title: Common Genetic Variation Near Melatonin Receptor 1A Gene Linked to Job-Related Exhaustion in Shift Workers.
abstract: Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work.
  
  
  
  We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data.
  
  
  
  The second strongest signal identified in the GWAS (p = 2.3 × 10E-6) was replicated in two of the replication studies with p < .05 (p = 2.0 × 10E-4 when combining the replication studies) and indicated an association of job-related exhaustion in shift workers with rs12506228, located downstream of the melatonin receptor 1A gene (MTNR1A). The risk allele was also associated with reduced in silico gene expression levels of MTNR1A in brain tissue and suggestively associated with changes in DNA methylation in the 5' regulatory region of MTNR1A.
  
  
  
  These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work.
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sulkava
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|The Stanford Center for Sleep Sciences, Stanford University, Palo Alto, CA.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Ollila
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Alasaari
authors.affiliation: Modern Work and Leadership, Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Puttonen
authors.affiliation: Modern Work and Leadership, Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Härmä
authors.affiliation: Finnair Health Services, Vantaa, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Viitasalo
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lahtinen
authors.affiliation: Department of Health, Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Lindström
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Auli
authors.initials: A
authors.lastname: Toivola
authors.affiliation: Unit of Geriatrics, University of Eastern Finland, Kuopio, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Sulkava
authors.affiliation: Modern Work and Leadership, Finnish Institute of Occupational Health, Helsinki, Finland.|Department of Epidemiology and Public Health, University College London, London, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.affiliation: Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Vahtera
authors.affiliation: Department of Health, Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Partonen
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.affiliation: Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Porkka-Heiskanen
authors.affiliation: Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.|Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
mesh_terms: D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D003198:Computer Simulation; D019175:DNA Methylation; D005221:Fatigue / Q000235:genetics*; D005260:Female; D005387:Finland; D015870:Gene Expression; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008550:Melatonin / Q000378:metabolism; D008875:Middle Aged; D044122:Receptor, Melatonin, MT1 / Q000235:genetics*; D015398:Signal Transduction; D014940:Work Schedule Tolerance; D055815:Young Adult
chemical_list: C000610981:MTNR1A protein, human; D044122:Receptor, Melatonin, MT1; D008550:Melatonin
keywords: DNA methylation.; MTNR1A; genome-wide association study; job-related exhaustion; shift work