Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis

被引：358

作者：

Arnold, Paul D. ^{[1
]}

Askland, Kathleen D. ^{[2
]}

Barlassina, Cristina ^{[1
]}

Bellodi, Laura ^{[1
]}

Bienvenu, O. J. ^{[1
,2
]}

Black, Donald ^{[1
]}

Bloch, Michael ^{[1
]}

Brentani, Helena ^{[1
]}

Burton, Christie L. ^{[1
]}

Camarena, Beatriz ^{[1
]}

Cappi, Carolina ^{[1
]}

Cath, Danielle ^{[1
]}

Cavallini, Maria ^{[1
]}

Conti, David

Cook, Edwin ^{[1
]}

Coric, Vladimir ^{[1
]}

Cullen, Bernadette A. ^{[1
,2
]}

Cusi, Danielle ^{[1
]}

Davis, Lea K. ^{[1
]}

Delorme, Richard ^{[1
]}

Denys, Damiaan ^{[1
]}

Derks, Eske ^{[1
]}

Eapen, Valsamma ^{[1
]}

Edlund, Christopher ^{[1
]}

Erdman, Lauren ^{[1
]}

Falkai, Peter ^{[1
]}

Figee, Martijn ^{[1
]}

Fyer, Abigail J. ^{[1
,2
]}

Geller, Daniel A. ^{[1
]}

Goes, Fernando S. ^{[2
]}

Grabe, Hans ^{[1
]}

Grados, Marcos A. ^{[1
]}

Greenberg, Benjamin D. ^{[2
]}

Grunblatt, Edna ^{[1
]}

Guo, Wei ^{[1
,2
]}

Hanna, Gregory L. ^{[1
]}

Hemmings, Sian ^{[1
]}

Hounie, Ana G. ^{[1
]}

Jenicke, Michael ^{[1
,2
]}

Keenan, Clare ^{[1
]}

Kennedy, James ^{[1
]}

Khramtsova, Ekaterina A. ^{[1
]}

Konkashbaev, Anuar ^{[1
]}

Knowles, James A. ^{[1
,2
]}

Krasnow, Janice ^{[1
,2
]}

Lange, Cristophe ^{[2
]}

Lanzagorta, Nuria ^{[1
]}

Leboyer, Marion ^{[1
]}

Lennertz, Leonhard ^{[1
]}

Li, Bingbin ^{[2
]}

机构：

[1] OCDF GC, Boston, MA 02196 USA

[2] OCGAS, Las Vegas, NV 89129 USA

来源：

MOLECULAR PSYCHIATRY | 2018年 / 23卷 / 05期

关键词：

GENOME-WIDE ASSOCIATION; LINKAGE ANALYSIS; FAMILY; NEUROBIOLOGY; TRAITS; LOCI; TWIN;

D O I：

10.1038/mp.2017.154

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P = 7.1 x 10(-7); odds ratio (OR) = 1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P = 1.1 x 10(-6); OR = 1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P = 1.6 x 10(-6); OR = 1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P = 0.003) and 0.3% (P = 0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e. = 0.04). Strikingly, similar to 65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of >= 40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

引用

页码：1181 / 1188

页数：8

共 50 条

[1] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[2] Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study [J].

Arnold, PD ;

Rosenberg, DR ;

Mundo, E ;

Tharmalingam, S ;

Kennedy, JL ;

Richter, MA .

PSYCHOPHARMACOLOGY, 2004, 174 (04) :530-538

[3] Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs [J].

Below, Jennifer E. ;

Parra, Esteban J. ;

Gamazon, Eric R. ;

Torres, Jason ;

Krithika, S. ;

Candille, Sophie ;

Lu, Yingchang ;

Manichakul, Ani ;

Peralta-Romero, Jesus ;

Duan, Qing ;

Li, Yun ;

Morris, Andrew P. ;

Gottesman, Omri ;

Bottinger, Erwin ;

Wang, Xin-Qun ;

Taylor, Kent D. ;

Chen, Y. -D. Ida ;

Rotter, Jerome I. ;

Rich, Stephen S. ;

Loos, Ruth J. F. ;

Tang, Hua ;

Cox, Nancy J. ;

Cruz, Miguel ;

Hanis, Craig L. ;

Valladares-Salgado, Adan .

