Thomas L. Lowe

Genome-wide association study of Tourette's syndrome

Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control

Background: Self injurious behaviour (SIB), the deliberate, repetitive infliction of self harm, is present in a wide variety of neuropsychiatric disorders, including Tourette syndrome (TS). Although SIB occurs in up to 60% of individuals with TS, and can cause significant clinical impairment and distress, little is known about its aetiology. Objective: This study examined the relationship between SIB and other behavioural features that commonly co-occur with TS in nearly 300 subjects with TS participating in three genetic studies. SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviours, and rages were systematically assessed in all subjects. Methods: Using logistic regression, a best fit model was determined for both mild to moderate SIB and severe SIB. Results: Mild/moderate SIB in TS was correlated with the presence of obsessive and compulsive symptoms such as the presence of aggressive obsessions or violent or aggressive compulsions, and with the presence of obsessive−compulsive disorder and overall number of obsessions. Severe SIB in TS was correlated with variables related to affect or impulse dysregulation; in particular, with the presence of episodic rages and risk taking behaviours. Both mild/moderate and severe SIB were also correlated with tic severity. Conclusions: This study suggests that mild/moderate and severe SIB in TS may represent different phenomena, which has implications for clinical management of these symptoms.

Tic Symptom Profiles in Subjects with Tourette Syndrome from two Genetically Isolated Populations

BACKGROUND Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.

CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations.

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive–compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.

Thyroid hormone in autistic children

Thyroid hormone plays an important role in the pre- and postnatal development and function of the central nervous system. Disturbances in thyroid hormone regulation have been hypothesized in childhood autism. We evaluated blood indices of thyroid function, including serum thyroxine, triiodothyronine, and thyroid-stimulating hormone, in a large population of autistic children. No differences were found between autistic and normal children.

Prevalence and clinical correlates of explosive outbursts in Tourette Syndrome

The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.

Folic Acid and B12 in Autism and Neuropsychiatric Disturbances of Childhood

Serum and red blood cell (RBC) folate and serum vitamin B12 were measured in autistic patients (N = 43), nonautistic neuropsychiatric patients (N = 59), and normal controls (N = 19). Cerebrospinal fluid (CSF) from 16 autistic and nonautistic patients was assayed for CSF folate and metabolites of dopamine and serotonin (HVA and 5-HIAA, respectively). Serum folate, serum B12, and RBC folate were normal in all 3 groups. A subgroup of autistic children receiving folic acid vitamin supplements had elevated serum and RBC folate without evidence of clinical improvement. CSF folate levels were within the normal range in both patient groups and did not correlate with either serum folate levels or monoamine metabolite levels. These findings are consistent with an active transport system regulating CSF folate independently of blood levels execpt in cases of extreme folate deficiency. Therapeutic folic acid supplementation in the autistic population is not supported by the findings of this investigation.

Cultural Influences on Diagnosis and Perception of Tourette Syndrome in Costa Rica

BACKGROUND AND OBJECTIVES Tourette syndrome (TS) is a neuropsychiatric disorder in which the pattern of symptom presentation can vary greatly between individuals. Although globally described, TS has not been well characterized in many parts of the world. Differences in individual and cultural perceptions of TS may impact its expression and recognition in some countries, confounding the identification of affected individuals. This study examines the phenomenology and presentation of TS in Costa Rica. METHOD Clinical data on 85 Costa Rican subjects with TS (aged 5-29 years) initially recruited for a genetic study between 1996 and early 2000 were obtained by direct interview and review of medical records. RESULTS The clinical characteristics of TS were similar to that found elsewhere. The gender ratio was 4.6:1, the mean age of onset was 6.1 years, and 20% of subjects had coprolalia. However, the perceived impact of TS was different. Many subjects denied that their TS caused impairment or distress, even when objective evidence of impairment was available. CONCLUSIONS TS in Costa Rica is phenomenologically similar to TS seen in other parts of the world, but differs in perceived impairment. In other countries where cultural forces affect disease definition, close scrutiny of symptom expression and possible adjustment of phenotype definition may be important.

Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.