Gene-environment interactions defining the onset and clinical course of tics and obsessive compulsive symptoms (WP1)

Objectives: 1. Identification of genes and gene pathways for the pathogenesis of tics and obsessive-compulsive symptoms. 2. Identification of gene pathways that affect the clinical course of TS. 3. Exploration of the complex interaction between environment, autoimmunity and genetics related to the onset and clinical course of the disorder spectrum.

Fellow ESR3   
Host institution: Democritus University of Thrace
Duration: 36 months    
Supervisor: P. Paschou, DUTH; Co-Supervisor: P. Hoekstra, UMCG; Associated partner: P. Drineas, RPI; Seconding company: deCODE.

Tasks and methodology: We will take advantage of our access to the TSGeneSEE sample (300 patients with TS available at Dr. Paschou’s lab), as well as, two longitudinal cohorts of patients which will be followed up within the FP7 funded project EMTICS (P. Hoekstra is the PI). The EMTICS cohorts include 500 high risk individuals followed up for 3 years for onset of symptoms (ONSET cohort) and 700 TS patients followed up on a monthly basis for 12 months (COURSE cohort). The follow-up includes detailed clinical characterization, diaries, as well as immunological profiling and investigation of exposure to Group A streptococcal infections and stress.

  • Task 1: Whole-genome genotyping association study. Genotyping of 1,000 samples from the EMTICS and TSGeneSEE cohorts, using a genomewide array. Published genome wide genotyping data for individuals of European descent is going to be used for the control dataset (eg POPRES dataset). Data, to be analysed using existing tools as well as by designing novel statistical techniques and data-mining techniques, aiming to uncover single gene, gene-gene and gene-environment interactions. ESR will receive relevant training through secondments at deCODE genetics and the Dept. of Computer Science at RPI (Associated Partner).
  • Task 2: Collection of RNA samples. In a subset of 200 patients from the COURSE cohort RNA from blood will be extracted at one point (at least) of symptom exacerbation and one point of symptom remission. RNA samples are also going to be collected from a subset of 100 newly diagnosed patients.
  • Task 3: Genome wide gene-expression analysis. Samples as collected in task 2 are going to be analysed using a genomewide array of coding transcripts and variants. Normalised transcript levels are going to be analysed for correlation with disease onset and course (tic onset vs tic exacerbations vs remission) with standard statistical tests (eg T-tests, ANOVA, ANCOVA and Partek, GeneSpring, PAM and BRB-ArrayTools) Other prediction algorithms including support vector machine methods will be used to confirm these results. Results are also going to be correlated to available data on environmental exposures.




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