Genome Scan for Tourette Disorder in Affected-Sibling-Pair and Multigenerational Families

Abstract

Tourette disorder (TD) is a neuropsychiatric disorder with a complex mode of inheritance and is characterized by multiple waxing and waning motor and phonic tics. This article reports the results of the largest genetic linkage study yet undertaken for TD. The sample analyzed includes 238 nuclear families yielding 304 "independent" sibling pairs and 18 separate multigenerational families, for a total of 2,040 individuals. A whole-genome screen with the use of 390 microsatellite markers was completed. Analyses were completed using two diagnostic classifications: (1) only individuals with TD were included as affected and (2) individuals with either TD or chronic-tic (CT) disorder were included as affected. Strong evidence of linkage was observed for a region on chromosome 2p (-log P = 4.42, P = 3.8 x 10(-5) in the analyses that included individuals with TD or CT disorder as affected. Results in several other regions also provide moderate evidence (-log P >2.0) of additional susceptibility loci for TD.

Psychometric Properties of a Self-Report Instrument for the Assessment of Tic Severity in Adults With Tic Disorders

“…The present study employed the diagnostic assessment procedure recommended by the Tourette Syndrome Association International Consortium for Genetics (Tourette Syndrome Association International Consortium for Genetics (TSAICG), 2007). The Structured Clinical Interview for DSM-IV-TR Axis I Disorders, research version, patient edition , a semistructured clinician administered interview (SCID; First, Spitzer, Gibbon, & Williams, 2002) was administered in order to establish and screen for DSM-IV diagnoses.…”

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

“…There is widespread agreement that genetics plays a significant role in TD etiology based on twin and family studies (Browne et al, 2015; Mataix-Cols et al, 2015; Pauls et al, 1981, 1991; Price et al, 1985). To date, non-parametric linkage analyses (The Tourette Syndrome Association International Consortium for Genetics, 1999, 2007) and a genome-wide association study (Scharf et al, 2013) have not yet led to reproducible, statistically significant findings. Studies of rare pedigrees have identified putative risk genes expressed in the developing striatum and mediating neurite outgrowth (Abelson et al, 2005; Stillman et al, 2009) or involved in histaminergic neurotransmission (Ercan-Sencicek et al, 2010), signal transduction and cell adhesion (Lawson-Yuen et al, 2008; Verkerk et al, 2003), or serotonin transport (Moya et al, 2013).…”

The inheritance of Tourette Disorder: A review

“…In addition, a sibling who also carried the NLGN4X deletion had a diagnosis of TD and ADHD, and the carrier mother was described as having a learning disorder, anxiety, and depression. Of note, the region identified on chromosome 2p 24 that was inserted into 7q35-q36 lies under the genome-wide significant linkage peak reported by the TSAICG 1516 .…”

“…However, when the study was extended to 238 sib pairs and 18 large multigenerational families, the evidence for linkage in these regions on chromosomes 4 and 8 diminished. However, a locus on chromosome 2p was detected that achieved genome-wide significance (p=9.8×10 −8 ) 1516 . Several other linkage studies have resulted in logarithm of the odds (LOD) scores approaching genome-wide significance 17–20 , but only one to date 21 has led to the identification of a mutation that alters the structure or function of a transcript mapping within or near a suggestive linkage region.…”