Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system

Abstract

Fibromyalgia (FM) is a highly disabling syndrome defined by a low pain threshold and a permanent state of pain. The mechanisms explaining this complex disorder remain unclear, and its genetic factors have not yet been identified. With the aim of elucidating FM genetic susceptibility factors, we selected 313 FM cases having low comorbidities, and we genotyped them on the Illumina 1 million duo array. Genotypic data from 220 control women (Illumina 610k array) was obtained for genome-wide association scan (GWAS) analysis. Copy number variants in FM susceptibility were analyzed by array comparative genomic hybridization (aCGH) experiments on pooled samples using the Agilent 2×400K platform. No single nucleotide polymorphism (SNP) reached GWAS association threshold, but 21 of the most associated SNPs were chosen for replication in 952 cases and 644 controls. Four of the SNPs selected for replication showed a nominal association in the joint analysis, and rs11127292 (MYT1L) was found to be associated to FM with low comorbidities (P=4.28×10(-5), odds ratio [95% confidence interval]=0.58 [0.44-0.75]). aCGH detected 5 differentially hybridized regions. They were followed up, and an intronic deletion in NRXN3 was demonstrated to be associated to female cases of FM with low levels of comorbidities (P=.021, odds ratio [95% confidence interval]=1.46 [1.05-2.04]). Both GWAS and aCGH results point to a role for the central nervous system in FM genetic susceptibility. If the proposed FM candidate genes were further validated in replication studies, this would highlight a neurocognitive involvement in agreement with latest reports.

Fibromyalgia: A Critical and Comprehensive Review

“…Several approaches have been adopted to circumvent this problem, including the use of a dedicated candidate gene platform that genotypes>3,000 SNPs in >350 gene [473], the study of genome-wide associations in CWP [474] and FMS [475], and whole exome sequencing with various filters [476]. These failed to confirm any of the associations previously reported in candidate gene studies, and each identified only one or a few genes as showing associations with CWP or FMS, but these genes all differed between studies.…”

Update on the genetics of the fibromyalgia syndrome

“…A second study utilizing GWAS for the study of FMS has recently been published [70]. In this study, Docampo et al performed both GWAS analysis and copy number variant (CNV) analysis by array comparative genomic hybridization (aCGH).…”

Genome-wide methylation analysis of a large population sample shows neurological pathways involvement in chronic widespread musculoskeletal pain

“…8,58 Over the last decade, several candidate genes have been identified that are potentially linked to CWP 31,45,47 , however, only a few of these genes have been reliably replicated. Agnostic approaches such as at genome-wide linkage and association have produced some novel findings 13,16 but together they explain only a fraction of the genetic contribution.…”