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Am J Psychiatry. 2015 Jan;172(1):82-93. doi: 10.1176/appi.ajp.2014.13101306. Epub 2014 Oct 31.

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Yu D1, Mathews CA, Scharf JM, Neale BM, Davis LK, Gamazon ER, Derks EM, Evans P, Edlund CK, Crane J, Fagerness JA, Osiecki L, Gallagher P, Gerber G, Haddad S, Illmann C, McGrath LM, Mayerfeld C, Arepalli S, Barlassina C, Barr CL, Bellodi L, Benarroch F, Berrió GB, Bienvenu OJ, Black DW, Bloch MH, Brentani H, Bruun RD, Budman CL, Camarena B, Campbell DD, Cappi C, Silgado JC, Cavallini MC, Chavira DA, Chouinard S, Cook EH, Cookson MR, Coric V, Cullen B, Cusi D, Delorme R, Denys D, Dion Y, Eapen V, Egberts K, Falkai P, Fernandez T, Fournier E, Garrido H, Geller D, Gilbert DL, Girard SL, Grabe HJ, Grados MA, Greenberg BD, Gross-Tsur V, Grünblatt E, Hardy J, Heiman GA, Hemmings SM, Herrera LD, Hezel DM, Hoekstra PJ, Jankovic J, Kennedy JL, King RA, Konkashbaev AI, Kremeyer B, Kurlan R, Lanzagorta N, Leboyer M, Leckman JF, Lennertz L, Liu C, Lochner C, Lowe TL, Lupoli S, Macciardi F, Maier W, Manunta P, Marconi M, McCracken JT, Mesa Restrepo SC, Moessner R, Moorjani P, Morgan J, Muller H, Murphy DL, Naarden AL, Nurmi E, Ochoa WC, Ophoff RA, Pakstis AJ, Pato MT, Pato CN, Piacentini J, Pittenger C, Pollak Y, Rauch SL, Renner T, Reus VI, Richter MA, Riddle MA, Robertson MM, Romero R, Rosário MC, Rosenberg D, Ruhrmann S, Sabatti C, Salvi E, Sampaio AS, Samuels J, Sandor P, Service SK, Sheppard B, Singer HS, Smit JH, Stein DJ, Strengman E, Tischfield JA, Turiel M, Valencia Duarte AV, Vallada H, Veenstra-VanderWeele J, Walitza S, Wang Y, Weale M, Weiss R, Wendland JR, Westenberg HG, Shugart YY, Hounie AG, Miguel EC, Nicolini H, Wagner M, Ruiz-Linares A, Cath DC, McMahon W, Posthuma D, Oostra BA, Nestadt G, Rouleau GA, Purcell S, Jenike MA, Heutink P, Hanna GL, Conti DV, Arnold PD, Freimer NB, Stewart SE, Knowles JA, Cox NJ, Pauls DL.

Author information

1
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women's Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Lo

Abstract

OBJECTIVE:

Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.

METHOD:

The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.

RESULTS:

Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).

CONCLUSIONS:

Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

PMID:
25158072
PMCID:
PMC4282594
DOI:
10.1176/appi.ajp.2014.13101306
[Indexed for MEDLINE]
Free PMC Article

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