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

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 genomewide single-nucleotide polymorphism (SNP) data from B2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of B1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (Po5 Â 10 À8 ). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P ¼ 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 ¼ 1.5 Â 10 À7 , paternal-specific P ¼ 0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

Genetic risk factors for orofacial clefts in Central Africans and Southeast Asians

“…Other small studies have identified a selected few variants in candidate genes [Rubini et al, ; Reutter et al, ; Sull et al, ; Sull et al, ; Park et al, ; Sull et al, ]. Butali et al [] showed significant excess transmission of the minor allele from both parents, but especially the mother for VAX1 , and Garg et al [] observed an excess of loci showing maternal versus paternal transmission for 8q21.3. In this study, we were not able to delineate maternal versus paternal effects due to the limited number of triads.…”

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

“…PoO effects indicate differential effects in fetal genes depending on whether they were inherited from the mother or the father. Two studies of MG and PoO effects based on GWAS data (Shi et al 2012; Garg et al 2014) found nonsignificant effects. However, their study samples were relatively modest for a meaningful assessment of such effects.…”

Genetic variants in GRHL3 and risk for neural tube defects: A case–control and case–parent triad/control study

“…The PoO effect occurs when a locus expressed in mothers or fathers has a causal influence on the phenotype of the infant, and it is often considered a genomic imprinting effect (Gjerdevik et al, ; Lawson, Cheverud, & Wolf, ). Some studies have detected gene PoO effects in birth defects, such as nonsyndromic orofacial clefts (Garg et al, ) and conotruncal heart defects (Nembhard et al, ). However, no study has reported PoO effects for PCP pathway genes related to the occurrence of NTDs.…”