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

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veröffentlicht: Public Library Science, 2013
Medientyp: Artikel
Sprache: Englisch
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Details: 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. ; Judah Foundation ; NIH ; Tourette Syndrome Association International Consortium for Genetics (TSAICG) ; New Jersey Center for Tourette Syndrome and Associated Disorders ; NIMH ; Obsessive Compulsive Foundation ; Ontario Mental Health Foundation ; Tourette Syndrome Association ; American Academy of Child and Adolescent Psychiatry (AACAP) ; Anxiety Disorders Association of America (ADAA) ; University of British Columbia ; Michael Smith Foundation ; American Recovery and Re-investment Act (ARRA) ; Australian Research Council ; Australian National Health and Medical Research Council ; German Research Foundation ; NIH Genes, Environment and Health Initiative [GEI] ; Gene Environment Association Studies (GENEVA) under GEI ; NIH GEI ; National Institute on Alcohol Abuse and Alcoholism ; National Institute on Drug Abuse ; Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA ; Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat,Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA ; Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA ; Univ Chicago, Dept Med, Chicago, IL 60637 USA ; Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA ; Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands ; Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA ; Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia ; Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia ; Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada ; Hosp Sick Children, Toronto, ON M5G 1X8, Canada ; 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Univ Illinois, Dept Psychiat, Inst Human Genet, Chicago, IL 60612 USA ; Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South Africa ; Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA ; UCI, Sch Med, Dept Psychiat & Human Behav, Irvine, CA USA ; Univ Utah, Salt Lake City, UT USA ; NIMH Intramural Res Program, Clin Sci Lab, Bethesda, MD USA ; Med City Dallas Hosp, Dept Clin Res, Dallas, TX USA ; Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands ; Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA ; Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA ; Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA ; Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA ; Yale Univ, Dept Psychol, New Haven, CT 06520 USA ; Partners Psychiat & McLean Hosp, Boston, MA USA ; Sunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, Canada ; St George Hosp, London, England ; Sch Med, London, England ; Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA ; Detroit Med Ctr, Detroit, MI USA ; McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada ; Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany ; Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil ; Youthdale Treatment Ctr, Toronto, ON, Canada ; Johns Hopkins Univ Sch Med, Baltimore, MD USA ; Univ Cape Town, ZA-7925 Cape Town, South Africa ; Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat & Pharmacol, Nashville, TN 37235 USA ; Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA ; Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland ; Univ Wurzburg, Dept Child & Adolescent Psychiat, D-97070 Wurzburg, Germany ; Univ Amsterdam, Acad Med Ctr, Ctr Psychiat, NL-1105 BC Amsterdam, Netherlands ; Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands ; NIMH Intramural Res Program, Unit Stat Genom, Bethesda, MD USA ; Univ Utah, Dept Psychiat, Salt Lake City, UT USA ; Natl Inst Genom Med SAP, Carracci Med Grp, Mexico City, DF, Mexico ; Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands ; Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands ; Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands ; Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA ; Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands ; German Ctr Neurodegenerat Dis, Tubingen, Germany ; Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada ; Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands ; Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada ; Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA ; Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; NIH: NS40024 ; NIH: NS16648 ; NIH: MH079489 ; NIH: MH073250 ; NIH: NS037484 ; NIH: 1R01MH079487-01A1 ; NIH: K20 MH01065 ; NIH: R01 MH58376 ; NIH: MH085057 ; NIH: MH079494 ; NIH: HHSN268200782096C ; NIMH: R01MH092293 ; American Recovery and Re-investment Act (ARRA): NS40024-07S1 ; American Recovery and Re-investment Act (ARRA): NS16648-29S1 ; Australian Research Council: FT0991360 ; Australian Research Council: DE130100614 ; Australian National Health and Medical Research Council: 1047956 ; Australian National Health and Medical Research Council: 1052684 ; German Research Foundation: DFG GR 1912/1-1 ; NIH Genes, Environment and Health Initiative [GEI]: U01 HG004422 ; NIH GEI: U01HG004438 ; : R01 MH090937 ; : P50MH094267 ; Web of Science
Kollektion: Universidade Federal de São Paulo (UNIFESP): Repositório Institucional
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