Candidate transmission disequilibrium analysis for quantitative traits in tourette syndrome in a chinese family trio sample

Abstract

Tourette's syndrome is a complex and heritable behavioral disorder with early onset (2-15 years), prominently characterized by motor and vocal ticks affecting up to 1/100 boys and 1/700 girls. Several neurotransmitter receptor pathways and related biosynthetic enzymes have been implicated in its etiology through previous genetic and/or biological analysis. Using genotypes from functional polymorphisms in the catechol-O-methyltransferase gene COMT (Val158Met), dopamine D4 receptor gene DRD4 (exon III VNTR and a promoter SNP), dopamine D2 receptor gene DRD2 (promoter SNP), monoamine oxidase A MAOA (promoter CA repeat sequence) and serotonin receptor gene HTR2A (promoter SNP), we performed association analysis using the Quantitative Transmission Disequilibrium approach with scores for the Conners, CBCL and Depression scale for the affected children and three QTD Tests proposed by Abecasis et al., Rabinowitz et al., and Allison et al. Significant associations (<0.05) were found between the 5-HTR2A gene and the traits 'delinquent' (p=0.0147, 66 probands), 'thought' (p=0.0417, 66 probands) and 'extrovert' (p=0.0347, 66 probands); COMT gene with the "compulsive" trait (p=0.0458, 69 probands); and DRD4 VNTR with the 'bad behavior' trait (p=0.048). Using the method proposed by Fulker et al. (1999) a test for population stratification was performed on all trios and no significant evidence for population stratification was found. Therefore, an overall test for association was performed (i.e. not a TDT). Significant associations (0.01) were found between the DRD2 promoter and the traits 'depression mood' (p=0.01, 94 probands), 'low confidence' (p=0.002); DRD4 VNTR and traits 'bad behavior' (p < 0.001, 95 probands), 'group activity' (p=0.008, 95 probands); MAO polymorphism and traits 'bad behavior' (p=0.007, 38 probands), 'somatic' (p=0.0046, 56 probands), 'aggressive' (p<0.001, 56 probands), 'extrovert' (p<0.001, 56 probands).