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Genome-Wide Association Study of Genetic Variants Associated with Lower Extremity Amputation Risk in Peripheral

Rajashekar Korutla^1,2, Tanisha Garg³, Michael P Wilczek³

¹College of Engineering, The Roux Institute, Northeastern University, Portland, ME 04101, USA.

International Journal of Molecular Sciences

|May 4, 2026

Summary

Researchers explored the genetic factors behind lower extremity amputations in peripheral artery disease (PAD) patients. Genome-wide association studies identified potential genetic variants linked to amputation risk, offering new avenues for PAD treatment.

Area of Science:

Genetics
Cardiovascular Disease
Genomic Epidemiology

Background:

Peripheral artery disease (PAD) affects over 200 million people globally.
Limb-threatening ischemia is a common complication of PAD, often resulting in amputation.
The genetic underpinnings of amputation risk in PAD are not well understood.

Purpose of the Study:

To identify genetic variants associated with lower extremity amputation in PAD patients.
To leverage the "All of Us" Research Program data for genetic discovery.
To explore novel genetic risk factors for amputation in PAD.

Main Methods:

Conducted a multi-pronged genome-wide association study (GWAS).
Employed two analytical strategies: targeted GWAS using ClinVar variants and comprehensive GWAS using Allele Count/Allele Frequency (ACAF) data.
Analyzed data from a large cohort of PAD patients, including cases with and without amputation.

Main Results:

The ClinVar analysis identified 3 suggestive genetic associations.
The ACAF analysis revealed 35 suggestive associations (p < 1 × 10^-5).
No single variant reached suggestive significance across both analytical approaches.

Conclusions:

Identified candidate genetic loci requiring further validation.
Findings may contribute to improved risk prediction models for PAD-related amputations.
Potential to inform targeted interventions aimed at reducing limb loss in PAD patients.

Keywords:

Firth correction amputation genetic risk factors genome-wide association study peripheral artery disease single nucleotide polymorphisms

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