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Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree

Abstract

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as “cases” (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

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Fig. 1: The pedigree for the family being studied.
Fig. 2: Manhattan plots for single locus and variant tests in affected pedigree members versus unaffected controls.
Fig. 3: Comparisons of common variant genetic risk scores for Tourette syndrome in unrelated controls (n = 2832), unrelated TS cases (n = 2171), unaffected family members (n = 22), and affected family members (n = 43).

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Acknowledgements

Genotyping and sequencing was performed by the SNP&SEQ Technology Platform in Uppsala, Sweden. The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. Dr. Crowley was supported by NIH grants R01MH105500 and R01MH110427 and the Foundation of Hope. We finally wish to thank once again, the pedigree members, albeit years ago, for their extraordinary help and cooperation with the interviews, examnation, and venepunctures.

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Correspondence to James J. Crowley.

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DMC reports receiving personal fees for editorial tasks (Elsevier) and contributing articles (UpToDate, Inc), both outside the submitted work. CAM has received fees from W.W. Norton and Co. for a book on hoarding disorder, also outside the submitted work. The remaining authors report no biomedical financial interests or potential competing interests.

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Halvorsen, M., Szatkiewicz, J., Mudgal, P. et al. Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01277-w

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