Genome-wide association study identifies five new schizophrenia loci

Stephan Ripke; Alan R Sanders; Kenneth S Kendler; Douglas F Levinson; Pamela Sklar; Peter A Holmans; Dan-Yu Lin; Jubao Duan; Roel A Ophoff; Ole A Andreassen; Edward Scolnick; Sven Cichon; David St Clair; Aiden Corvin; Hugh Gurling; Thomas Werge; Dan Rujescu; Douglas H R Blackwood; Carlos N Pato; Anil K Malhotra; Shaun Purcell; Frank Dudbridge; Benjamin M Neale; Lizzy Rossin; Peter M Visscher; Danielle Posthuma; Douglas M Ruderfer; Ayman Fanous; Hreinn Stefansson; Stacy Steinberg; Bryan J Mowry; Vera Golimbet; Marc De Hert; Erik G Jönsson; István Bitter; Olli P H Pietiläinen; David A Collier; Anders Fink-Jensen; Birte Glenthøj; Andrés Ingason; Klaus D Jakobsen; Gesche Jürgens; Merete Nordentoft; Line Olsen; Henrik Berg Rasmussen; Johan H Thygesen; Sally Timm; August G. Wang; The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium; Thomas Werge; Thomas F Hansen

doi:10.1038/ng.940

Genome-wide association study identifies five new schizophrenia loci

Stephan Ripke, Alan R Sanders, Kenneth S Kendler, Douglas F Levinson, Pamela Sklar, Peter A Holmans, Dan-Yu Lin, Jubao Duan, Roel A Ophoff, Ole A Andreassen, Edward Scolnick, Sven Cichon, David St Clair, Aiden Corvin, Hugh Gurling, Thomas Werge, Dan Rujescu, Douglas H R Blackwood, Carlos N Pato, Anil K MalhotraShaun Purcell, Frank Dudbridge, Benjamin M Neale, Lizzy Rossin, Peter M Visscher, Danielle Posthuma, Douglas M Ruderfer, Ayman Fanous, Hreinn Stefansson, Stacy Steinberg, Bryan J Mowry, Vera Golimbet, Marc De Hert, Erik G Jönsson, István Bitter, Olli P H Pietiläinen, David A Collier, Anders Fink-Jensen, Birte Glenthøj, Andrés Ingason, Klaus D Jakobsen, Gesche Jürgens, Merete Nordentoft, Line Olsen, Henrik Berg Rasmussen, Johan H Thygesen, Sally Timm, August G. Wang, The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Thomas Werge, Thomas F Hansen

Deildin fyri heilsu- og sjúkrarøktarvísindi - Faculty of Health Sciences

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Abstract

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

Original language	English
Pages (from-to)	969-976
Number of pages	8
Journal	Nature Genetics
Volume	43
DOIs	https://doi.org/10.1038/ng.940
Publication status	Published - 18 Sept 2011

Keywords

bipolar disorders
disease genetics
genome-wide association studies
schizophrenia

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10.1038/ng.940

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Ripke, S., Sanders, A. R., Kendler, K. S., Levinson, D. F., Sklar, P., Holmans, P. A., Lin, D.-Y., Duan, J., Ophoff, R. A., Andreassen, O. A., Scolnick, E., Cichon, S., Clair, D. S., Corvin, A., Gurling, H., Werge, T., Rujescu, D., Blackwood, D. H. R., Pato, C. N., ... Hansen, T. F. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 43, 969-976. https://doi.org/10.1038/ng.940

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title = "Genome-wide association study identifies five new schizophrenia loci",

abstract = "We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).",

keywords = "bipolar disorders, disease genetics, genome-wide association studies, schizophrenia",

