title: 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.
authors.affiliation: Genomics and Disease Group, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Catalonia, Spain Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Catalonia, Spain Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia, Spain Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain National School of Public Health, Athens, Greece Fibromyalgia Unit, Rheumatology Service, Hospital Clínic, Barcelona, Catalonia, Spain FSGCDB Group, Fibromyalgia and Chronic Fatigue Syndrome, Spanish Genetic and Clinical Data Bank, Foundation FF (www.laff.es), Spain Fibromyalgia Unit, Rheumatology Service, Parc de Salut Mar, and Hospital del Mar Research Institute, Barcelona, Catalonia, Spain Rheumatology Unit, Instituto Provincial de Rehabilitación, Hospital Universitario Gregorio Marañón, Madrid, Spain Rheumatology Unit, Hospital General de Guadalajara, Guadalajara, Spain Chronic Fatigue Syndrome Unit, Hospital Vall d'Hebron, Barcelona, 08035 Catalonia, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Docampo
authors.forename: Georgia
authors.initials: G
authors.lastname: Escaramís
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Sergi
authors.initials: S
authors.lastname: Villatoro
authors.forename: Anna
authors.initials: A
authors.lastname: Puig
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Antonio
authors.initials: A
authors.lastname: Collado
authors.forename: Jordi
authors.initials: J
authors.lastname: Carbonell
authors.forename: Javier
authors.initials: J
authors.lastname: Rivera
authors.forename: Javier
authors.initials: J
authors.lastname: Vidal
authors.forename: Jose
authors.initials: J
authors.lastname: Alegre
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Raquel
authors.initials: R
authors.lastname: Rabionet
mesh_terms: D002490:Central Nervous System / Q000473:pathology / Q000502:physiology*; D016000:Cluster Analysis; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005356:Fibromyalgia / Q000175:diagnosis* / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
keywords: CNV; Copy number variants; Fibromyalgia; GWAS; Genome-wide association scan; Single nucleotide polymorphism