A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption

Abstract

Background: Although both genetic and environmental factors have been reported to influence the risk of isolated cleft lip with or without cleft palate (CL/P), the exact mechanisms behind CL/P are still largely unaccounted for. We recently developed new methods to identify parent-of-origin (PoO) interactions with environmental exposures (PoOxE) and now apply them to data from a genome-wide association study (GWAS) of families with children born with isolated CL/P. Methods: Genotypes from 1594 complete triads and 314 dyads (1908 nuclear families in total) with CL/P were available for the current analyses. Of these families, 1024 were Asian, 825 were European and 59 had other ancestries. After quality control, 341,191 SNPs remained from the original 569,244. The exposures were maternal cigarette smoking, use of alcohol, and use of vitamin supplements in the periconceptional period. Our new methodology detects if PoO effects are different across environmental strata and is implemented in the R-package Haplin. Results: Among Europeans, there was evidence of a PoOxSmoke effect for ANK3 with three SNPs (rs3793861, q=0.20, p=2.6e-6; rs7087489, q=0.20, p=3.1e-6; rs4310561, q=0.67, p=4.0e-5) and a PoOxAlcohol effect for ARHGEF10 with two SNPs (rs2294035, q=0.32, p=2.9e-6; rs4876274, q=0.76, p=1.3e-5). Conclusion: Our results indicate that the detected PoOxE effects have a plausible biological basis, and thus warrant replication in other independent cleft samples. Our demonstration of the feasibility of identifying complex interactions between relevant environmental exposures and PoO effects offers new avenues for future research aimed at unravelling the complex etiology of cleft lip defects.

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

“…Another candidate at 9p21.3 is FOCAD , located ~350Kb downstream of the peak SNP, which is a potential tumor suppressor highly expressed in brain tissues. Haaland et al identified a parent-of-origin interaction effect between FOCAD and maternal smoking contributing to cleft lip [ 37 ]. In order to determine the possible roles of genes at this locus on facial traits, subsequent functional studies are needed.…”

Design efficiency in genetic association studies

“…8,39 Analysis methods such as log-linear and multinomial modeling approaches are particularly appealing as they can readily be adapted to accommodate the broad spectrum of various hybrid designs as well as a wide array of causal scenarios and genetic effects. 11,13,17,24,27,29,35,40 As an example, they can easily be extended to include the maternal-fetal genotype incompatibility test. 41 Nevertheless, although the hybrid design combines the merits of both the case-control and case-parent designs, a straightforward combined analysis may still be influenced by population stratification or non-Mendelian transmission.…”

“…For example, maternal exposures such as alcohol consumption, smoking, or vitamin intake during the periconceptional period might modify the association between SNPs and a birth defect. 25,28,29 Interactions between genetic effects and categorical exposure variables are incorporated into the log-linear framework of Haplin by fitting the log-linear model separately for each exposure stratum. A Wald test is then applied to detect whether the relative risk estimates differ significantly across exposure levels.…”

“…4,11,13 For applications of Haplin to GWAS data, readers are referred to some of our previous publications. [24][25][26][27][28][29]…”

Genome-wide interaction study implicates VGLL2 and alcohol exposure and PRL and smoking in orofacial cleft risk

“…Following one such GWAS study in European and Asian case-parent trios (Beaty 2010), candidate gene and pathway-based GxE analyses have suggested interactions between smoking and RUNX2 (11), and between multiple exposures and BMP4 (12). Genome-wide GxE using a variety of statistical approaches have identified interactions for maternal smoking, alcohol, or folate supplementation in cleft palate (13-15) and cleft lip with or without cleft palate (16, 17).…”