title: GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos.
abstract: Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10-8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.
authors.affiliation: 1 Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|2 Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Sanders
authors.affiliation: 3 Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jain
authors.affiliation: 3 Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sofer
authors.affiliation: 3 Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Kerr
authors.affiliation: 3 Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Laurie
authors.affiliation: 4 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.|5 Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Shaffer
authors.affiliation: 4 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.|6 Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|7 Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|8 Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|9 Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: 10 Department of Pediatric Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Kaste
authors.affiliation: 11 Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|12 Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Slade
authors.affiliation: 12 Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Fillingim
authors.affiliation: 13 Department of Oral Diagnostic Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ohrbach
authors.affiliation: 14 Department of Anesthesiology, Center for Translational Pain Medicine, Duke University, Durham, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Maixner
authors.affiliation: 15 Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kocher
authors.affiliation: 15 Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Bernhardt
authors.affiliation: 16 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Teumer
authors.affiliation: 17 Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, Greifswald, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schwahn
authors.affiliation: 18 Institute of Dentistry, University of Eastern Finland, Kuopio, Finland.|19 Oral and Maxillofacial Department, Kuopio University Hospital, Kuopio, Finland.|20 Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.|21 Oral and Maxillofacial Department, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Sipilä
authors.affiliation: 20 Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.|22 Oral and Maxillofacial Department, Medical Research Center Oulu, Oulu University Hospital, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Lähdesmäki
authors.affiliation: 23 Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.|24 Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Männikkö
authors.affiliation: 20 Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Pesonen
authors.affiliation: 25 Biocenter Oulu, University of Oulu, Center for Life Course Health Research, University of Oulu, Finland.|26 Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Järvelin
authors.affiliation: 27 Department of Prosthesis and Periodontology, Piracicaba Dental Scholl, University of Campinas, Piracicaba, Brazil.
authors.forename: C M
authors.initials: CM
authors.lastname: Rizzatti-Barbosa
authors.affiliation: 28 The Alan Edwards Centre for Research on Pain, Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: C B
authors.initials: CB
authors.lastname: Meloto
authors.affiliation: 29 University of Florida, College of Dentistry, Gainesville, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ribeiro-Dasilva
authors.affiliation: 30 Alan Edwards Pain Centre, McGill University, Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: 31 Piracicaba Dental School, State University of Campinas, Department of Prosthesis and Periodontology, Brazil.
authors.forename: P
authors.initials: P
authors.lastname: Serrano
authors.affiliation: 14 Department of Anesthesiology, Center for Translational Pain Medicine, Duke University, Durham, NC, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Smith
mesh_terms: D001938:Brazil / Q000453:epidemiology; D016022:Case-Control Studies; D016189:Dystrophin; D005260:Female; D005387:Finland / Q000453:epidemiology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D043562:Receptors, G-Protein-Coupled; D049031:Sarcoglycans; D051706:Sp4 Transcription Factor; D011795:Surveys and Questionnaires; D013705:Temporomandibular Joint Disorders / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D014481:United States / Q000453:epidemiology
chemical_list: C484258:DMD protein, human; D016189:Dystrophin; C472867:RXFP2 protein, human; D043562:Receptors, G-Protein-Coupled; C526571:SGCA protein, human; C497124:SP4 protein, human; D049031:Sarcoglycans; D051706:Sp4 Transcription Factor
keywords: Hispanic Americans; epidemiology; functional annotation; genetics; musculoskeletal pain; population