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

Clive J. Hoggart, Giulia Venturini, Massimo Mangino, Felicia Gomez, Giulia Ascari, Jing H ua Zhao, Alexander Teumer, Thomas W. Winkler, Natalia Tšernikova, Jian'an Luan, Evelin Mihailov, Georg B. Ehret, Weihua Zhang, David Lamparter, Tõnu Esko, Aurelien Macé, Sina Rüeger, Pierre Yves Bochud, Matteo Barcella, Yves DauvilliersBeben Benyamin, David M. Evans, Caroline Hayward, Mary F. Lopez, Lude Franke, Alessia Russo, Iris M. Heid, Erika Salvi, Sailaja Vendantam, Dan E. Arking, Eric Boerwinkle, John C Chambers, Giovanni Fiorito, Harald Grallert, Simonetta Guarrera, Georg Homuth, Jennifer E. Huffman, David Porteous, Darius Moradpour, Alex Iranzo, Johannes Hebebrand, John P. Kemp, Gert J. Lammers, Vincent Aubert, Markus H. Heim, Nicholas G. Martin, Grant W. Montgomery, Rosa Peraita-Adrados, Joan Santamaria, Francesco Negro, Carsten O. Schmidt, Robert A Scott, Tim D. Spector, Konstantin Strauch, Henry Völzke, Nicholas J. Wareham, Wei Yuan, Jordana T. Bell, Aravinda Chakravarti, Jaspal S. Kooner, Annette Peters, Giuseppe Matullo, Henri Wallaschofski, John B. Whitfield, Fred Paccaud, Peter Vollenweider, Sven Bergmann, Jacques S. Beckmann, Mehdi Tafti, Nicholas D. Hastie, Daniele Cusi, Murielle Bochud, Timothy M. Frayling, Andres Metspalu, Marjo Riitta Jarvelin, André Scherag, Ingrid B. Borecki, Valentin Rousson, Joel N. Hirschhorn, Carlo Rivolta, Ruth J F Loos, Zoltán Kutalik, George Davey Smith

Research output: Contribution to journalArticle (Academic Journal)peer-review

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e1004508
JournalPLoS Genetics
Volume10
Issue number7
DOIs
Publication statusPublished - 1 Jul 2014

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