neuropathy.
• Validated dysregulated gene expression in the blood of human patients with diabetes.

Main Results:

• Eleven out of 452 FUSION-derived genes were altered in the sciatic nerve of early-stage diabetic neuropathy mouse models.
• Significant expression changes for HSD17B4, DHX32, MERTK, and SFXN4 were observed in the blood of human patients.
• These genes are regulated by diabetes GWAS loci and show altered expression in neuropathy.

Conclusions:

• The study identified genes implicated in sciatic nerve function relevant to diabetic neuropathy.
• These findings suggest potential for noninvasive early detection of diabetic neuropathy.
• The identified genes offer new insights into the genetic underpinnings of diabetic complications.