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PLoS Genet. 2014 Jul 31;10(7):e1004508. doi: 10.1371/journal.pgen.1004508. eCollection 2014 Jul.

Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.

Collaborators (390)

de Bakker P, Bültmann U, Geleijnse M, Harst Pv, Koppelman G, Rosmalen JG, van Rossum L, Smidt H, Swertz MA, Stolk RP, Alizadeh B, de Boer R, Boezen HM, Bruinenberg M, Franke L, van der Harst P, Hillege H, van der Klauw M, Navis G, Ormel J, Postma D, Rosmalen J, Slaets J, Snieder H, Stolk R, Wolffenbuttel B, Wijmenga C, Berg J, Blackwood D, Campbell H, Cavanagh J, Connell J, Connor M, Cunningham-Burley S, Deary I, Dominiczak A, Ellis P, FitzPatrick B, Ford I, Gertz R, Grau A, Haddow G, Jackson C, Kerr S, Lindsay R, McGilchrist M, McIntyre D, Morris A, Morton R, Muir W, Murray G, Palmer C, Pell J, Philp A, Porteous D, Porteous M, Procter R, Ralston S, Reid D, Sinnott R, Smith B, Clair DS, Sullivan F, Sweetland M, Ure J, Watt G, Wolf R, Wright A, Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau- Chonka DC, Day FR, Esko T, Fall T, Ferreira T, Gentilini D, Jackson AU, Luan J, Randall JC, Vedantam S, Willer CJ, Winkler TW, Wood AR, Workalemahu T, Hu YJ, Lee SH, Liang L, Lin DY, Min JL, Neale BM, Thorleifsson G, Yang J, Albrecht E, Amin N, Bragg-Gresham JL, Cadby G, den Heijer M, Eklund N, Fischer K, Goel A, Hottenga JJ, Huffman JE, Jarick I, Johansson A, Johnson T, Kanoni S, Kleber ME, König IR, Kristiansson K, Kutalik Z, Lamina C, Lecoeur C, Li G, Mangino M, McArdle WL, Medina-Gomez C, Müller-Nurasyid M, Ngwa JS, Nolte IM, Paternoster L, Pechlivanis S, Perola M, Peters MJ, Preuss M, Rose LM, Shi J, Shungin D, Smith AV, Strawbridge RJ, Surakka I, Teumer A, Trip MD, Tyrer J, Van Vliet- Ostaptchouk JV, Vandenput L, Waite LL, Zhao JH, Absher D, Asselbergs FW, Atalay M, Attwood AP, Balmforth AJ, Basart H, Beilby J, Bonnycastle LL, Brambilla P, Bruinenberg M, Campbell H, Chasman DI, Chines PS, Collins FS, Connell JM, Cookson W, de Faire U, de Vegt F, Dei M, Dimitriou M, Edkins S, Estrada K, Evans DM, Farrall M, Ferrario MM, Ferrières J, Franke L, Frau F, Gejman PV, Grallert H, Grönberg H, Gudnason V, Hall AS, Hall P, Hartikainen AL, Hayward C, Heard-Costa NL, Heath AC, Hebebrand J, Homuth G, Hu FB, Hunt SE, Hyppönen E, Iribarren C, Jacobs KB, Jansson JO, Jula A, Kähönen M, Kathiresan S, Kee F, Khaw KT, Kivimaki M, Koenig W, Kraja AT, Kumari M, Kuulasmaa K, Kuusisto J, Laitinen JH, Lakka TA, Langenberg C, Launer LJ, Lind L, Lindström J, Liu J, Liuzzi A, Lokki ML, Lorentzon M, Madden PA, Magnusson PK, Manunta P, Marek D, März W, Mateo Leach I, McKnight B, Medland SE, Mihailov E, Milani L, Montgomery GW, Mooser V, Mühleisen TW, Munroe PB, Musk AW, Narisu N, Navis G, Nicholson G, Nohr EA, Ong KK, Oostra BA, Palmer CN, Palotie A, Peden JF, Pedersen N, Peters A, Polasek O, Pouta A, Pramstaller PP, Prokopenko I, Pütter C, Radhakrishnan A, Raitakari O, Rendon A, Rivadeneira F, Rudan I, Saaristo TE, Sambrook JG, Sanders AR, Sanna S, Saramies J, Schipf S, Schreiber S, Schunkert H, Shin SY, Signorini S, Sinisalo J, Skrobek B, Soranzo N, Stancakova A, Stark K, Stephens JC, Stirrups K, Stolk RP, Stumvoll M, Swift AJ, Theodoraki EV, Thorand B, Tregouet DA, Tremoli E, Van der Klauw MM, van Meurs JB, Vermeulen SH, Viikari J, Virtamo J, Vitart V, Waeber G, Wang Z, Widen E, Wild SH, Willemsen G, Winkelmann BR, Witteman JC, Wolffenbuttel BH, Wong A, Wright AF, Zillikens M, Amouyel P, Boehm BO, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Cupples L, Cusi D, Dedoussis GV, Erdmann J, Eriksson JG, Franks PW, Froguel P, Gieger C, Gyllensten U, Hamsten A, Harris TB, Hengstenberg C, Hicks AA, Hingorani A, Hinney A, Hofman A, Hovingh KG, Hveem K, Illig T, Jarvelin MR, Jöckel KH, Keinanen-Kiukaanniemi SM, Kiemeney LA, Kuh D, Laakso M, Lehtimäki T, Levinson DF, Martin NG, Metspalu A, Morris AD, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Ouwehand WH, Palmer LJ, Penninx B, Power C, Province MA, Psaty BM, Qi L, Rauramaa R, Ridker PM, Ripatti S, Salomaa V, Samani NJ, Snieder H, Sørensen TI, Spector TD, Stefansson K, Tönjes A, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Vollenweider P, Wallaschofski H, Wareham NJ, Watkins H, Wichmann H-, Wilson JF, Abecasis GR, Assimes TL, Barroso I, Boehnke M, Borecki IB, Deloukas P, Fox CS, Frayling T, Groop LC, Haritunian T, Heid IM, Hunter D, Kaplan RC, Karpe F, Moffatt M, Mohlke KL, O'Connell JR, Pawitan Y, Schadt EE, Schlessinger D, Steinthorsdottir V, Strachan DP, Thorsteinsdottir U, van Duijn CM, Visscher PM, Di Blasio AM, Hirschhorn JN, Lindgren CM, Morris AP, Meyre D, Scherag A, McCarthy MI, Speliotes EK, North KE, Loos RJ, Ingelsson E.

