Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination

Abstract

Background:

Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking.

Objective:

A GWAS was performed to identify variants associated with TD.

Methods:

The case–control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p-value threshold of 5 × 10⁻⁸ was GWAS significant and 5 × 10⁻⁶ nominally significant. A polygenic risk score (PRS) was compared across TD and controls.

Results:

Variants on chromosome 14 (rs117797734, p = 2.06 × 10⁻¹¹, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10⁻⁷, OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls.

Conclusion:

We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.