author = "Stephan Ripke and Sanders, {Alan R} and Kendler, {Kenneth S} and Levinson, {Douglas F} and Pamela Sklar and Holmans, {Peter A} and Dan-Yu Lin and Jubao Duan and Ophoff, {Roel A} and Andreassen, {Ole A} and Edward Scolnick and Sven Cichon and Clair, {David St} and Aiden Corvin and Hugh Gurling and Thomas Werge and Dan Rujescu and Blackwood, {Douglas H R} and Pato, {Carlos N} and Malhotra, {Anil K} and Shaun Purcell and Frank Dudbridge and Neale, {Benjamin M} and Lizzy Rossin and Visscher, {Peter M} and Danielle Posthuma and Ruderfer, {Douglas M} and Ayman Fanous and Hreinn Stefansson and Stacy Steinberg and Mowry, {Bryan J} and Vera Golimbet and Hert, {Marc De} and J{\"o}nsson, {Erik G} and Istv{\'a}n Bitter and Pietil{\"a}inen, {Olli P H} and Collier, {David A} and Anders Fink-Jensen and Birte Glenth{\o}j and Andr{\'e}s Ingason and Jakobsen, {Klaus D} and Gesche J{\"u}rgens and Merete Nordentoft and Line Olsen and Rasmussen, {Henrik Berg} and Thygesen, {Johan H} and Sally Timm and Wang, {August G.} and Consortium, {The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS)} and Thomas Werge and Hansen, {Thomas F}",

year = "2011",

month = sep,

day = "18",

doi = "10.1038/ng.940",

language = "English",

volume = "43",

pages = "969--976",

journal = "Nature Genetics",

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Ripke, S, Sanders, AR, Kendler, KS, Levinson, DF, Sklar, P, Holmans, PA, Lin, D-Y, Duan, J, Ophoff, RA, Andreassen, OA, Scolnick, E, Cichon, S, Clair, DS, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, DHR, Pato, CN, Malhotra, AK, Purcell, S, Dudbridge, F, Neale, BM, Rossin, L, Visscher, PM, Posthuma, D, Ruderfer, DM, Fanous, A, Stefansson, H, Steinberg, S, Mowry, BJ, Golimbet, V, Hert, MD, Jönsson, EG, Bitter, I, Pietiläinen, OPH, Collier, DA, Fink-Jensen, A, Glenthøj, B, Ingason, A, Jakobsen, KD, Jürgens, G, Nordentoft, M, Olsen, L, Rasmussen, HB, Thygesen, JH, Timm, S, Wang, AG, Consortium, TSPG-WAS, Werge, T & Hansen, TF 2011, 'Genome-wide association study identifies five new schizophrenia loci', Nature Genetics, vol. 43, pp. 969-976. https://doi.org/10.1038/ng.940

TY - JOUR

T1 - Genome-wide association study identifies five new schizophrenia loci

AU - Ripke, Stephan

AU - Sanders, Alan R

AU - Kendler, Kenneth S

AU - Levinson, Douglas F

AU - Sklar, Pamela

AU - Holmans, Peter A

AU - Lin, Dan-Yu

AU - Duan, Jubao

AU - Ophoff, Roel A

AU - Andreassen, Ole A

AU - Scolnick, Edward

AU - Cichon, Sven

AU - Clair, David St

AU - Corvin, Aiden

AU - Gurling, Hugh

AU - Werge, Thomas

AU - Rujescu, Dan

AU - Blackwood, Douglas H R

AU - Pato, Carlos N

AU - Malhotra, Anil K

AU - Purcell, Shaun

AU - Dudbridge, Frank

AU - Neale, Benjamin M

AU - Rossin, Lizzy

AU - Visscher, Peter M

AU - Posthuma, Danielle

AU - Ruderfer, Douglas M

AU - Fanous, Ayman

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Mowry, Bryan J

AU - Golimbet, Vera

AU - Hert, Marc De

AU - Jönsson, Erik G

AU - Bitter, István

AU - Pietiläinen, Olli P H

AU - Collier, David A

AU - Fink-Jensen, Anders

AU - Glenthøj, Birte

AU - Ingason, Andrés

AU - Jakobsen, Klaus D

AU - Jürgens, Gesche

AU - Nordentoft, Merete

AU - Olsen, Line

AU - Rasmussen, Henrik Berg

AU - Thygesen, Johan H

AU - Timm, Sally

AU - Wang, August G.

AU - Consortium, The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS)

AU - Werge, Thomas

AU - Hansen, Thomas F

PY - 2011/9/18

Y1 - 2011/9/18

N2 - We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

AB - We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

KW - bipolar disorders

KW - disease genetics

KW - genome-wide association studies

KW - schizophrenia

UR - https://research.regionh.dk/en/publications/genomewide-association-study-identifies-five-new-schizophrenia-loci(ca82d7f5-49c4-4b41-8695-4b2acec2b768).html

U2 - 10.1038/ng.940

DO - 10.1038/ng.940

M3 - Article

C2 - 21926974

SN - 1546-1718

VL - 43

SP - 969

EP - 976

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide association study identifies five new schizophrenia loci

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