Abstract
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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Acknowledgements
We thank Shaun Purcell for helpful discussions. This work was supported by NIH Grants HD073731, DA033660, HG006696 and Grant NIRG69983 from the Alzheimer’s Association to AJS, and also by the Deutsche Forschungsgemeinschaft (FOR 423 and individual Grants MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1). KUL and ACB received support from the BONFOR program of the Medical Faculty, University of Bonn. The details of the collection and methods for samples used in this study are described by Beaty et al.7 The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000094.v1.p1 through dbGaP accession number phs000094.v1.p1. Funding support for the study entitled ‘International Consortium to Identify Genes and Interactions Controlling Oral Clefts’ was provided by several previous Grants from the National Institute of Dental and Craniofacial Research (NIDCR), including: R21-DE-013707, R01-DE-014581, R37-DE-08559, P50-DE-016215, R01-DE-09886, R01-DE-012472, R01-DE-014677, R01-DE-016148, R21-DE-016930; R01-DE-013939. Additional support was provided in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, the Smile Train Foundation for recruitment in China and a Grant from the Korean government. The genome-wide association study, also known the Cleft Consortium, is part of the Gene Environment Association Studies (GENEVA) program of the trans-NIH Genes, Environment and Health Initiative [GEI] supported by U01-DE-018993. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01-HG-004446) and by the National Center for Biotechnology Information (NCBI).
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Garg, P., Ludwig, K., Böhmer, A. et al. Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts. Eur J Hum Genet 22, 822–830 (2014). https://doi.org/10.1038/ejhg.2013.235
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DOI: https://doi.org/10.1038/ejhg.2013.235
