Meta-analysis of 32 genome-wide linkage studies of schizophrenia

M. Y.M. Ng; D. F. Levinson; S. V. Faraone; B. K. Suarez; L. E. Delisi; T. Arinami; B. Riley; T. Paunio; A. E. Pulver; Irmansyah; P. A. Holmans; M. Escamilla; D. B. Wildenauer; N. M. Williams; C. Laurent; B. J. Mowry; L. M. Brzustowicz; M. Maziade; P. Sklar; D. L. Garver; G. R. Abecasis; B. Lerer; M. D. Fallin; H. M.D. Gurling; P. V. Gejman; E. Lindholm; H. W. Moises; W. Byerley; E. M. Wijsman; P. Forabosco; M. T. Tsuang; H. G. Hwu; Y. Okazaki; K. S. Kendler; B. Wormley; A. Fanous; D. Walsh; F. A. O'Neill; L. Peltonen; G. Nestadt; V. K. Lasseter; K. Y. Liang; G. M. Papadimitriou; D. G. Dikeos; S. G. Schwab; M. J. Owen; M. C. O'Donovan; N. Norton; E. Hare; H. Raventos; H. Nicolini; M. Albus; W. Maier; V. L. Nimgaonkar; L. Terenius; J. Mallet; M. Jay; S. Godard; D. Nertney; M. Alexander; R. R. Crowe; J. M. Silverman; A. S. Bassett; M. A. Roy; C. Mérette; C. N. Pato; M. T. Pato; J. Louw Roos; Y. Kohn; D. Amann-Zalcenstein; G. Kalsi; A. McQuillin; D. Curtis; J. Brynjolfson; T. Sigmundsson; H. Petursson; A. R. Sanders; J. Duan; E. Jazin; M. Myles-Worsley; M. Karayiorgou; C. M. Lewis

doi:10.1038/mp.2008.135

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

M. Y.M. Ng, D. F. Levinson, S. V. Faraone, B. K. Suarez, L. E. Delisi, T. Arinami, B. Riley, T. Paunio, A. E. Pulver, Irmansyah, P. A. Holmans, M. Escamilla, D. B. Wildenauer, N. M. Williams, C. Laurent, B. J. Mowry, L. M. Brzustowicz, M. Maziade, P. Sklar, D. L. GarverG. R. Abecasis, B. Lerer, M. D. Fallin, H. M.D. Gurling, P. V. Gejman, E. Lindholm, H. W. Moises, W. Byerley, E. M. Wijsman, P. Forabosco, M. T. Tsuang, H. G. Hwu, Y. Okazaki, K. S. Kendler, B. Wormley, A. Fanous, D. Walsh, F. A. O'Neill, L. Peltonen, G. Nestadt, V. K. Lasseter, K. Y. Liang, G. M. Papadimitriou, D. G. Dikeos, S. G. Schwab, M. J. Owen, M. C. O'Donovan, N. Norton, E. Hare, H. Raventos, H. Nicolini, M. Albus, W. Maier, V. L. Nimgaonkar, L. Terenius, J. Mallet, M. Jay, S. Godard, D. Nertney, M. Alexander, R. R. Crowe, J. M. Silverman, A. S. Bassett, M. A. Roy, C. Mérette, C. N. Pato, M. T. Pato, J. Louw Roos, Y. Kohn, D. Amann-Zalcenstein, G. Kalsi, A. McQuillin, D. Curtis, J. Brynjolfson, T. Sigmundsson, H. Petursson, A. R. Sanders, J. Duan, E. Jazin, M. Myles-Worsley, M. Karayiorgou, C. M. Lewis

Research output: Contribution to journal › Article › peer-review

187 Scopus citations

Abstract

A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for aggregate genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Original language	English (US)
Pages (from-to)	774-785
Number of pages	12
Journal	Molecular psychiatry
Volume	14
Issue number	8
DOIs	https://doi.org/10.1038/mp.2008.135
State	Published - Aug 2009

Keywords

Genetic predisposition to disease
Genome
Human
Humans
Linkage (genetics)
Meta-analysis
Schizophrenia/genetics

