Allowing for Missing Data at Highly Polymorphic Genes when Testing for Maternal, Offspring and Maternal-Fetal Genotype Incompatibility Effects

Abstract

Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.

Combined linkage disequilibrium and linkage mapping: Bayesian multilocus approach

“…At HLA-DRB1, the interaction between offspring alleles and NIMA appears to increase the risk of RA in offspring [39,45,80,102]. Under MODEL = 2, Mendel estimates a sex-specific NIMA incompatibility effect, as seen in Table 26.1.…”

Detection of Intergenerational Genetic Effects with Application to <i>HLA-B</i> Matching as a Risk Factor for Schizophrenia

“…All unaffected individuals are considered to be phenotype unknown. This low prevalence disease assumption [15] is reasonable for schizophrenia, which has less than 2% prevalence. For diseases with a prevalence less than ϳ 10%, unaffected offspring contribute little to the likelihood, and therefore the affected-only approach is a reasonable approximation [14,63] .…”

“…The primary strength of the MFG test derives from its ability to jointly model maternal genetic effects, offspring genetic effects, and interactions between maternal and offspring genotypes without confounding. Extensions to the original test allow for: multiple affected offspring in a nuclear family [17] , sparse data [19] , adjustment for the genetic effects of viability when testing for the effect of MFG incompatibility on disease [14] , and handling incomplete parental genotypes [15,20] .…”

Gene-Gene Interaction in Maternal and Perinatal Research

“…In their analysis of the association of TNF- α G308A polymorphisms with preterm delivery (PTD), Liang et al [8] make the necessary modifications to a hybrid case-parent trio and control-parent model to allow for MFG incompatibility. Rather than limiting the analysis to a specific form of MFG incompatibility such as HLA matching [6] or noninherited maternal antibody effects [9], they model joint maternal and child allelic effects, which requires 6 parameters for a diallelic locus. The maternal and fetal main effect model requires only 4 parameters, so the null hypothesis of no MFG incompatibility can be tested with a likelihood ratio test that compares these two models without specifying the MFG mechanism.…”

“…The MFG test is independent of the mating-type frequencies of controls [6] and so cannot be used to test this hypothesis. The significant results in [11], however, cannot be explained by this gene-environment covariation alone [12] because they are the consequence of mating asymmetry to a lesser extent and of transmission distortion to a greater extent [6, 9, 11]. Olfactory deficits in the parents should not lead to transmission distortion.…”