Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.

Abstract

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Keywords: CNTN6; NRXN1; Tourette Syndrome; copy number variation; genetics; neurodevelopmental disorders; structural variation; tic disorders.

MeSH terms

  • Adolescent
  • Adult
  • Calcium-Binding Proteins
  • Case-Control Studies
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Child
  • Contactins / genetics*
  • DNA Copy Number Variations*
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Nerve Tissue Proteins / genetics*
  • Neural Cell Adhesion Molecules
  • Odds Ratio
  • Tourette Syndrome / genetics*
  • Whites / genetics
  • Young Adult

Substances

  • CNTN6 protein, human
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Contactins
  • NRXN1 protein, human
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules