There have been considerable recent advances in understanding the genetic architecture of Tourette syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS—and its main symptom dimensions—influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy—the same SNP affecting two traits—and concordance—the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10−4) and caudate (p = 4 × 10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10−3). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10−3), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10−7) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
Bibliographical noteFunding Information:
PGC-TS members: Harald Aschauer; Gil Atzmon; Cathy Barr; Csaba Barta; Robert Batterson; Fortu Benarroch; Chester Berlin; Gabriel Berrio; Julia Bohnenpoll; Lawrence Brown; Ruth Bruun; Randy Buckner; Cathy Budman; Julio Cardona Silgado; Danielle Cath; Keun-Ah Cheon; Sylvain Chouinard; Barbara Coffey; Giovanni Coppola; Nancy Cox; Sabrina Darrow; Lea Davis; Christel Depienne; Andrea Dietrich; Yves Dion; Valsamma Eapen; Lonneke Elzerman; Thomas Fernandez; Nelson Freimer; Odette Fründt; Blanca Garcia-Delgar; Donald Gilbert; Marco Grados; Erica Greenberg; Dorothy Grice; Varda Gross-Tsur; Julie Hagstrøm; Andreas Hartmann; Johannes Hebebrand; Tammy Hedderly; Gary Heiman; Luis Herrera; Isobel Heyman; Matthew Hirschtritt; Pieter Hoekstra; Hyun Ju Hong; Alden Huang; Chaim Huyser; Laura Ibanez-Gomez; Cornelia Illmann; Joseph Jankovic; Judith Kidd; Kenneth Kidd; Young Key Kim; Young-Shin Kim; Robert King; Yun-Joo Koh; Anastasios Konstantinidis; Sodahm Kook; Samuel Kuperman; Roger Kurlan; James Leckman; Paul C. Lee; Bennett Leventhal; Thomas Lowe; Andrea Ludolph; Claudia Lührs da Silva; Gholson Lyon; Marcos Madruga-Garrido; Irene Malaty; Athanasios Maras; Carol A. Mathews; William McMahon; Sandra Mesa Restrepo; Pablo Mir; Astrid Morer; Kirsten Müller-Vahl; Alexander Münchau; Tara Murphy; Allan Naarden; Peter Nagy; Benjamin Neale; Markus Noethen; William Ochoa; Michael Okun; Lisa Osiecki; Peristera Paschou; David Pauls; Christopher Pittenger; Kerstin Plessen; Yehuda Pollak; Danielle Posthuma; Eliana Ramos; Victor Reus; Renata Rizzo; Mary Robertson; Veit Roessner; Josh Roffman; Guy Rouleau; Andres Ruiz-Linares; Paul Sandor; Jeremiah Scharf; Monika Schlögelhofer; Eun-Young Shin; Harvey Singer; Jan Smit; Jordan Smoller; Dong-Ho Song; Jungeun Song; Mara Stamenkovic; Matthew State; Manfred Stuhrmann; Jae-Hoon Sul; Urszula Szymanska; Zsanett Tarnok; Jay Tischfield; Fotis Tsetsos; Jennifer Tübing; Ana Valencia Duarte; Frank Visscher; Sina Wanderer; Tomasz Wolanczyk; Martin Woods; Yulia Worbe; Dongmei Yu; Ivette Zelaya; Samuel Zinner. ENIGMA was supported in part by a Consortium grant (U54 EB020403 to PMT) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB and NCI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PGC-TS was supported by grants from the Judah Foundation, the Tourette Association of America, NIH Grants NS40024, NS016648, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1, NS16648-29S1, NS040024-09S1, MH092289, MH092290, MH092291, MH092292, MH092293, MH092513, MH092516, MH092520, and the New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS). D.J.S. was supported by the SA Medical Research Council. N.G. was supported by the Claude Leon Foundation. M.S.M. was supported by the South African National Research Fund and the David and Elaine Potter Foundation.
© 2019, The Author(s).
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Biological Psychiatry