SCIENTIFIC REPORTS, 2016, 6

[4] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[5] Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis [J].

Cacheaux, Luisa P. ;

Ivens, Sebastian ;

David, Yaron ;

Lakhter, Alexander J. ;

Bar-Klein, Guy ;

Shapira, Michael ;

Heinemann, Uwe ;

Friedman, Alon ;

Kaufer, Daniela .

JOURNAL OF NEUROSCIENCE, 2009, 29 (28) :8927-8935

[6]

Carter MJ, 2014, THER RECREAT J, V48, P275

[7] GENETIC AND ENVIRONMENTAL-INFLUENCES ON OBSESSIONAL TRAITS AND SYMPTOMS [J].

CLIFFORD, CA ;

MURRAY, RM ;

FULKER, DW .

PSYCHOLOGICAL MEDICINE, 1984, 14 (04) :791-800

[8] GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia [J].

Coutelier, Marie ;

Burglen, Lydie ;

Mundwiller, Emeline ;

Abada-Bendib, Myriam ;

Rodriguez, Diana ;

Chantot-Bastaraud, Sandra ;

Rougeot, Christelle ;

Cournelle, Marie-Anne ;

Milh, Mathieu ;

Toutain, Annick ;

Bacq, Delphine ;

Meyer, Vincent ;

Afenjar, Alexandra ;

Deleuze, Jean-Francois ;

Brice, Alexis ;

Heron, Delphine ;

Stevanin, Giovanni ;

Durr, Alexandra .

NEUROLOGY, 2015, 84 (17) :1751-1759

[9] Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture [J].

Davis, Lea K. ;

Yu, Dongmei ;

Keenan, Clare L. ;

Gamazon, Eric R. ;

Konkashbaev, Anuar I. ;

Derks, Eske M. ;

Neale, Benjamin M. ;

Yang, Jian ;

Lee, S. Hong ;

Evans, Patrick ;

Barr, Cathy L. ;

Bellodi, Laura ;

Benarroch, Fortu ;

Berrio, Gabriel Bedoya ;

Bienvenu, Oscar J. ;

Bloch, Michael H. ;

Blom, Rianne M. ;

Bruun, Ruth D. ;

Budman, Cathy L. ;

Camarena, Beatriz ;

Campbell, Desmond ;

Cappi, Carolina ;

Silgado, Julio C. Cardona ;

Cath, Danielle C. ;

Cavallini, Maria C. ;

Chavira, Denise A. ;

Chouinard, Sylvain ;

Conti, David V. ;

Cook, Edwin H. ;

Coric, Vladimir ;

Cullen, Bernadette A. ;

Deforce, Dieter ;

Delorme, Richard ;

Dion, Yves ;

Edlund, Christopher K. ;

Egberts, Karin ;

Falkai, Peter ;

Fernandez, Thomas V. ;

Gallagher, Patience J. ;

Garrido, Helena ;

Geller, Daniel ;

Girard, Simon L. ;

Grabe, Hans J. ;

Grados, Marco A. ;

Greenberg, Benjamin D. ;

Gross-Tsur, Varda ;

Haddad, Stephen ;

Heiman, Gary A. ;

Hemmings, Sian M. J. ;

Hounie, Ana G. .

PLOS GENETICS, 2013, 9 (10)

[10] Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci [J].

Davis, Lea K. ;

Gamazon, Eric R. ;

Kistner-Griffin, Emily ;

Badner, Judith A. ;

Liu, Chunyu ;

Cook, Edwin H. ;

Sutcliffe, James S. ;

Cox, Nancy J. .

MOLECULAR AUTISM, 2012, 3

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