Association Test for X-Linked QTL in Family-Based Designs

Family-based association methods for detecting quantitative trait loci (QTL) have been developed primarily for autosomes, and comparable methods for X-linked QTL have received less attention. We have developed a family-based association test for quantitative traits, named XQTL, which uses X-linked markers in a nuclear family design. XQTL adopts the framework of the orthogonal model implemented in the QTDT program, modifying the sex-specific score for X-linked genotypes. XQTL also takes into account the dosage effect due to female X chromosome inactivation. Restricted maximum likelihood (REML) and Fisher's scoring method are used to estimate variance components of random effects. Fixed effects, derived from the phenotypic differences among and within families, are estimated by the least-squares method. Our proposed XQTL can perform allelic and two-locus haplotypic association tests and can provide estimates of additive genetic effects and variance components. Simulation studies show correct type I error rates under the null hypothesis and robust statistical power under alternative scenarios. The loss of power observed when parental genotypes are missing can be compensated by an increase of offspring number. By treating age at onset of Parkinson disease as a quantitative trait, we illustrate our method, using MAO polymorphisms in 780 families.