Incorporating Serotypes into Family Based Association Studies Using the MFG Test

Abstract

SummaryFamily based association tests are widely used to detect genetic effects. The focus of this paper is the maternal-fetal genotype (MFG) incompatibility test, a family based association test which can be used to detect genetic effects that contribute to disease, including alleles in the child that increase disease risk, maternal alleles that increase disease risk in the child, and maternal-fetal genotype incompatibilities. Consideration of incomplete data resulting from using serotypes could expand the power of the MFG test for detecting genetic effects. Serotypes may be all that are available in certain families, or preferred because of convenience or low cost, and thus a modification of the MFG test will allow optimal use of such data. The modified MFG likelihood can accommodate the incomplete data that result from using serotypes rather than the corresponding codominant genotypes. The modified MFG test was evaluated with serotypes and genotypes from families with members affected with schizophrenia. In addition, simulation studies were performed. Results of the data analyses and simulation studies showed that serotypes can be used to augment genotypes within a sample, to increase power to detect effects when the candidate gene produces serotypes.

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

“…As an example, multi-locus SNP genotypes can be used by letting haplotypes serve as the underlying unobserved states and the unordered multi-locus genotypes serve as the observed marker phenotypes [67] . This construct is consistent with our theory development because the likelihood equation 1 sums over all possible genotypes, and alleles need not be co-dominant [20] .…”

“…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] .…”

Modeling maternal‐offspring gene‐gene interactions: the extended‐MFG test

“…The conditional likelihood (1) must be summed over all possible parental genotypes ( g r , g s ) consistent with the observed genotypes in the family, which now include the genotypes of unaffected or phenotype unknown offspring [Hsieh et al, 2006b; Kraft et al, 2004; Minassian et al, 2006; Palmer et al, 2002]. The denominator remains the same.…”

“…The MFG test is an affected-only analysis, however, the genotypes of unaffected or phenotype unknown offspring contribute if there are missing parental data. The conditional likelihood (1) must be summed over all possible parental genotypes (g r , g s ) consistent with the observed genotypes in the family, which now include the genotypes of unaffected or phenotype unknown offspring [Hsieh et al, 2006b;Kraft et al, 2004;Minassian et al, 2006; f2=2; 1=2g 2P(2/2)P(1/2) 3 f2=2; 1=1g 2P(2/2)P(1/1) 4 f1=2; 1=2g P(1/2) 2 5 f1=2; 1=1g 2P(1/2)P(1/1) 6 f1=1; 1=1g P(1/1) 2 Palmer et al, 2002]. The denominator remains the same.…”

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

“…Alternatively, the observed data loglikelihood can be maximized directly [13,16] using non-linear optimization software, e.g., Search [17] . When alleles at a polymorphic locus must be treated as distinct alleles due to specific hypothesized genetic effects, a large number of nuisance parameters may need to be estimated.…”