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 Hua 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, Karen L. Mohlke, The GIANT Consortium, Generation Scotland Consortium, The LifeLines Cohort study

Research output: Contribution to journalArticle

32 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 (US)
Article numbere1004508
Pages (from-to)1-12
Number of pages12
JournalPLoS Genetics
Volume10
Issue number7
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

body mass
single nucleotide polymorphism
Single Nucleotide Polymorphism
body mass index
allele
polymorphism
Body Mass Index
Alleles
alleles
gene
genotype
Genotype
obesity
Genome-Wide Association Study
phenotypic variation
Genes
Real-Time Polymerase Chain Reaction
heterozygosity
quantitative polymerase chain reaction
genes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Hoggart, C. J., Venturini, G., Mangino, M., Gomez, F., Ascari, G., Zhao, J. H., ... The LifeLines Cohort study (2014). Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. PLoS Genetics, 10(7), 1-12. [e1004508]. https://doi.org/10.1371/journal.pgen.1004508

Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. / Hoggart, Clive J.; Venturini, Giulia; Mangino, Massimo; Gomez, Felicia; Ascari, Giulia; Zhao, Jing Hua; Teumer, Alexander; Winkler, Thomas W.; Tšernikova, Natalia; Luan, Jian'an; Mihailov, Evelin; Ehret, Georg B.; Zhang, Weihua; Lamparter, David; Esko, Tõnu; Macé, Aurelien; Rüeger, Sina; Bochud, Pierre Yves; Barcella, Matteo; Dauvilliers, Yves; Benyamin, Beben; Evans, David M.; Hayward, Caroline; Lopez, Mary F.; Franke, Lude; Russo, Alessia; Heid, Iris M.; Salvi, Erika; Vendantam, Sailaja; Arking, Dan E.; Boerwinkle, Eric; Chambers, John C.; Fiorito, Giovanni; Grallert, Harald; Guarrera, Simonetta; Homuth, Georg; Huffman, Jennifer E.; Porteous, David; Moradpour, Darius; Iranzo, Alex; Hebebrand, Johannes; Kemp, John P.; Lammers, Gert J.; Aubert, Vincent; Heim, Markus H.; Martin, Nicholas G.; Montgomery, Grant W.; Peraita-Adrados, Rosa; Santamaria, Joan; Mohlke, Karen L.; The GIANT Consortium; Generation Scotland Consortium; The LifeLines Cohort study.

In: PLoS Genetics, Vol. 10, No. 7, e1004508, 01.01.2014, p. 1-12.

Research output: Contribution to journalArticle

Hoggart, CJ, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, JH, Teumer, A, Winkler, TW, Tšernikova, N, Luan, J, Mihailov, E, Ehret, GB, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, PY, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, DM, Hayward, C, Lopez, MF, Franke, L, Russo, A, Heid, IM, Salvi, E, Vendantam, S, Arking, DE, Boerwinkle, E, Chambers, JC, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, JE, Porteous, D, Moradpour, D, Iranzo, A, Hebebrand, J, Kemp, JP, Lammers, GJ, Aubert, V, Heim, MH, Martin, NG, Montgomery, GW, Peraita-Adrados, R, Santamaria, J, Mohlke, KL, The GIANT Consortium, Generation Scotland Consortium & The LifeLines Cohort study 2014, 'Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index', PLoS Genetics, vol. 10, no. 7, e1004508, pp. 1-12. https://doi.org/10.1371/journal.pgen.1004508
Hoggart, Clive J. ; Venturini, Giulia ; Mangino, Massimo ; Gomez, Felicia ; Ascari, Giulia ; Zhao, Jing Hua ; Teumer, Alexander ; Winkler, Thomas W. ; Tšernikova, Natalia ; Luan, Jian'an ; Mihailov, Evelin ; Ehret, Georg B. ; Zhang, Weihua ; Lamparter, David ; Esko, Tõnu ; Macé, Aurelien ; Rüeger, Sina ; Bochud, Pierre Yves ; Barcella, Matteo ; Dauvilliers, Yves ; Benyamin, Beben ; Evans, David M. ; Hayward, Caroline ; Lopez, Mary F. ; Franke, Lude ; Russo, Alessia ; Heid, Iris M. ; Salvi, Erika ; Vendantam, Sailaja ; Arking, Dan E. ; Boerwinkle, Eric ; Chambers, John C. ; Fiorito, Giovanni ; Grallert, Harald ; Guarrera, Simonetta ; Homuth, Georg ; Huffman, Jennifer E. ; Porteous, David ; Moradpour, Darius ; Iranzo, Alex ; Hebebrand, Johannes ; Kemp, John P. ; Lammers, Gert J. ; Aubert, Vincent ; Heim, Markus H. ; Martin, Nicholas G. ; Montgomery, Grant W. ; Peraita-Adrados, Rosa ; Santamaria, Joan ; Mohlke, Karen L. ; The GIANT Consortium ; Generation Scotland Consortium ; The LifeLines Cohort study. / Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. In: PLoS Genetics. 2014 ; Vol. 10, No. 7. pp. 1-12.
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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.",
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AU - Hoggart, Clive J.

AU - Venturini, Giulia

AU - Mangino, Massimo

AU - Gomez, Felicia

AU - Ascari, Giulia

AU - Zhao, Jing Hua

AU - Teumer, Alexander

AU - Winkler, Thomas W.

AU - Tšernikova, Natalia

AU - Luan, Jian'an

AU - Mihailov, Evelin

AU - Ehret, Georg B.

AU - Zhang, Weihua

AU - Lamparter, David

AU - Esko, Tõnu

AU - Macé, Aurelien

AU - Rüeger, Sina

AU - Bochud, Pierre Yves

AU - Barcella, Matteo

AU - Dauvilliers, Yves

AU - Benyamin, Beben

AU - Evans, David M.

AU - Hayward, Caroline

AU - Lopez, Mary F.

AU - Franke, Lude

AU - Russo, Alessia

AU - Heid, Iris M.

AU - Salvi, Erika

AU - Vendantam, Sailaja

AU - Arking, Dan E.

AU - Boerwinkle, Eric

AU - Chambers, John C.

AU - Fiorito, Giovanni

AU - Grallert, Harald

AU - Guarrera, Simonetta

AU - Homuth, Georg

AU - Huffman, Jennifer E.

AU - Porteous, David

AU - Moradpour, Darius

AU - Iranzo, Alex

AU - Hebebrand, Johannes

AU - Kemp, John P.

AU - Lammers, Gert J.

AU - Aubert, Vincent

AU - Heim, Markus H.

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Peraita-Adrados, Rosa

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