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 Dauvilliers; Beben 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; Elina Hyppönen; The GIANT Consortium; Generation Scotland Consortium; The LifeLines Cohort study

doi:10.1371/journal.pgen.1004508

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, Elina Hyppönen, The GIANT Consortium, Generation Scotland Consortium, The LifeLines Cohort study

Australian Centre For Precision Health

Research output: Contribution to journal › Article › peer-review

50 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 language	English
Article number	e1004508
Pages (from-to)	1-12
Number of pages	12
Journal	PLoS Genetics
Volume	10
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1004508
Publication status	Published or Issued - 1 Jan 2014

ASJC Scopus subject areas

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

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Hoggart, C. J., Venturini, G., Mangino, M., Gomez, F., Ascari, G., Zhao, J. H., Teumer, A., Winkler, T. W., Tšernikova, N., Luan, J., Mihailov, E., Ehret, G. B., Zhang, W., Lamparter, D., Esko, T., Macé, A., Rüeger, S., Bochud, P. Y., Barcella, M., ... 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. Article e1004508. https://doi.org/10.1371/journal.pgen.1004508

@article{b090607f17ff4e32824ec381d09beeef,

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.",

author = "Hoggart, {Clive J.} and Giulia Venturini and Massimo Mangino and Felicia Gomez and Giulia Ascari and Zhao, {Jing Hua} and Alexander Teumer and Winkler, {Thomas W.} and Natalia T{\v s}ernikova and Jian'an Luan and Evelin Mihailov and Ehret, {Georg B.} and Weihua Zhang and David Lamparter and T{\~o}nu Esko and Aurelien Mac{\'e} and Sina R{\"u}eger and Bochud, {Pierre Yves} and Matteo Barcella and Yves Dauvilliers and Beben Benyamin and Evans, {David M.} and Caroline Hayward and Lopez, {Mary F.} and Lude Franke and Alessia Russo and Heid, {Iris M.} and Erika Salvi and Sailaja Vendantam and Arking, {Dan E.} and Eric Boerwinkle and Chambers, {John C.} and Giovanni Fiorito and Harald Grallert and Simonetta Guarrera and Georg Homuth and Huffman, {Jennifer E.} and David Porteous and Darius Moradpour and Alex Iranzo and Johannes Hebebrand and Kemp, {John P.} and Lammers, {Gert J.} and Vincent Aubert and Heim, {Markus H.} and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Rosa Peraita-Adrados and Joan Santamaria and Elina Hypp{\"o}nen and {The GIANT Consortium} and {Generation Scotland Consortium} and {The LifeLines Cohort study}",

note = "Publisher Copyright: {\textcopyright} 2014, Hoggart et al.",

year = "2014",

month = jan,

day = "1",

doi = "10.1371/journal.pgen.1004508",

language = "English",

volume = "10",

pages = "1--12",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

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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, Hyppönen, E, 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

TY - JOUR

T1 - Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index

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

AU - Santamaria, Joan

AU - Hyppönen, Elina

AU - The GIANT Consortium

AU - Generation Scotland Consortium

AU - The LifeLines Cohort study

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84905474692&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004508

DO - 10.1371/journal.pgen.1004508

M3 - Article

C2 - 25078964

AN - SCOPUS:84905474692

SN - 1553-7390

VL - 10

SP - 1

EP - 12

JO - PLoS Genetics

JF - PLoS Genetics

IS - 7

M1 - e1004508

ER -

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

Abstract

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