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Additional support for the association of SLITRK1 var321 and Tourette syndrome

Molecular Psychiatry volume 15, pages 447–450 (2010)Cite this article

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We identified SLIT and NTRK-like 1 (SLITRK1) as a candidate gene for Tourette syndrome (TS) based on the mapping of a de novo chr13 inversion, the finding of a rare frameshift mutation in a family with TS, and the association of a functional rare 3′ UTR variant (var321) corresponding to highly conserved miRNA binding domain.1 This rare allele was identified in 2 of 174 individuals with TS and was not present in 2148 controls (P=0.0056). Based on the absence of haplotype sharing between the var321 probands, we concluded that the alleles were likely to represent independent mutations, further supporting the association. In this study, we present additional data based on genome-wide genotyping, multidimensional scaling analysis (MDS), and dense haplotype mapping, providing additional evidence in favor of these initial conclusions.

Two subsequent reports and a recent review have asserted that this reported association might have been the result of population stratification.2, 3, 4 These conclusions were based primarily on the observation of a single var321 allele seen among 512 Ashkenazi Jewish control chromosomes,2 which suggested, but did not confirm, a higher frequency among this population than observed in our self-identified White controls,1 which accounted for the majority of the initial control chromosomes screened (1/512 versus 0/3562, Fisher's exact test P=0.126). Interestingly, both reports found relatively high rates of var321 among affected Ashkenazi families.2, 3 However, in some of these families, the allele was identified in an affected parent but not transmitted to the ascertained proband. Despite other possible explanations such as the high rate of bi-lineal inheritance observed in TS and the low power in these subsequent studies to detect the association using a transmission disequilibrium approach, these findings were interpreted to mean that our initial result was spurious.

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Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    B J O'Roak, K K Kidd, J Cho, R P Lifton & M W State

  2. Program on Neurogenetics, Yale University School of Medicine, New Haven, CT, USA

    B J O'Roak, D O Fishman & M W State

  3. Child Study Center, Yale University School of Medicine, New Haven, CT, USA

    B J O'Roak, D O Fishman & M W State

  4. Department of Pediatrics, Vanderbilt University, Nashville, TN, USA

    T M Morgan

  5. CIBERESP (CIBER en Epidemiología y Salud Pública), Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain

    E Saus, M Gratacòs & X Estivill

  6. Psychiatry Department, OCD Clinical and Research Unit, Hospital Universitari de Bellvitge, L′Hospitalet de Llobregat, Barcelona, Spain

    P Alonso

  7. Experimental and Health Sciences Department, Pompeu Fabra University, Barcelona, Spain

    X Estivill

  8. Biological Psychiatry Laboratory, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    O Teltsh & Y Kohn

  9. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    J Cho

  10. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

    R P Lifton

Authors
  1. B J O'Roak
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  2. T M Morgan
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  3. D O Fishman
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  4. E Saus
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  5. P Alonso
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  6. M Gratacòs
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  9. Y Kohn
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  10. K K Kidd
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  11. J Cho
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  12. R P Lifton
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  13. M W State
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Correspondence to M W State.

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O'Roak, B., Morgan, T., Fishman, D. et al. Additional support for the association of SLITRK1 var321 and Tourette syndrome. Mol Psychiatry 15, 447–450 (2010). https://doi.org/10.1038/mp.2009.105

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