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Eur J Hum Genet. 2014 Jun;22(6):822-30. doi: 10.1038/ejhg.2013.235. Epub 2013 Oct 30.

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts.

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Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, NY, USA.
1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Experimental and Diagnostic Medicine, Medical Genetics Unit, University of Ferrara, Ferrara, Italy.
1] Department of Obstetrics and Gynaecology, and Clinical Genetics, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Radboud University Nijmegen, Nijmegen, The Netherlands.
Orthodontic Unit, Dental Hospital and School, University of Dundee, Dundee, UK.
Institute of Human Genetics, University of Bonn, Bonn, Germany.


Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genome-wide single-nucleotide polymorphism (SNP) data from ∼2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of ∼1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (P<5 × 10(-8)). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P=0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P=1.5 × 10(-7), paternal-specific P=0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

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