title: Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
abstract: The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.
authors: Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.
authors: Clive J
authors: CJ
authors: Hoggart
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Giulia
authors: G
authors: Venturini
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
authors: Massimo
authors: M
authors: Mangino
authors: Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
authors: Felicia
authors: F
authors: Gomez
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Giulia
authors: G
authors: Ascari
authors: MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors: Jing Hua
authors: JH
authors: Zhao
authors: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors: Alexander
authors: A
authors: Teumer
authors: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors: Thomas W
authors: TW
authors: Winkler
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors: Natalia
authors: N
authors: Tšernikova
authors: MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors: Jian'an
authors: J
authors: Luan
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
authors: Evelin
authors: E
authors: Mihailov
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Center for Complex Disease Genomics, Baltimore, Maryland, United States of America; Cardiology, Geneva University Hospitals, Geneva, Switzerland.
authors: Georg B
authors: GB
authors: Ehret
authors: Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors: Weihua
authors: W
authors: Zhang
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: David
authors: D
authors: Lamparter
authors: Center for Basic and Translational Obesity Research and Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts, United States of America; Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Tõnu
authors: T
authors: Esko
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Aurelien
authors: A
authors: Macé
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Sina
authors: S
authors: Rüeger
authors: Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Pierre-Yves
authors: PY
authors: Bochud
authors: Department of Health Sciences, University of Milan, Milan, Italy.
authors: Matteo
authors: M
authors: Barcella
authors: INSERM-U1061, Montpellier, France; National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France.
authors: Yves
authors: Y
authors: Dauvilliers
authors: Queensland Brain Institute, University of Queensland, Brisbane, Australia; Genetic Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors: Beben
authors: B
authors: Benyamin
authors: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom; Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Australia.
authors: David M
authors: DM
authors: Evans
authors: MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: Caroline
authors: C
authors: Hayward
authors: Center for Basic and Translational Obesity Research and Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts, United States of America; Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Mary F
authors: MF
authors: Lopez
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Lude
authors: L
authors: Franke
authors: Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation and Dept. of Medical Sciences, University of Turin, Turin, Italy.
authors: Alessia
authors: A
authors: Russo
authors: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors: Iris M
authors: IM
authors: Heid
authors: Department of Health Sciences, University of Milan, Milan, Italy.
authors: Erika
authors: E
authors: Salvi
authors: Center for Basic and Translational Obesity Research and Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts, United States of America; Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Sailaja
authors: S
authors: Vendantam
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Center for Complex Disease Genomics, Baltimore, Maryland, United States of America.
authors: Dan E
authors: DE
authors: Arking
authors: Human Genetics Center, Houston, Texas, United States of America.
authors: Eric
authors: E
authors: Boerwinkle
authors: Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors: John C
authors: JC
authors: Chambers
authors: Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation and Dept. of Medical Sciences, University of Turin, Turin, Italy.
authors: Giovanni
authors: G
authors: Fiorito
authors: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Harald
authors: H
authors: Grallert
authors: Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy.
authors: Simonetta
authors: S
authors: Guarrera
authors: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors: Georg
authors: G
authors: Homuth
authors: MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: Jennifer E
authors: JE
authors: Huffman
authors: Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: David
authors: D
authors: Porteous
authors: Department of Medicine, Service of Gastroenterology and Hepatology, Lausanne, Switzerland.
authors: Darius
authors: D
authors: Moradpour
authors: Neurology Service, Hospital Clinic, Barcelona, Spain.
authors: Alex
authors: A
authors: Iranzo
authors: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors: Johannes
authors: J
authors: Hebebrand
authors: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors: John P
authors: JP
authors: Kemp
authors: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands; Sleep Wake Center SEIN, Heemstede, The Netherlands.
authors: Gert J
authors: GJ
authors: Lammers
authors: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Vincent
authors: V
authors: Aubert
authors: Department of Gastroenterology, University Hospital Basel, Basel, Switzerland.
authors: Markus H
authors: MH
authors: Heim
authors: Genetic Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Molecular Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors: Grant W
authors: GW
authors: Montgomery
authors: Sleep and Epilepsy Unit - Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain.
authors: Rosa
authors: R
authors: Peraita-Adrados
authors: Neurology Service, Hospital Clinic, Barcelona, Spain.
authors: Joan
authors: J
authors: Santamaria
authors: Service of Gastroenterology and Hepatology, Service of Clinical Pathology, Geneva, Switzerland.
authors: Francesco
authors: F
authors: Negro
authors: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors: Carsten O
authors: CO
authors: Schmidt
authors: MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors: Robert A
authors: RA
authors: Scott
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
authors: Tim D
authors: TD
authors: Spector
authors: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Konstantin
authors: K
authors: Strauch
authors: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors: Henry
authors: H
authors: Völzke
authors: MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors: Nicholas J
authors: NJ
authors: Wareham
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
authors: Wei
authors: W
authors: Yuan
authors: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
authors: Jordana T
authors: JT
authors: Bell
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Center for Complex Disease Genomics, Baltimore, Maryland, United States of America.
authors: Aravinda
authors: A
authors: Chakravarti
authors: Cardiovascular Science, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors: Jaspal S
authors: JS
authors: Kooner
authors: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany; Deutsches Zentrum für Diabetes, Neuherberg, Germany.
authors: Annette
authors: A
authors: Peters
authors: Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation and Dept. of Medical Sciences, University of Turin, Turin, Italy.
authors: Giuseppe
authors: G
authors: Matullo
authors: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors: Henri
authors: H
authors: Wallaschofski
authors: Genetic Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors: John B
authors: JB
authors: Whitfield
authors: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Fred
authors: F
authors: Paccaud
authors: Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Peter
authors: P
authors: Vollenweider
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Sven
authors: S
authors: Bergmann
authors: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Jacques S
authors: JS
authors: Beckmann
authors: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland; Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Mehdi
authors: M
authors: Tafti
authors: MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: Nicholas D
authors: ND
authors: Hastie
authors: Department of Health Sciences, University of Milan, Milan, Italy.
authors: Daniele
authors: D
authors: Cusi
authors: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Murielle
authors: M
authors: Bochud
authors: University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
authors: Timothy M
authors: TM
authors: Frayling
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland; Department of Epidemiology and Biostatistics, School of Public Health, MRC-HPA Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, United Kingdom; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
authors: Marjo-Riitta
authors: MR
authors: Jarvelin
authors: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors: André
authors: A
authors: Scherag
authors: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors: George Davey
authors: GD
authors: Smith
authors: Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
authors: Ingrid B
authors: IB
authors: Borecki
authors: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Valentin
authors: V
authors: Rousson
authors: Center for Basic and Translational Obesity Research and Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts, United States of America; Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Joel N
authors: JN
authors: Hirschhorn
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Carlo
authors: C
authors: Rivolta
authors: MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom; The Charles Bronfman Institute of Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Ruth J F
authors: RJ
authors: Loos
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors: Zoltán
authors: Z
authors: Kutalik
mesh_terms: D000328:Adult; D015992:Body Mass Index; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain; C430746:SLC2A10 protein, human