We aim to understand the relative risk associated with prenatal environmental exposure to maternal lifestyle factors and mood (e.g. poor nutrition and anxiety) and the relative risk associated with the transmission of genotypes from parent to child. By examining the transmission to the child of maternal and paternal alleles separately, we can examine a) the effect of environmental exposure in utero on genetic imprinting and b) relative risks associated with mothers or fathers genetic contributions to child disease.
The aim in our study is to examine (1) whether the genes of the fetus directly influence the risk of disease, i.e., fetal gene-effects; (2) whether the mother’s genotype exerts an influence on the child’s phenotype, i.e. maternal effects and (3) to compare non-transmitted alleles in case mothers with that of non-transmitted alleles in case fathers, i.e. a parent-of origins analysis.
Methods and analyses
Haplin
The analyses will be performed in Haplin, a statistical software package primarily designed for analyzing genetic and environmental exposures in a so-called hybrid design. The hybrid design combines the merits of the case-parent trio design, in which a case child and his/her parents have been genotyped, and the case-control design. Thus, it consists of case-parent trios together with control-parent trios, not necessarily the same number of controls as cases (see Figure 2). Haplin is based on a log-linear model and implements a full maximum-likelihood model for estimation. The method is described in Gjessing and Lie (2006). Haplin allows for genetic association analyses of GWAS data as well as candidate genes. The software is implemented in the statistical package R (R Core Team, 2016) and can be downloaded from our website at http://folk.uib.no/gjessing/genetics/software/haplin.
Gene-environment interactions
Haplin also allows for analyses of gene-environment interactions (GxE), occurring when a genetic effect is modified by an environmental exposure. The interaction approach examines case and control triads in each exposure stratum separately and then applies a Wald-based post-test of parameters across strata (Skare et al., 2012).
GWAS analyses of single-SNPs and haplotypes
In genetic association analysis, most studies use a single-marker approach in which each single nucleotide polymorphism (SNP) is analyzed individually. However, haplotype analysis could enhance the possibility of “bracketing” a causal variant if the haplotype has a SNP on each side of the variant (Gjerdevik et al., 2017). A priori, there is no way of selecting the best approach. Hence, we will analyze both single-markers and haplotypes.