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2008.135

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Ng, M. Y. M., Levinson, D. F., Faraone, S. V., Suarez, B. K., Delisi, L. E., Arinami, T., Riley, B., Paunio, T., Pulver, A. E., Irmansyah, Holmans, P. A., Escamilla, M., Wildenauer, D. B., Williams, N. M., Laurent, C., Mowry, B. J., Brzustowicz, L. M., Maziade, M., Sklar, P., ... Lewis, C. M. (2009). Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Molecular psychiatry, 14(8), 774-785. https://doi.org/10.1038/mp.2008.135

Ng, MYM, Levinson, DF, Faraone, SV, Suarez, BK, Delisi, LE, Arinami, T, Riley, B, Paunio, T, Pulver, AE, Irmansyah, Holmans, PA, Escamilla, M, Wildenauer, DB, Williams, NM, Laurent, C, Mowry, BJ, Brzustowicz, LM, Maziade, M, Sklar, P, Garver, DL, Abecasis, GR, Lerer, B, Fallin, MD, Gurling, HMD, Gejman, PV, Lindholm, E, Moises, HW, Byerley, W, Wijsman, EM, Forabosco, P, Tsuang, MT, Hwu, HG, Okazaki, Y, Kendler, KS, Wormley, B, Fanous, A, Walsh, D, O'Neill, FA, Peltonen, L, Nestadt, G, Lasseter, VK, Liang, KY, Papadimitriou, GM, Dikeos, DG, Schwab, SG, Owen, MJ, O'Donovan, MC, Norton, N, Hare, E, Raventos, H, Nicolini, H, Albus, M, Maier, W, Nimgaonkar, VL, Terenius, L, Mallet, J, Jay, M, Godard, S, Nertney, D, Alexander, M, Crowe, RR, Silverman, JM, Bassett, AS, Roy, MA, Mérette, C, Pato, CN, Pato, MT, Roos, JL, Kohn, Y, Amann-Zalcenstein, D, Kalsi, G, McQuillin, A, Curtis, D, Brynjolfson, J, Sigmundsson, T, Petursson, H, Sanders, AR, Duan, J, Jazin, E, Myles-Worsley, M, Karayiorgou, M & Lewis, CM 2009, 'Meta-analysis of 32 genome-wide linkage studies of schizophrenia', Molecular psychiatry, vol. 14, no. 8, pp. 774-785. https://doi.org/10.1038/mp.2008.135

@article{4b7954c741234025acecc1ec4f1a0b93,

title = "Meta-analysis of 32 genome-wide linkage studies of schizophrenia",

abstract = "A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for aggregate genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.",

keywords = "Genetic predisposition to disease, Genome, Human, Humans, Linkage (genetics), Meta-analysis, Schizophrenia/genetics",

author = "Ng, {M. Y.M.} and Levinson, {D. F.} and Faraone, {S. V.} and Suarez, {B. K.} and Delisi, {L. E.} and T. Arinami and B. Riley and T. Paunio and Pulver, {A. E.} and Irmansyah and Holmans, {P. A.} and M. Escamilla and Wildenauer, {D. B.} and Williams, {N. M.} and C. Laurent and Mowry, {B. J.} and Brzustowicz, {L. M.} and M. Maziade and P. Sklar and Garver, {D. L.} and Abecasis, {G. R.} and B. Lerer and Fallin, {M. D.} and Gurling, {H. M.D.} and Gejman, {P. V.} and E. Lindholm and Moises, {H. W.} and W. Byerley and Wijsman, {E. M.} and P. Forabosco and Tsuang, {M. T.} and Hwu, {H. G.} and Y. Okazaki and Kendler, {K. S.} and B. Wormley and A. Fanous and D. Walsh and O'Neill, {F. A.} and L. Peltonen and G. Nestadt and Lasseter, {V. K.} and Liang, {K. Y.} and Papadimitriou, {G. M.} and Dikeos, {D. G.} and Schwab, {S. G.} and Owen, {M. J.} and O'Donovan, {M. C.} and N. Norton and E. Hare and H. Raventos and H. Nicolini and M. Albus and W. Maier and Nimgaonkar, {V. L.} and L. Terenius and J. Mallet and M. Jay and S. Godard and D. Nertney and M. Alexander and Crowe, {R. R.} and Silverman, {J. M.} and Bassett, {A. S.} and Roy, {M. A.} and C. M{\'e}rette and Pato, {C. N.} and Pato, {M. T.} and Roos, {J. Louw} and Y. Kohn and D. Amann-Zalcenstein and G. Kalsi and A. McQuillin and D. Curtis and J. Brynjolfson and T. Sigmundsson and H. Petursson and Sanders, {A. R.} and J. Duan and E. Jazin and M. Myles-Worsley and M. Karayiorgou and Lewis, {C. M.}",

