Abstract and Introduction
Abstract
Background Gilles de la Tourette Syndrome is a neurodevelopmental disorder that is caused by the interaction of environment with a complex genetic background. The genetic etiology of the disorder remains, so far, elusive, although multiple promising leads have been recently reported. The recent implication of the histamine decarboxylase (HDC) gene, the key enzyme in histamine production, raises the intriguing hypothesis of a possible role of histaminergic dysfunction leading to TS onset.
Methods Following up on the finding of a nonsense mutation in a single family with TS, we investigated variation across the HDC gene for association with TS. As a result of a collaborative international effort, we studied a large sample of 520 nuclear families originating from seven European populations (Greek, Hungarian, Italian, Polish, German, Albanian, Spanish) as well as a sample collected in Canada.
Results and Conclusions Interrogating 12 tagging SNPs (tSNP) across the HDC region, we find strong over-transmission of alleles at two SNPs (rs854150 and rs1894236) in the complete sample, as well as a statistically significant associated haplotypes. Analysis of individual populations also reveals signals of association in the Canadian, German and Italian samples. Our results provide strong support for the histaminergic hypothesis in TS etiology and point to a possible role of histamine pathways in neuronal development.
Introduction
Gilles de la Tourette Syndrome (TS) is a multifactorial neurodevelopmental disorder resulting from the complex interaction of environment with genetic backround. TS is characterised by the appearance of multiple motor and vocal tics, and high comorbidity rates with other neuropsychiatric disorders of childhood such as obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and autism, suggesting the possibility of a common aetiological background. Due to lack of education of health professionals and the general public, TS remains poorly understood and severely underdiagnosed in many countries despite the fact that recent investigations have reported a prevalence of 0.4–1% in populations of European origin. Results from large-scale studies and collaborative efforts have only very recently started to become available (eg, refs. ) and the genetic basis of the disorder remains, so far, elusive, although multiple chromosomal regions have been implicated, providing several promising leads that warrant further investigation.
Tics are thought to result from dysfunctions in cortical and subcortical regions that are involved in habit formation, including the basal ganglia and related cortical and thalamic structures. TS has traditionally been viewed as a disorder of dopaminergic neurotransmission; however, other transmitters and neuromodulators have also been implicated. In fact, the recent implication of the L-histidine decarboxylase (HDC) gene in TS aetiology has raised the intriguing hypothesis of the involvement of histaminergic neural pathways in the onset of the disorder.HDC is highly conserved throughout different species and catalyses the oxidative decarboxylation of histidine to histamine. Ercan–Sencicek et al studied a family with one father and eight of his children affected with TS, and found a linkage signal on chromosome 15. Sequencing of all genes within the linked interval led to the discovery of a single rare coding mutation, a premature termination codon (p. W317*, c.951G>A) in exon 9 of the HDC gene. The mutation could not be found in any of the 3000 control individuals of Western European origin who were screened. At the same time, resequencing of the coding region of HDC in 720 patients with TS and 360 controls revealed no additional nonsense variants, demonstrating the fact that the nonsense mutation identified in the index family is extremely rare.
Since the original study that implicated HDC in TS aetiology, Lei et al screened the HDC gene for exonic mutations in 100 Chinese Han patients with TS, and could only find three variants, not predicted to result in amino acid changes: a C>T intronic transition (IVS1 +52C>T), which did not affect the splicing site, a synonymous C>A transition (c.426C>A) in exon 4 and a synonymous G>A transition (c.1743G>A) in exon 12. The first genomewide association study for TS only produced a weak association signal close to the HDC gene (p value of 0.02 with rs7166052). However, a recent genomewide scan for de novo or transmitted rare CNVs in TS found enrichment of genes within histamine receptor signalling pathways. Furthermore, a genomewide study of 95 French Canadian trios with familial history of TS showed association to a chromosome 15 microsatellite marker (D15S1016) that lies within the same interval found to be linked with TS in the original study that implicated the HDC gene in TS aetiology.
Following up on the novel hypothesis of the involvement of HDC and histaminergic neural pathways in TS aetiology, we investigated the possible association of variation across the HDCgene in a large sample of families originating from Canada as well as multiple countries in Europe. We find significant association to the HDC gene in our sample, providing strong support for the role of histamine in the genesis and mediation of tics, and pointing to new lines of research in this area.