Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.
- Authors
- Fernandez, Thomas V; Sanders, Stephan J; Yurkiewicz, Ilana R; Ercan-Sencicek, A Gulhan; Kim, Young-Shin; Fishman, Daniel O; Raubeson, Melanie J; Song, Youeun; Yasuno, Katsuhito; Ho, Winson S C; Bilguvar, Kaya; Glessner, Joseph; Chu, Su Hee; Leckman, James F; King, Robert A; Gilbert, Donald L; Heiman, Gary A; Tischfield, Jay A; Hoekstra, Pieter J; Devlin, Bernie; Hakonarson, Hakon; Mane, Shrikant M; GΓΌnel, Murat; State, Matthew W
- Year
- 2012
- Journal
- Biological psychiatry
- PMID
- 22169095
- DOI
- 10.1016/j.biopsych.2011.09.034
- PMCID
- PMC3282144
BACKGROUND: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. METHODS: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. RESULTS: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 Γ 10(-4) - 1.6 Γ 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. CONCLUSIONS: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
Copy number variant (CNV) discovery, quality control, and annotation workflowTourette syndrome (TS) and control samples were genotyped on Illumina single nucleotide polymorphism (SNP) microarrays. Quality control was performed simultaneously in both cases and controls using SNP, LogR values, and CNV algorithm output. CNVs in remaining samples were annotated to determine rarity. Only CNVs meeting the definition of rare (occurring in <1% of all study samples and Database of Genomic Variants) were carried into further analysis for global burden, de novo burden, overlap with other neurodevelopmental disorders, and pathway analysis.
Rare copy number variant (CNV) burden in known autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SCZ) genes/regionsP-values were calculated using two-tailed Fisher exact test and are shown for each comparison between cases and controls. Comparisons were made for proportion of samples with CNV overlap with ASD implicated genes, ASD candidate genes, all (implicated + candidate) ASD genes, ID genes, and SCZ genes. Threshold for significance using a standard Bonferroni approach is p<0.013. TS subjects show significantly more overlap for ASD genes compared to controls, but no significant difference for ID or SCZ genes.
Large de novo copy number variants (CNV) in Tourette syndrome (TS) subjectsPlots of relative microarray probe Log R Ratios (LRR) and B Allele Frequencies (BAF) in unaffected father, TS proband, and unaffected mother. CNV regions are bounded by horizontal lines in LRR and BAF plots, outlined in red on chromosome ideograms, and represented by green (duplication) or red (deletion) below chromosome bands. Data is shown for (A) a 51.8 Mb heterozygous duplication on chromosome 5 (chr5: 127,500,000-179,295,570), containing 447 RefSeq transcripts; (B) a 1.2 Mb region on chromosome 20p13 (chr20: 2,758,098-3,942,609), containing 27 RefSeq transcripts; and (C) a 2.5 Mb region on chromosome 22q11.21 (chr22:17,269,490-19,792,353), containing 56 RefSeq transcripts. All de novo deletions were confirmed by qPCR.
Distribution of number of RefSeq genes overlapped by rare de novo copy number variants (CNV) in Tourette syndrome (TS) probands, autism probands, and sibling controlsDashed line represents two standard deviations from the mean number of genes overlapped by de novo CNVs in a large study of unaffected sibling control subjects (dark grey). Number of genes for TS cases (red) and autism probands (light grey) (38) are also plotted. Three of four TS de novo CNVs (this study) and 46% of autism proband de novo CNVs are beyond this threshold.
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| 40 | DISCUSSION | the failure to detect a statistically significant difference, if it is a false negative finding, was⦠|
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