# Shared latent genetic liability across fibromyalgia and psychiatric traits: Novel insights from genomic structural equation modeling

## TL;DR

This study identifies a shared genetic factor linking fibromyalgia, insomnia, depression, and anxiety, revealing insights into their common biological pathways and potential treatment targets.

## Contribution

The study introduces a novel shared genetic factor (mvFibroPsych) linking fibromyalgia and psychiatric traits, supported by genomic and neurobiological evidence.

## Key findings

- Strong genetic correlations (rg = 0.55–0.84) were found among fibromyalgia, insomnia, depression, and anxiety.
- mvFibroPsych was linked to synaptic function pathways and brain structure integrity, including the splenium of the corpus callosum.
- Five proteins and CD40 were identified as potential targets related to the shared genetic factor.

## Abstract

Fibromyalgia, insomnia, depression, and anxiety share common clinical comorbidities, but their underlying genetic architecture and mechanism remain unclear.

We conducted phenotype-specific Genome-wide association study (GWAS) meta-analyses for fibromyalgia, insomnia, depression, and anxiety, respectively. Genomic structural equation modeling was employed to identify a shared genetic factor (mvFibroPsych). Lead SNPs and associated genes were annotated using Functional Mapping and Annotation (FUMA), followed by gene-set and tissue enrichment analyses. The Latent Causal Variable (LCV) method was utilized to identify modifiable risk factors and phenotypes influenced by mvFibroPsych. Additionally, brain-wide and proteome-wide Mendelian randomization (MR) analyses were applied to explore brain regions and biomarkers associated with mvFibroPsych. Multi-layer molecular quantitative trait locus (QTL) analyses were conducted for mechanistic insights into mvFibroPsych.

Strong genetic correlations were observed among the four phenotypes (rg = 0.55–0.84), with excellent model fit for the common factor [comparative fit index (CFI) = 0.999, standardized root mean square residual (SRMR) = 0.015]. The mvFibroPsych GWAS identified 49 lead SNPs across 43 loci, including 32 novel loci. Gene prioritization revealed 342 protein-coding genes, and pathway analysis indicated enrichment in synaptic function pathway. LCV identified 133 phenotypes causally linked to mvFibroPsych. Brain-wide MR found fractional anisotropy in the splenium of the corpus callosum to be inversely associated with mvFibroPsych. Proteome-wide MR identified five proteins significantly associated with mvFibroPsych, while multi-layer brain QTL analysis prioritized CD40 as a potential target.

This study provides strong evidence for a shared genetic factor underlying fibromyalgia, insomnia, depression, and anxiety, linked to synaptic function, brain structure integrity, and neuroinflammatory pathways.

Fibromyalgia, insomnia, depression, and anxiety are common health conditions that often occur together, but the genetic factors that connect them remain poorly understood. In this study, we combined data from large-scale genetic studies of these four conditions to identify shared genetic influences. Our analysis revealed a common genetic factor (mvFibroPsych) that underlies these conditions. We identified key genes and pathways, including synaptic function, which may play a role in their shared biological mechanisms. Additionally, we discovered brain region and proteins associated with this latent genetic factor, including markers of brain structure and inflammation. These findings highlight potential areas for developing new treatments targeting these interconnected conditions. By providing insights into how genetic and biological factors contribute to this underlying shared genetic component, our research paves the way for improving diagnosis and treatment for millions of people affected by these overlapping conditions.