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

被引：195

作者：

Davis, Lea K. ^{[1
]}

Yu, Dongmei ^{[2
,3
]}

Keenan, Clare L. ^{[4
,5
]}

Gamazon, Eric R. ^{[1
]}

Konkashbaev, Anuar I. ^{[1
]}

Derks, Eske M. ^{[6
]}

Neale, Benjamin M. ^{[3
,7
]}

Yang, Jian ^{[8
,9
]}

Lee, S. Hong ^{[9
]}

Evans, Patrick ^{[1
]}

Barr, Cathy L. ^{[10
,11
]}

Bellodi, Laura ^{[12
]}

Benarroch, Fortu ^{[13
]}

Berrio, Gabriel Bedoya ^{[14
]}

Bienvenu, Oscar J. ^{[15
]}

Bloch, Michael H. ^{[16
,17
]}

Blom, Rianne M. ^{[6
]}

Bruun, Ruth D. ^{[18
,19
]}

Budman, Cathy L. ^{[20
,21
]}

Camarena, Beatriz ^{[22
]}

Campbell, Desmond ^{[23
,24
]}

Cappi, Carolina ^{[25
]}

Silgado, Julio C. Cardona ^{[14
]}

Cath, Danielle C. ^{[26
,27
,28
]}

Cavallini, Maria C. ^{[29
]}

Chavira, Denise A. ^{[30
,31
]}

Chouinard, Sylvain ^{[32
]}

Conti, David V. ^{[33
]}

Cook, Edwin H. ^{[34
]}

Coric, Vladimir ^{[16
]}

Cullen, Bernadette A. ^{[15
]}

Deforce, Dieter ^{[35
]}

Delorme, Richard ^{[36
,37
,38
]}

Dion, Yves ^{[39
]}

Edlund, Christopher K. ^{[33
]}

Egberts, Karin ^{[40
]}

Falkai, Peter ^{[41
]}

Fernandez, Thomas V. ^{[17
,42
]}

Gallagher, Patience J. ^{[15
]}

Garrido, Helena ^{[44
]}

Geller, Daniel ^{[45
]}

Girard, Simon L. ^{[32
]}

Grabe, Hans J. ^{[43
]}

Grados, Marco A. ^{[15
]}

Greenberg, Benjamin D. ^{[44
]}

Gross-Tsur, Varda ^{[45
]}

Haddad, Stephen ^{[2
]}

Heiman, Gary A. ^{[46
]}

Hemmings, Sian M. J. ^{[47
]}

Hounie, Ana G. ^{[48
]}

机构：

[1] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat,Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA

[3] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA

[4] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[5] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[6] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands

[7] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[8] Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia

[9] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[10] Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada

[11] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[12] Univ Vita Salute San Raffaele, Milan, Italy

[13] Hadassah Hebrew Univ Med Ctr, Herman Dana Div Child & Adolescent Psychiat, Jerusalem, Israel

[14] Univ Pontificia Bolivariana, Univ Antioquia, Medellin, Colombia

[15] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[16] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA

[17] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA

[18] North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA

[19] NYU Med Ctr, New York, NY 10016 USA

[20] North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA

[21] Hofstra Univ, Sch Med, Hempstead, NY 11550 USA

[22] Inst Nacl Psiquiatria Ramon de la Fuente Muniz, Mexico City, DF, Mexico

[23] UCL, London, England

[24] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China

[25] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo, Brazil

[26] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands

[27] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands

[28] Altrecht Acad Anxiety Ctr, Utrecht, Netherlands

[29] Univ Milan, Osped San Raffaele, I-20127 Milan, Italy

[30] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA

[31] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[32] Univ Montreal, Montreal, PQ, Canada

[33] Univ Calif Los Angeles, Keck Sch Med, Div Biostat, Dept Preventat Med, Los Angeles, CA USA

[34] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA

[35] Univ Ghent, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium

[36] Inst Pasteur, Paris, France

[37] French Natl Sci Fdn, Fondat Fondamental, Creteil, France

[38] Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, F-75019 Paris, France

[39] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada

[40] Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, Germany

[41] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany

[42] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA

[43] Univ Med Greifswald, Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany

[44] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA

[45] Shaare Zedek Med Ctr, Neuropediatr Unit, Jerusalem, Israel

[46] Rutgers State Univ, Dept Genet, Human Genet Inst New Jersey, Piscataway, NJ USA

[47] Univ Stellenbosch, Dept Psychiat, ZA-7600 Stellenbosch, South Africa

[48] Univ Sao Paulo, Fac Med, Dept Psychiat, BR-05508 Sao Paulo, Brazil

[49] Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr, Houston, TX 77030 USA

[50] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA

来源：

PLOS GENETICS | 2013年 / 9卷 / 10期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

MISSING HERITABILITY; TIC DISORDERS; NEUROPSYCHIATRIC DISORDERS; GILLES; FAMILY; EXPRESSION; SCHOOL; PREVALENCE; AUTISM; RISK;

D O I：

10.1371/journal.pgen.1003864

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页数：14

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