note = "Funding Information: The work reported here was supported by: Medical Research Council (UK) Grants G0400960 (CML) and G9309834 (MO); National Institute of Mental Health Grants 7R01MH062276 (to DFL [Aust/US], CL [France/La R{\'e}union], MO [Cardiff] and DW [Bonn]), 5R01MH068922 (to PG [ENH]), 5R01MH068921 (to AEP [Johns Hopkins]), 5R01MH068881 (to BR [VCU/Ireland]), MH-41953 (to KSK [VCU/Ireland]); MH63356 and MH80299 (to WB [Palau]); MH58586 (to JMS [Aust/US]); MH 56242 (to VLM [US/Sweden]), MH61399 (EMW, MK [Kosrae, South Africa]), NIMH Grant MH062440, Canadian Institutes of Health Research Grants MOP-53216 and MOP-12155, a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award and Canada Research Chair in Schizophrenia Genetics (LMB, ASB [Canada]); Australian National Health and Medical Research Council Grants 910234, 941087, and 971095 (to BJM [Aust/US]), MRC project Grant G880473N, The European Science Foundation, SANE, the Iceland Department of Health, the General Hospital Reykjavik, the Joseph Levy Charitable Foundation, the Wellcome Trust Grant 055379, The Priory Hospital, the Neuroscience Research Charitable Trust, the University of Iceland and the Icelandic Science Council (HMDG [UCL]); Warner-Lambert, Parke-Davis Pharmaceuticals Company and NIMH Grant R01-MH44245 (LEL [US/International]); the Deutsche Forschungsgemeinschaft (HWM [Kiel]; MA WM, SGS, DBW [Indonesia]); the German Israeli Founda- tion for Scientific Research (BL; DBW); Mammalian Genotyping Service HV48141 (DBW [Indonesia]; CREST of JST (Japan Science and Technology Agency) TA [Japan]; Pfizer, Inc. and the SANE Foundation (LEL [Costa Rica]); the Israel Science Foundation, US. Israel Binational Science Foundation, the National Alliance for Research on Schizophrenia and Depression, and the Harry Stern Family Foundation (BL and YK [Israel]); the VA Merit Review Program (AF); recruitment of the NIMH Genetics Initiative sample was supported by NIMH Grants 5 UO1MH46318, UO1MH46289 and UO1MH46276; the Taiwan Schizophrenia Linkage Study was supported by NIMH Grant 1R01 MH59624-01 and Grant NHRI-90-8825PP, NHRI -EX91,92-9113PP from the National Health Research Institute, Taiwan, and support from the Genomic Medicine Research Program of Psychiatric Disorders, National Taiwan University Hospital; the VA Linkage Study was supported by funds from the Department of Veterans Affairs Cooperative Studies Program; the US/Mexico/Central America study was supported by a collaborative NIMH grant ({\textquoteleft}Genetics of Schizophrenia in Latino Populations{\textquoteright}) (MH60881 and MH60875) to ME [University of Texas Health Science Center at San Antonio], R Mendoza [University of California at Los Angeles-Harbor], HR [University of Costa Rica, San Jose, Costa Rica], A Ontiveros [Instituto de Informacion de Investigacion en Salud Mental, Monterrey, Mexico], HN [Medical and Family Research Group, Carracci SC, Mexico City, Mexico], and R Munoz [Family Health Centers of San Diego, CA].",

year = "2009",

month = aug,

doi = "10.1038/mp.2008.135",

language = "English (US)",

volume = "14",

pages = "774--785",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Meta-analysis of 32 genome-wide linkage studies of schizophrenia

AU - Ng, M. Y.M.

AU - Levinson, D. F.

AU - Faraone, S. V.

AU - Suarez, B. K.

AU - Delisi, L. E.

AU - Arinami, T.

AU - Riley, B.

AU - Paunio, T.

AU - Pulver, A. E.

AU - Irmansyah,

AU - Holmans, P. A.

AU - Escamilla, M.

AU - Wildenauer, D. B.

AU - Williams, N. M.

AU - Laurent, C.

AU - Mowry, B. J.

AU - Brzustowicz, L. M.

AU - Maziade, M.

AU - Sklar, P.

AU - Garver, D. L.