Author information

1
Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.
2
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
3
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
4
Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
5
MRC-Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
6
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
7
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
8
Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
9
Estonian Genome Center, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
10
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.
11
Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
12
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
13
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.
14
Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
15
Department of Health Sciences, University of Milan, Milan, Italy.
16
INSERM-U1061, Montpellier, France; National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France.
17
Queensland Brain Institute, University of Queensland, Brisbane, Australia; Genetic Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
18
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.
19
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
20
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.
21
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
22
Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation and Dept. of Medical Sciences, University of Turin, Turin, Italy.
23
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.
24
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Center for Complex Disease Genomics, Baltimore, Maryland, United States of America.
25
Human Genetics Center, Houston, Texas, United States of America.
26
Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
27
Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy.
28
Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
29
Department of Medicine, Service of Gastroenterology and Hepatology, Lausanne, Switzerland.
30
Neurology Service, Hospital Clinic, Barcelona, Spain.
31
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
32
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
33
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands; Sleep Wake Center SEIN, Heemstede, The Netherlands.
34
Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
35
Department of Gastroenterology, University Hospital Basel, Basel, Switzerland.
36
Genetic Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
37
Molecular Epidemiology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
38
Sleep and Epilepsy Unit - Clinical Neurophysiology Department, Gregorio Marañón University Hospital, Madrid, Spain.
39
Service of Gastroenterology and Hepatology, Service of Clinical Pathology, Geneva, Switzerland.
40
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
41
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.
42
Cardiovascular Science, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
43
Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany; Deutsches Zentrum für Diabetes, Neuherberg, Germany.
44
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
45
Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
46
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
47
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
48
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.
49
University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
50
Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
51
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.
52
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.
53
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.
54
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.

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.

PMID:
25078964
PMCID:
PMC4117451
DOI:
10.1371/journal.pgen.1004508
[Indexed for MEDLINE]
Free PMC Article

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