Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent–child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case–control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive–compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Perspectives on ‘the lens of risk’ interview series: interviews with Tom Horlick-Jones, Paul Slovic and Andy Alaszewski

This article is the fourth and final of an interview series with a selection of significant contributors to the social science of risk. It provides quasi-verbatim interviews with Tom Horlick-Jones, Paul Slovic and Andy Alaszewski. Tom Horlick-Jones contributed to Chapter 6 of the Royal Society Risk monograph, on risk management. He offers further insights into the debates which underlay its production to those given by Nick Pidgeon in the first article of this series. Paul Slovic provides a North American perspective on risk social science. Andy Alaszewski, in the last of the eight interviews, discusses his views about risk in relation to the evolution of his journal, Health, Risk & Society

Carbachol but not forskolin can increase mucosal to serosal transport of intact protein in rat ileum in vitro

The effects of the secretagogues forskolin and carbachol on protein uptake in isolated ileum of rats were studied. The mucosal-to-serosal transport of horseradish peroxidase (HRP, mol mass 40 kDa) was measured in Ussing chambers, and afterwards tissues were processed for electron microscopy. In the absence of secretagogues, the flux of enzymatically active HRP was 5 pmol.cm-2.h-1 at a mucosal concentration of 10 microM. Electron micrographs showed vesicles filled with active HRP in enterocytes but no HRP activity in intercellular spaces. Forskolin decreased HRP activity in the cells. Carbachol increased the amount of HRP-filled vesicles in enterocytes and induced HRP filling in some intercellular spaces and tight junctions in the upper parts of the villi. The transepithelial flux of intact HRP increased more than 2.5-fold. This effect was suppressed by atropine. We conclude that cholinergic activation can increase the uptake of intact protein via endocytosis and the transepithelial passage by the induction of a diffusional paracellular pathway. We speculate that the increased transport of intact protein through the intestinal barrier may influence immunologic sensitization to food allergen

Carbachol, but not forskolin increases mucosal-to-serosal transport of intact protein in rat ileum in vitro

The effects of the secretagogues forskolin and carbachol on protein uptake in isolated ileum of rats were studied. The mucosal-to-serosal transport of horseradish peroxidase (HRP, mol mass 40 kDa) was measured in Ussing chambers, and afterwards tissues were processed for electron microscopy. In the absence of secretagogues, the flux of enzymatically active HRP was 5 pmol.cm-2.h-1 at a mucosal concentration of 10 microM. Electron micrographs showed vesicles filled with active HRP in enterocytes but no HRP activity in intercellular spaces. Forskolin decreased HRP activity in the cells. Carbachol increased the amount of HRP-filled vesicles in enterocytes and induced HRP filling in some intercellular spaces and tight junctions in the upper parts of the villi. The transepithelial flux of intact HRP increased more than 2.5-fold. This effect was suppressed by atropine. We conclude that cholinergic activation can increase the uptake of intact protein via endocytosis and the transepithelial passage by the induction of a diffusional paracellular pathway. We speculate that the increased transport of intact protein through the intestinal barrier may influence immunologic sensitization to food allergen