title: DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis.
abstract: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved.
  
  
  
  We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect.
  
  
  
  We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families.
  
  
  
  We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association.
  
  
  
  By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.
authors.affiliation: INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Sarnowski
authors.affiliation: Université du Québec, à Chicoutimi, Québec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.affiliation: Section of Biology and Genetics, Department of Mother and Child, and Biology-Genetics, University of Verona, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
authors.affiliation: INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Dizier
authors.affiliation: Université du Québec, à Chicoutimi, Québec, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada.
authors.forename: Andréanne
authors.initials: A
authors.lastname: Morin
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, UMR1163, Paris, France; Université Paris Descartes, Imagine Institute, Paris, France.
authors.forename: Quentin B
authors.initials: QB
authors.lastname: Vincent
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rohde
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Centre, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.affiliation: INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Margaritte-Jeannin
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Mass.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
authors.affiliation: Hôpital Arnaud de Villeneuve, Service des Maladies Respiratoires, Montpellier, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bousquet
authors.affiliation: Université Grenoble Alpes, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; INSERM, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; CHU de Grenoble, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Siroux
authors.affiliation: Section of Biology and Genetics, Department of Mother and Child, and Biology-Genetics, University of Verona, Verona, Italy.
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: William O
authors.initials: WO
authors.lastname: Cookson
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France. Electronic address: emmanuelle.bouzigon@inserm.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
mesh_terms: D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D018899:CpG Islands; D019175:DNA Methylation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000072740:Paternal Inheritance; D044122:Receptor, Melatonin, MT1 / Q000235:genetics*; D065631:Rhinitis, Allergic / Q000453:epidemiology / Q000235:genetics*
chemical_list: C000610981:MTNR1A protein, human; D044122:Receptor, Melatonin, MT1
keywords: DNA methylation; Linkage analysis; allergic rhinitis; asthma; genetic association study; parent-of-origin effect; positional cloning