Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Lea K. Davis, Dongmei Yu, Clare L. Keenan, Eric R. Gamazon, Anuar I. Konkashbaev, Eske M. Derks, Benjamin M. Neale, Jian Yang, S. Hong Lee, Patrick Evans, Cathy L. Barr, Laura Bellodi, Fortu Benarroch, Gabriel Bedoya Berrio, Oscar J. Bienvenu, Michael H. Bloch, Rianne M. Blom, Ruth D. Bruun, Cathy L. Budman, Beatriz CamarenaDesmond Campbell, Carolina Cappi, Julio C. Cardona Silgado, Danielle C. Cath, Maria C. Cavallini, Denise A. Chavira, Sylvain Chouinard, David V. Conti, Edwin H. Cook, Vladimir Coric, Bernadette A. Cullen, Dieter Deforce, Richard Delorme, Yves Dion, Christopher K. Edlund, Karin Egberts, Peter Falkai, Thomas V. Fernandez, Patience J. Gallagher, Helena Garrido, Daniel Geller, Simon L. Girard, Hans J. Grabe, Marco A. Grados, Benjamin D. Greenberg, Varda Gross-Tsur, Stephen Haddad, Gary A. Heiman, Sian M.J. Hemmings, Ana G. Hounie, Cornelia Illmann, Joseph Jankovic, Michael A. Jenike, James L. Kennedy, Robert A. King, Barbara Kremeyer, Roger Kurlan, Nuria Lanzagorta, Marion Leboyer, James F. Leckman, Leonhard Lennertz, Chunyu Liu, Christine Lochner, Thomas L. Lowe, Fabio Macciardi, James T. McCracken, Lauren M. McGrath, Sandra C. Mesa Restrepo, Rainald Moessner, Jubel Morgan, Heike Muller, Dennis L. Murphy, Allan L. Naarden, William Cornejo Ochoa, Roel A. Ophoff, Lisa Osiecki, Andrew J. Pakstis, Michele T. Pato, Carlos N. Pato, John Piacentini, Christopher Pittenger, Yehuda Pollak, Scott L. Rauch, Tobias J. Renner, Victor I. Reus, Margaret A. Richter, Mark A. Riddle, Mary M. Robertson, Roxana Romero, Maria C. Rosàrio, David Rosenberg, Guy A. Rouleau, Stephan Ruhrmann, Andres Ruiz-Linares, Aline S. Sampaio, Jack Samuels, Paul Sandor, Brooke Sheppard, Harvey S. Singer, Jan H. Smit, Dan J. Stein, E. Strengman, Jay A. Tischfield, Ana V. Valencia Duarte, Homero Vallada, Filip Van Nieuwerburgh, Jeremy Veenstra-VanderWeele, Susanne Walitza, Ying Wang, Jens R. Wendland, Herman G.M. Westenberg, Yin Yao Shugart, Euripedes C. Miguel, William McMahon, Michael Wagner, Humberto Nicolini, Danielle Posthuma, Gregory L. Hanna, Peter Heutink, Damiaan Denys, Paul D. Arnold, Ben A. Oostra, Gerald Nestadt, Nelson B. Freimer, David L. Pauls, Naomi R. Wray, S. Evelyn Stewart, Carol A. Mathews, James A. Knowles, Nancy J. Cox, Jeremiah M. Scharf

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198 Scopus citations

Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Original languageAmerican English
Article numbere1003864
JournalPLoS Genetics
Volume9
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Bibliographical note

Funding Information:
The following authors have read the journal's policy and have the following conflicts: CLBu: Currently receiving funding for TS clinical trials from Otsuka Pharmaceutical, JFL: recevies research support from NIH and Grifols, LLC as well royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press, MARic: received honoraria from Lundbeck, and research funding from Great-West Life Assurance Company of Canada and Eli Lilly Canada Ltd, MCR: grant from CNPq (Brazilian National Counsil) and has received research grants and/or consultancy honoraria from Novartis and Shire, DR: received consulting fees for Shire, JMS: received research support, honoraria and travel support from the Tourette Syndrome Association (TSA), DJS: received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Biocodex, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, Tikvah, and Wyeth, TVF: received research funding from NIMH (K08 MH099424-01), the Simons Foundation, Allison Foundation, and Shire, PS: received research support for this study from the Tourette Syndrome Association (TSA), Tourette Syndrome Foundation of Canada and NIH, DY: received research support from the Tourette Syndrome Association (TSA) and NIH, MMR: received grants from the Tourette's Action-UK, TSA-USA, honoraria from Janssen-Cilag, and book royalties from Wiley - Blackwell, David Fulton/Granada/Taylor Francis, Oxford University Press and Jessica Kingsley Publishers, is a Patron of Tourette's Action (UK), sits on the Medical Advisory Board of the Italian Tourette Syndrome Association and The Tourette Syndrome Foundation of Canada, DAC: NIH/NIMH funding for K01 MH072952 and R34 MH090149, SLR: participated in research funded by Medtronic and Cyberonics, JRW: Past employee of F. Hoffmann-La Roche and current employee of Pfizer, SW: received lecture honoraria from Janssen Cilag, AstraZeneca and Eli Lilly, research funds Swiss National Science Foundation (SNF), Deutsche Forschungsgemeinschaft, EU FP7, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, JV: funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, and SynapDx. Consulting/Advisory Board for Novartis, JTM: Tourette Syndrome Association-Speaker honoraria; Otuska-research grant; Roche-consultant; 1R01MH079487-01A1, JLK: honoraria from Roche, Eli Lilly, and Novartis, PDA: Unrestricted research grant from DNA Genotek SLG, HJG, ML, DLP, SES, NL, JHS, CLBa, LB, FB, GBB, OJB, MHB, RMB, RDB, DC, CC, JCCS, DCC, MCC, SC, DVC, EHC, VC, NJC, BAC, LKD, DDen, DDef, RD, EMD, YD, CKE, KE, PF, NBF, PJG, ERG, HG, MAG, BDG, VGT, SH, GLH, GAH, SMJH, PH, AGH, CI, JJ, MAJ, CLK, RAK, JAK, AIK, BK, RK, SHL, LL, CLi, CLo, TLL, FM, CAM, LMM, WM, SCMR, ECM, RM, JM, HM, DLM, ALN, BMN, GN, HN, WCO, BAO, RAO, LO, AJP, MTP, CNP, CP, YP, DP, TJR, VIR, MARid, GAR, SR, ARL, ASS, JS, BS, HSS, ES, JAT, AVVD, HV, MW, YW, JY, HGMW, PE, BC, RR have declared that no competing interests exist.

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