Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

Authors:
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 Camarena Desmond 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

PLoS Genet 2013 Oct 24;9(10):e1003864. Epub 2013 Oct 24.

Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

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.

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http://dx.doi.org/10.1371/journal.pgen.1003864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812053PMC
October 2013
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