Collaborative Genome-Wide Association and Copy Number Variation Analysis of Tourette Syndrome

Abstract

Tourette Syndrome (TS) is a childhood-onset developmental disorder that has one of the highest heritabilities among neuropsychiatric diseases with non-Mendelian inheritance. However, no definitive TS susceptibility genes have been identified to date. We have previously demonstrated that TS is highly polygenic, and that 30-50% of TS heritability can be captured by SNP genotyping arrays.Here, we present the most recent results from the current TS genome-wide association study (GWAS) and copy number variant (CNV) analyses. In the current TS GWAS mega-analysis of 4232 European ancestry TS cases and 8318 ancestry matched controls, one locus on chromosome 2p16 surpassed the genome-wide significant threshold (rs2708146, p=5.1x10-8). This SNP lies within a large 1Mb haplotype containing one transcript, LINC01122, an uncharacterized long, intergenic, non-coding RNA (lincRNA), that is expressed primarily in mid-fetal human brain development (15-16 pcw), with strongest expression in developing cerebral cortex. Pairwise correlational analysis of Brainspan project data across pre-natal time points identified the highest co-expression of LINC01122 with BCL11A, a gene 1 Mb centromeric to LINC01122 that has been found previously to harbor recurrent de novo loss-of-function mutations in individuals with autism-spectrum disorder. Subsequent analyses demonstrate that LINC01122 and BCL11A lie within the same topologically-associated domain (TAD) in human fetal cortex, suggesting that both transcripts are co-regulated.In the CNV analysis of 2,434 European ancestry TS cases and 4,093 ancestry matched controls, we identified a significant global burden of rare (<1% frequency) genic CNVs that was most pronounced in large (>1 Mb), singleton CNVs (OR 2.28 [1.39-3.79], p=1.2x10-3) and in CNVs previously classified as pathogenic by the American College of Medical Genetics (OR 3.03 [1.85-5.07], p=1.5x10-5). Two individual CNV loci surpassed genome-wide significance both for point-wise and gene-based tests, as determined empirically by permutations: deletions in NRXN1-alpha (Pseg=7.0x10-6; Pseg-corr=1.0x10-3; OR 20.3[2.6-156.2]) and duplications across CNTN6 (Pseg=5.4x10-5, Pseg-corr=6.9x10-3; OR=10.1 [2.3-45.4]). 1% of TS cases carried one of these two CNVs, with an additional 0.5% harboring an ACMG pathogenic CNV outside these two loci.In conclusion, we present evidence for one GWAS locus and two rare CNVs that exceed the genome-wide significance threshold, representing the first convincing TS susceptibility loci. The members of this symposium are now preparing for large-scale meta-analyses of GWAS and CNV datasets from 5 international TS genetics consortia in 13,000 TS cases and 37,000 controls.