Abstract
Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10-8). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10-2). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10-5). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.
Original language | English (US) |
---|---|
Pages (from-to) | 579-591 |
Number of pages | 13 |
Journal | Pain |
Volume | 160 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2019 |
Keywords
- Bioinformatics
- Chronic pain
- Expression quantitative trait locus
- Genome-wide association study
- Meta-analysis
- Temporomandibular joint disease
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Anesthesiology and Pain Medicine
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In: Pain, Vol. 160, No. 3, 01.03.2019, p. 579-591.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males
AU - Smith, Shad B.
AU - Parisien, Marc
AU - Bair, Eric
AU - Belfer, Inna
AU - Chabot-Doré, Anne Julie
AU - Gris, Pavel
AU - Khoury, Samar
AU - Tansley, Shannon
AU - Torosyan, Yelizaveta
AU - Zaykin, Dmitri V.
AU - Bernhardt, Olaf
AU - De Oliveira Serrano, Priscila
AU - Gracely, Richard H.
AU - Jain, Deepti
AU - Järvelin, Marjo Riitta
AU - Kaste, Linda M.
AU - Kerr, Kathleen F.
AU - Kocher, Thomas
AU - Lähdesmäki, Raija
AU - Laniado, Nadia
AU - Laurie, Cathy C.
AU - Laurie, Cecelia A.
AU - Männikkö, Minna
AU - Meloto, Carolina B.
AU - Nackley, Andrea G.
AU - Nelson, Sarah C.
AU - Pesonen, Paula
AU - Ribeiro-Dasilva, Margarete C.
AU - Rizzatti-Barbosa, Celia M.
AU - Sanders, Anne E.
AU - Schwahn, Christian
AU - Sipilä, Kirsi
AU - Sofer, Tamar
AU - Teumer, Alexander
AU - Mogil, Jeffrey S.
AU - Fillingim, Roger B.
AU - Greenspan, Joel D.
AU - Ohrbach, Richard
AU - Slade, Gary D.
AU - Maixner, William
AU - Diatchenko, Luda
N1 - Funding Information: The authors thank the OPPERA program staff and participants at the respective host universities, and for resources specifically provided for this project by these institutions: University at Buffalo, University of Florida, University of Maryland– Baltimore, and University of North Carolina–Chapel Hill. They also thank the staff and participants of the replication cohorts for their important contributions. They gratefully acknowledge all the donor families who agreed to donate DRG tissue samples to pain research. OPPERA was supported by the National Institute of Dental and Craniofacial Research (NIDCR; https://www.nidcr.nih.gov/): grant number U01DE017018. S.B. Smith was supported by K12DE022793. The OPPERA program also acknowledges resources specifically provided for this project by the respective host universities: University at Buffalo, University of Florida, Funding Information: University of Maryland–Baltimore, and University of North Carolina–Chapel Hill. Funding for genotyping was provided by NIDCR through a contract to the Center for Inherited Disease Research at Johns Hopkins University (HHSN268201200008I). Funding Information: Data from the OPPERA study are available through the NIH dbGaP: phs000796.v1.p1 and phs000761.v1.p1. L. Diatchenko and the analytical team at McGill University were supported by the Canadian Excellence Research Chairs (CERC) Program grant (http://www.cerc.gc.ca/home-accueil-eng.aspx, CERC09). CERC09 also funded genotyping and cDNA array assays for DRG and blood expression studies. Funding for DRG cohort collection was kindly provided by the US Cancer Pain Relief Committee (Career Development Award “Neurochemistry and Physiology of Human Pain-Processing Nuclei” to I.B.). They gratefully acknowledge all the donor families who agreed to donate tissue samples to pain research, without whose participation and cooperation this work would not have been possible. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (https://www.bmbf.de; grant numbers 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED),” funded by the Federal Ministry of Education and Research (grant number 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant number 03ZIK012) and a joint grant from Siemens Healthcare (Erlangen, Germany) and the Federal State of Mecklenburg–West Pomer-ania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The Northern Finland Birth Cohort 1966 has received financial support from the Academy of Finland (http://www.aka.fi; project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTH Ageing-277849, the Medical Research Council (G0500539, G0600705, G1002319, PrevMetSyn/SALVE), and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action and Academy of Finland EGEAproject (285547). The DNA extractions, sample quality controls, biobank upkeeping, and aliquoting were performed in the National Public Health Institute, Biomedicum Helsinki, and supported financially by the Academy of Finland and Biocentrum Helsinki. They thank the late Professor Paula Rantakallio (launch of NFBCs) and Ms Outi Tornwall and Ms Minttu Jussila (DNA biobanking). They would like to acknowledge the contribution of the late Academian of Science Leena Peltonen. The study has been financially supported by the Academy of Finland, the European Commission (EURO-BLCS, https://ec.europa.eu/commission; Framework 5 award QLG1-CT-2000-01643), the Sigrid Jusélius Foundation (http://sigridjuselius.fi), and US National Institute of Mental Health (https://www.nimh.nih.gov; 5R01 MH 63706:02). The Brazilian cohort has been funded by the São Paulo Research Foundation (http://www.fapesp.br; grant numbers 2006/56019-8R and 2009/02520-6), and genotyping was funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09). The Complex Persistent Pain Conditions: Unique and Shared Pathways of Vulnerability Program Project were supported by NIH/National Institute of Neurological Disorders and Stroke (NINDS; https://www.ninds.nih.gov) grant NS045685 to the University of North Carolina at Chapel Hill, and genotyping was Funding Information: funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09). The OPPERA II study was supported by the NIDCR under Award Number U01DE017018, and genotyping was funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09). The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI; https://www.nhlbi.nih.-gov) to the University of North Carolina (HHSN268201300001I/ N01-HC-65233), University of Miami (HHSN268201300004I/ N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I/ N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. Data from HCHS/SOL are available through the NIH database of Genotypes and Phenotypes (dbGaP): phs000810. v1.p1. They thank the staff and participants of HCHS/SOL for their important contributions. The current study was conducted under UK Biobank (http:// www.ukbiobank.ac.uk) application number 20802. Dr. Belfer contributed to this article in her personal capacity. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government. Dr. Zaykin was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Publisher Copyright: © 2018 International Association for the Study of Pain.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10-8). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10-2). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10-5). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.
AB - Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10-8). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10-2). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10-5). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.
KW - Bioinformatics
KW - Chronic pain
KW - Expression quantitative trait locus
KW - Genome-wide association study
KW - Meta-analysis
KW - Temporomandibular joint disease
UR - http://www.scopus.com/inward/record.url?scp=85061610268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061610268&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000001438
DO - 10.1097/j.pain.0000000000001438
M3 - Article
C2 - 30431558
AN - SCOPUS:85061610268
SN - 0304-3959
VL - 160
SP - 579
EP - 591
JO - Pain
JF - Pain
IS - 3
ER -