Family-based genetic risk prediction of multifactorial disease - PubMed (original) (raw)
Family-based genetic risk prediction of multifactorial disease
Douglas M Ruderfer et al. Genome Med. 2010.
Abstract
Genome-wide association studies have detected dozens of variants underlying complex diseases, although it is uncertain how often these discoveries will translate into clinically useful predictors. Here, to improve genetic risk prediction, we consider including phenotypic and genotypic information from related individuals. We develop and evaluate a family-based liability-threshold prediction model and apply it to a simulation of known Crohn's disease risk variants. We show that genotypes of a relative of known phenotype can be informative for an individual's disease risk, over and above the same locus genotyped in the individual. This approach can lead to better-calibrated estimates of disease risk, although the overall benefit for prediction is typically only very modest.
Figures
Figure 1
Predicted index disease risk. Predicted index disease risks from a single locus (MAF = 0.425, GRR = 1.25): unconditonal, P(D I); conditional on index genotype, P(D I|G I); conditional on affected sibling phenotype, P(D I|D S); conditional on index genotype and affected sibling phenotype, P(D I|G I, D S); conditional on index and sibling genotypes and affected sibling phenotype, P(D I|G I, G S, D S). The inserted table contains frequencies of sibling pair genotype combinations conditional on at least one sibling being affected. Red represents the homozygous risk-increasing genotype; green the heterozygous genotype; blue the homozygous risk-decreasing genotype.
Figure 2
Predicted index disease risks from a single locus, under a variety of genetic models. Predicted index disease risk stratified by (a) effect size and (b) total sibling relative risk. See Figure 1 legend for details. In all cases, risk allele frequency is 0.425, disease prevalence is 1/250. (a) Varying the familial variance component of the residual variance from 20%, 50% to 80%, with corresponding sibling relative risks of 3.25, 12.25 and 35.5. (b) Varying additive genetic effect from a = 0.01, a = 0.05 to a = 0.1, with corresponding genotypic relative risks of 1.03, 1.16 and 1.30.
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