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Causal Relationship Between Circulating Leukocyte Characteristics and Immune Cell Traits With Multiple Sclerosis

Jia-Jia Yun¹, Ya-Lei Li¹, Jing-Man Qiu²

¹School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, 264003, China.

Cellular and Molecular Neurobiology

|July 13, 2026

Summary

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Genome-wide Association Studies-GWAS

Genome-wide Association Studies-GWAS

Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...

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Increased white blood cell and lymphocyte counts are linked to a higher risk of multiple sclerosis (MS). Certain immune cell traits may decrease MS risk, but MS does not appear to cause changes in these blood cell counts.

Area of Science:

Immunology
Genetics
Neurology

Background:

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
The role of circulating immune cells and their traits in MS etiology remains incompletely understood.
Genetic factors influencing immune cell populations may contribute to MS susceptibility.

Purpose of the Study:

To investigate potential causal relationships between circulating leukocytes, immune cell traits, and multiple sclerosis (MS) using a bidirectional Mendelian randomization (MR) approach.
To determine if genetic predisposition to specific immune cell profiles increases or decreases MS risk.
To assess whether MS influences circulating immune cell counts or traits.

Main Methods:

Utilized a two-sample, bidirectional Mendelian randomization (MR) analysis with summary-level data from large genome-wide association studies.

Keywords:

Immune cells Mendelian randomisation Multiple sclerosis White blood cells

Related Experiment Videos

Employed multiple MR methods including Inverse Variance Weighted (IVW), weighted mode, weighted median, simple mode, and MR-Egger.

Assessed horizontal pleiotropy using MR-Egger intercept, genetic heterogeneity with Cochran's Q test, and result sensitivity with leave-one-out procedures, adjusting for multiple comparisons using False Discovery Rate (FDR).

Main Results:

Forward MR indicated that genetically predicted higher white blood cell count (OR=1.16) and lymphocyte count (OR=1.18) are associated with increased MS risk.
Specific immune cell traits, including CD25hi CD45RA-CD4 not Treg %CD4+ (OR=0.87) and CD16-CD56 on HLA DR+ NK (OR=0.85), were associated with reduced MS risk.
Reverse MR analyses found no robust evidence for MS causally affecting white blood cell or lymphocyte counts, with one potential association for B-cell counts deemed unreliable due to sensitivity analysis.

Conclusions:

Genetic predisposition to elevated white blood cell and lymphocyte counts is a risk factor for developing multiple sclerosis.
Certain immune cell phenotypes are associated with a protective effect against MS.
Evidence does not support a causal role for MS in altering circulating white blood cell or lymphocyte levels.