# Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK biobank

## TL;DR

This study explores genetic factors linked to metabolic changes in ME/CFS, revealing distinct genetic influences on lipid and hormone pathways.

## Contribution

The study identifies unique SNP-biomarker associations in ME/CFS patients, highlighting lipid metabolism and immune-related pathways.

## Key findings

- Two SNPs specific to ME/CFS are linked to phospholipids and fatty acids in VLDLs.
- Genetic effects on VLDLs show low correlation between ME/CFS and healthy controls.
- Enrichment analysis highlights lipid metabolism, neurotransmitter transport, and inflammation pathways.

## Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility toward a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in patients with ME/CFS (n = 875) and healthy controls (HCs) (n = 36,033). We identified 112 significant SNP-biomarker associations in ME/CFS, compared with 4,114 in HCs. Two SNPs specific to ME/CFS, mapping to HSD11B1 and SCGN, were associated with phospholipids in extra-large very low-density lipoproteins (VLDLs) and total fatty acids, respectively. Genetic effects of VLDL associations were among the least correlated between ME/CFS and HCs. Heterogeneity tests found differential effects for several lipid traits at ADAP1, NR1H3, and CD40, which are involved in immune regulation. ME/CFS mGWAS summary statistics were decomposed to uncover shared genetic-metabolic patterns, where enrichment analysis highlighted pathways in lipid metabolism, neurotransmitter transport, and inflammation. These findings provide a genetic and molecular rationale for patient heterogeneity and suggest a polygenic predisposition in which many small-effect variants may jointly perturb metabolic mechanisms.

•ME/CFS shows distinct genetic influences on metabolic regulation•Lipid and hormone-related pathways emerge as key areas of interest•Many small genetic effects may collectively disrupt metabolic resilience in ME/CFS

ME/CFS shows distinct genetic influences on metabolic regulation

Lipid and hormone-related pathways emerge as key areas of interest

Many small genetic effects may collectively disrupt metabolic resilience in ME/CFS

Health sciences; medicine; genetics