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Meta-Analysis
. 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

Clive J Hoggart  1 , Giulia Venturini  2 , Massimo Mangino  3 , Felicia Gomez  4 , Giulia Ascari  2 , Jing Hua Zhao  5 , Alexander Teumer  6 , Thomas W Winkler  7 , Natalia Tšernikova  8 , Jian'an Luan  5 , Evelin Mihailov  9 , Georg B Ehret  10 , Weihua Zhang  11 , David Lamparter  12 , Tõnu Esko  13 , Aurelien Macé  12 , Sina Rüeger  12 , Pierre-Yves Bochud  14 , Matteo Barcella  15 , Yves Dauvilliers  16 , Beben Benyamin  17 , David M Evans  18 , Caroline Hayward  19 , Mary F Lopez  20 , Lude Franke  21 , Alessia Russo  22 , Iris M Heid  7 , Erika Salvi  15 , Sailaja Vendantam  23 , Dan E Arking  24 , Eric Boerwinkle  25 , John C Chambers  11 , Giovanni Fiorito  22 , Harald Grallert  26 , Simonetta Guarrera  27 , Georg Homuth  6 , Jennifer E Huffman  19 , David Porteous  28 ; Generation Scotland Consortium; LifeLines Cohort study; GIANT Consortium; Darius Moradpour  29 , Alex Iranzo  30 , Johannes Hebebrand  31 , John P Kemp  32 , Gert J Lammers  33 , Vincent Aubert  34 , Markus H Heim  35 , Nicholas G Martin  36 , Grant W Montgomery  37 , Rosa Peraita-Adrados  38 , Joan Santamaria  30 , Francesco Negro  39 , Carsten O Schmidt  40 , Robert A Scott  5 , Tim D Spector  3 , Konstantin Strauch  41 , Henry Völzke  40 , Nicholas J Wareham  5 , Wei Yuan  3 , Jordana T Bell  3 , Aravinda Chakravarti  24 , Jaspal S Kooner  42 , Annette Peters  43 , Giuseppe Matullo  22 , Henri Wallaschofski  44 , John B Whitfield  36 , Fred Paccaud  45 , Peter Vollenweider  46 , Sven Bergmann  12 , Jacques S Beckmann  47 , Mehdi Tafti  48 , Nicholas D Hastie  19 , Daniele Cusi  15 , Murielle Bochud  45 , Timothy M Frayling  49 , Andres Metspalu  50 , Marjo-Riitta Jarvelin  51 , André Scherag  52 , George Davey Smith  32 , Ingrid B Borecki  4 , Valentin Rousson  45 , Joel N Hirschhorn  13 , Carlo Rivolta  2 , Ruth J F Loos  53 , Zoltán Kutalik  54
Collaborators, Affiliations
Meta-Analysis

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

Clive J Hoggart et al. PLoS Genet. .

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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Conflict of interest statement

Prof. Dauvilliers has received speaker's honoraria and support for travel to meetings from UCB Pharma, JAZZ and Bioprojet. Prof. Dauvilliers participated in advisory boards of UCB Pharma, JAZZ and Bioprojet. All other authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Explanation of the POE test.
Top panel illustrates the phenotype distributions in the four genotype groups that would be observed if the parent-of-origin of the alleles were known. Bottom panel shows how these distributions change if the parent-of-origin is unobserved. The resulting heterozygous group will have increased variance due to its heterogeneity. This example describes a scenario we observe for the two replicated hits, namely that the paternal- and maternal effects are of the same size, but opposite in direction (formula image). Therefore the average phenotype in the B/B group is the same as in the A/A group, as the paternal and maternal B allele effects cancel each other out. In the A/B group there are two subpopulations: the A-pat/B-mat group with phenotypic mean of formula image and the A-mat/B-pat group with formula image mean. Thus, the two subpopulations combined also have zero mean, but increased variance.
Figure 2
Figure 2. Local association plots.
Panels show the local POE association P-values for the KCNK9 (left panel) and SLC2A10 (right panel) loci.
See this image and copyright information in PMC

References

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