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

PLoS Genet
Authors
Clive Hoggart
Giulia Venturini
Massimo Mangino
Felicia Gomez
Giulia Ascari
Jing Zhao
Alexander Teumer
Thomas Winkler
Natalia TÅ¡ernikova
Jian'an Luan
Evelin Mihailov
Georg Ehret
Weihua Zhang
David Lamparter
Tõnu Esko
Aurelien Macé
Sina Rüeger
Pierre-Yves Bochud
Matteo Barcella
Yves Dauvilliers
Beben Benyamin
David Evans
Caroline Hayward
Mary Lopez
Lude Franke
Alessia Russo
Iris Heid
Erika Salvi
Sailaja Vendantam
Dan Arking
Eric Boerwinkle
John Chambers
Giovanni Fiorito
Harald Grallert
Simonetta Guarrera
Georg Homuth
Jennifer Huffman
David Porteous
Generation Scotland Consortium
LifeLines Cohort Study
GIANT Consortium
Darius Moradpour
Alex Iranzo
Johannes Hebebrand
John Kemp
Gert Lammers
Vincent Aubert
Markus Heim
Nicholas Martin
Grant Montgomery
Rosa Peraita-Adrados
Joan Santamaria
Francesco Negro
Carsten Schmidt
Robert Scott
Tim Spector
Konstantin Strauch
Henry Völzke
Nicholas Wareham
Wei Yuan
Jordana Bell
Aravinda Chakravarti
Jaspal Kooner
Annette Peters
Giuseppe Matullo
Henri Wallaschofski
John Whitfield
Fred Paccaud
Peter Vollenweider
Sven Bergmann
Jacques Beckmann
Mehdi Tafti
Nicholas Hastie
Daniele Cusi
Murielle Bochud
Timothy Frayling
Andres Metspalu
Marjo-Riitta Jarvelin
André Scherag
George Smith
Ingrid Borecki
Valentin Rousson
Joel Hirschhorn
Carlo Rivolta
Ruth Loos
Zoltán Kutalik
Keywords
Female
Humans
Male
Gene Expression Regulation
Adult
Genetic Predisposition to Disease
Genotype
Genome-Wide Association Study
Polymorphism, Single Nucleotide
European Continental Ancestry Group
Obesity
Body Mass Index
Genomic Imprinting
Glucose Transport Proteins, Facilitative
Potassium Channels, Tandem Pore Domain
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), P0.0027) 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 (P0.01). 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.
Year of Publication
2014
Journal
PLoS Genet
Volume
10
Issue
7
Pages
e1004508
Date Published
2014 Jul
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004508
PubMed ID
25078964
PubMed Central ID
PMC4117451
Links
Grant list
UL1RR025005 / RR / NCRR NIH HHS / United States
G0100266 / Medical Research Council / United Kingdom
084723/Z/08/Z / Wellcome Trust / United Kingdom
RP-PG-0310-1002 / Department of Health / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
AA13320 / AA / NIAAA NIH HHS / United States
HHSN268201100005C / PHS HHS / United States
R01DK8925601 / DK / NIDDK NIH HHS / United States
DA12854 / DA / NIDA NIH HHS / United States
AA13321 / AA / NIAAA NIH HHS / United States
AA10248 / AA / NIAAA NIH HHS / United States
HHSN268201100009C / PHS HHS / United States
G0700931 / Medical Research Council / United Kingdom
5R01MH63706:02 / MH / NIMH NIH HHS / United States
0927310 / Wellcome Trust / United Kingdom
P30 DK079637 / DK / NIDDK NIH HHS / United States
T32 HL091823 / HL / NHLBI NIH HHS / United States
1RL1MH083268-01 / MH / NIMH NIH HHS / United States
HHSN268200625226C / PHS HHS / United States
MC_UP_0801/1 / Medical Research Council / United Kingdom
MR/K026992/1 / Medical Research Council / United Kingdom
G0500539 / Medical Research Council / United Kingdom
HHSN268201100010C / PHS HHS / United States
102215 / Wellcome Trust / United Kingdom
MC_UU_12015/1 / Medical Research Council / United Kingdom
U01HG004402 / HG / NHGRI NIH HHS / United States
0927310 / Medical Research Council / United Kingdom
097117 / Wellcome Trust / United Kingdom
WT083431MA / Wellcome Trust / United Kingdom
MC_PC_15018 / Medical Research Council / United Kingdom
HHSN268201100008C / PHS HHS / United States
HHSN268201100012C / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
MC_UU_12013/1 / Medical Research Council / United Kingdom
G0701863 / Medical Research Council / United Kingdom
MC_UU_12013/4 / Medical Research Council / United Kingdom
CZD/16/6/4 / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
RG/09/012/28096 / British Heart Foundation / United Kingdom
G0601966 / Medical Research Council / United Kingdom
HHSN268201100007C / PHS HHS / United States
AA014041 / AA / NIAAA NIH HHS / United States
MR/K006584/1 / Medical Research Council / United Kingdom
MR/K013351/1 / Medical Research Council / United Kingdom
HHSN268201100011C / PHS HHS / United States
MC_U106179471 / Medical Research Council / United Kingdom
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
BB/F019394/1 / Biotechnology and Biological Sciences Research Council / United Kingdom
HHSN268201100006C / PHS HHS / United States
G1002319 / Medical Research Council / United Kingdom
AA07535 / AA / NIAAA NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
AA13326 / AA / NIAAA NIH HHS / United States
G9815508 / Medical Research Council / United Kingdom
G0600705 / Medical Research Council / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States

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