Common variants conferring risk of schizophrenia

被引：1268

作者：

Stefansson, Hreinn ^{[1
]}

Ophoff, Roel A. ^{[2
,3
,4
]}

Steinberg, Stacy ^{[1
]}

Andreassen, Ole A. ^{[5
,6
]}

Cichon, Sven ^{[7
]}

Rujescu, Dan ^{[8
]}

Werge, Thomas ^{[9
]}

Pietilainen, Olli P. H. ^{[10
,11
]}

Mors, Ole ^{[12
]}

Mortensen, Preben B. ^{[13
]}

Sigurdsson, Engilbert ^{[14
,15
]}

Gustafsson, Omar ^{[1
]}

Nyegaard, Mette ^{[16
]}

Tuulio-Henriksson, Annamari

Ingason, Andres ^{[1
]}

Hansen, Thomas ^{[9
]}

Suvisaari, Jaana ^{[17
]}

Lonnqvist, Jouko ^{[17
]}

Paunio, Tiina ^{[18
]}

Borglum, Anders D. ^{[12
,16
]}

Hartmann, Annette ^{[8
]}

Fink-Jensen, Anders ^{[19
]}

Nordentoft, Merete ^{[20
]}

Hougaard, David ^{[21
]}

Norgaard-Pedersen, Bent ^{[21
]}

Bottcher, Yvonne ^{[1
]}

Olesen, Jes ^{[22
]}

Breuer, Rene ^{[23
]}

Moeller, Hans-Jurgen ^{[24
]}

Giegling, Ina ^{[8
]}

Rasmussen, Henrik B. ^{[9
]}

Timm, Sally ^{[25
]}

Mattheisen, Manuel ^{[7
]}

Bitter, Istvan ^{[26
]}

Rethelyi, Janos M. ^{[26
]}

Magnusdottir, Brynja B. ^{[14
,15
]}

Sigmundsson, Thordur ^{[14
,15
]}

Olason, Pall ^{[1
]}

Mason, Gisli ^{[1
]}

Gulcher, Jeffrey R. ^{[1
]}

Haraldsson, Magnus ^{[14
,15
]}

Fossdal, Ragnheidur ^{[1
]}

Thorgeirsson, Thorgeir E. ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
]}

Ruggeri, Mirella ^{[27
]}

Tosato, Sarah ^{[27
]}

Franke, Barbara ^{[28
]}

Strengman, Eric ^{[2
,3
]}

Kiemeney, Lambertus A. ^{[29
,30
]}

Melle, Ingrid ^{[5
,6
]}

机构：

[1] DeCODE Genet, IS-101 Reykjavik, Iceland

[2] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CG Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, NL-3584 CG Utrecht, Netherlands

[4] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA

[5] Ullevaal Univ Hosp, Dept Psychiat, N-0407 Oslo, Norway

[6] Univ Oslo, Inst Psychiat, N-0407 Oslo, Norway

[7] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany

[8] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-80336 Munich, Germany

[9] Univ Copenhagen, Mental Hlth Ctr Sct Hans, Res Inst Biol Psychiat, DK-4000 Roskilde, Denmark

[10] Biomedicum Helsinki, Inst Mol Med, Helsinki 00290, Finland

[11] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[12] Aarhus Univ Hosp, Ctr Psychiat Res, DK-8240 Risskov, Denmark

[13] Aarhus Univ, Natl Ctr Register Based Res, DK-8000 Aarhus, Denmark

[14] Natl Univ Hosp Reykjavik, Dept Psychiat, IS-101 Reykjavik, Iceland

[15] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland

[16] Aarhus Univ, Dept Human Genet, DK-8000 Aarhus C, Denmark

[17] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, FIN-00300 Helsinki, Finland

[18] Biomedicum, Natl Publ Hlth Inst, Dept Mol Med, Helsinki 00290, Finland

[19] Copenhagen Univ Hosp, Mental Hlth Ctr, Rigshosp, DK-2100 Copenhagen O, Denmark

[20] Bispebjerg Hosp, Psychiat Ctr Bisbebjerg, DK-2400 Copenhagen NV, Denmark

[21] State Serum Inst, Sect Neonatal Screening & Hormones, Dept Clin Chem & Immunol, DK-2300 Copenhagen S, Denmark

[22] Glostrup Cty Hosp, Dept Neurol, DK-2600 Glostrup, Denmark

[23] Heidelberg Univ, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany

[24] Univ Munich, Dept Psychiat, D-80336 Munich, Germany

[25] Copenhagen Univ Hosp, Mental Hlth Ctr Frederiksberg, DK-2000 Copenhagen, Denmark

[26] Semmelweis Univ, Dept Psychiat & Psychotherapy, H-1083 Budapest, Hungary

[27] Univ Verona, Sect Psychiat & Clin Psychol, I-37134 Verona, Italy

[28] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[29] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol & Biostat, NL-6500 HB Nijmegen, Netherlands

[30] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands

[31] Ullevaal Univ Hosp, Dept Med Genet, N-0407 Oslo, Norway

[32] Univ Oslo, Inst Psychiat, N-0407 Oslo, Norway

[33] Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 117152, Russia

[34] Univ Valencia, Unidad Psiquiatria, Fac Biol, CIBERSAM, Valencia 46010, Spain

[35] Univ Valencia, Dept Genet, Fac Biol, CIBERSAM, Valencia 46010, Spain

[36] Kings Coll London, Inst Psychiat, Div Psychol Med, London SE5 8AF, England

[37] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England

[38] Univ Aberdeen, Royal Cornhill Hosp, Dept Mental Hlth, Aberdeen AB25 2ZD, Scotland

[39] Ravenscraig Hosp, Greenock PA16 9HA, Scotland

[40] Duke Univ, Inst Genome Sci & Policy, Ctr Populat Genom & Pharmacogenet, Durham, NC 27708 USA

[41] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[42] Univ Santiago de Compostela, Fdn Publ Galega Med, Xenom Complexo Univ Hosp Santiago, IML, Santiago De Compostela 15782, Spain

[43] Univ Santiago de Compostela, CIBERER, IML, Santiago De Compostela 15782, Spain

[44] Hosp Gen Univ Gregorio Maran, CIBERSAM, Madrid, Spain

[45] Fdn Publ Galega Med Xen, Valencia 46010, Spain

[46] CIBERER, Valencia 46010, Spain

[47] Karolinska Hosp & Inst, Dept Clin Neurosci, HUBIN Project, SE-17176 Stockholm, Sweden

[48] Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany

[49] GlaxoSmithKline, Hammersmith Hosp, Clin Imaging Ctr, Clin Pharmacol & Discovery Med, London W12 ONN, England

[50] GlaxoSmithKline R&D, Med Genet, I-37135 Verona, Italy

来源：

NATURE | 2009年 / 460卷 / 7256期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; MENTAL-RETARDATION; GENE; NEUROGRANIN; POPULATION; DELETIONS; DISEASES; 1Q21.1; MEMORY; SCAN;

D O I：

10.1038/nature08186

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders(1-3). The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized(4). Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

引用

页码：744 / U99

页数：5

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