AU - Abecasis, G. R.

AU - Lerer, B.

AU - Fallin, M. D.

AU - Gurling, H. M.D.

AU - Gejman, P. V.

AU - Lindholm, E.

AU - Moises, H. W.

AU - Byerley, W.

AU - Wijsman, E. M.

AU - Forabosco, P.

AU - Tsuang, M. T.

AU - Hwu, H. G.

AU - Okazaki, Y.

AU - Kendler, K. S.

AU - Wormley, B.

AU - Fanous, A.

AU - Walsh, D.

AU - O'Neill, F. A.

AU - Peltonen, L.

AU - Nestadt, G.

AU - Lasseter, V. K.

AU - Liang, K. Y.

AU - Papadimitriou, G. M.

AU - Dikeos, D. G.

AU - Schwab, S. G.

AU - Owen, M. J.

AU - O'Donovan, M. C.

AU - Norton, N.

AU - Hare, E.

AU - Raventos, H.

AU - Nicolini, H.

AU - Albus, M.

AU - Maier, W.

AU - Nimgaonkar, V. L.

AU - Terenius, L.

AU - Mallet, J.

AU - Jay, M.

AU - Godard, S.

AU - Nertney, D.

AU - Alexander, M.

AU - Crowe, R. R.

AU - Silverman, J. M.

AU - Bassett, A. S.

AU - Roy, M. A.

AU - Mérette, C.

AU - Pato, C. N.

AU - Pato, M. T.

AU - Roos, J. Louw

AU - Kohn, Y.

AU - Amann-Zalcenstein, D.

AU - Kalsi, G.

AU - McQuillin, A.

AU - Curtis, D.

AU - Brynjolfson, J.

AU - Sigmundsson, T.

AU - Petursson, H.

AU - Sanders, A. R.

AU - Duan, J.

AU - Jazin, E.

AU - Myles-Worsley, M.

AU - Karayiorgou, M.

AU - Lewis, C. M.

N1 - Funding Information: The work reported here was supported by: Medical Research Council (UK) Grants G0400960 (CML) and G9309834 (MO); National Institute of Mental Health Grants 7R01MH062276 (to DFL [Aust/US], CL [France/La Réunion], MO [Cardiff] and DW [Bonn]), 5R01MH068922 (to PG [ENH]), 5R01MH068921 (to AEP [Johns Hopkins]), 5R01MH068881 (to BR [VCU/Ireland]), MH-41953 (to KSK [VCU/Ireland]); MH63356 and MH80299 (to WB [Palau]); MH58586 (to JMS [Aust/US]); MH 56242 (to VLM [US/Sweden]), MH61399 (EMW, MK [Kosrae, South Africa]), NIMH Grant MH062440, Canadian Institutes of Health Research Grants MOP-53216 and MOP-12155, a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award and Canada Research Chair in Schizophrenia Genetics (LMB, ASB [Canada]); Australian National Health and Medical Research Council Grants 910234, 941087, and 971095 (to BJM [Aust/US]), MRC project Grant G880473N, The European Science Foundation, SANE, the Iceland Department of Health, the General Hospital Reykjavik, the Joseph Levy Charitable Foundation, the Wellcome Trust Grant 055379, The Priory Hospital, the Neuroscience Research Charitable Trust, the University of Iceland and the Icelandic Science Council (HMDG [UCL]); Warner-Lambert, Parke-Davis Pharmaceuticals Company and NIMH Grant R01-MH44245 (LEL [US/International]); the Deutsche Forschungsgemeinschaft (HWM [Kiel]; MA WM, SGS, DBW [Indonesia]); the German Israeli Founda- tion for Scientific Research (BL; DBW); Mammalian Genotyping Service HV48141 (DBW [Indonesia]; CREST of JST (Japan Science and Technology Agency) TA [Japan]; Pfizer, Inc. and the SANE Foundation (LEL [Costa Rica]); the Israel Science Foundation, US. Israel Binational Science Foundation, the National Alliance for Research on Schizophrenia and Depression, and the Harry Stern Family Foundation (BL and YK [Israel]); the VA Merit Review Program (AF); recruitment of the NIMH Genetics Initiative sample was supported by NIMH Grants 5 UO1MH46318, UO1MH46289 and UO1MH46276; the Taiwan Schizophrenia Linkage Study was supported by NIMH Grant 1R01 MH59624-01 and Grant NHRI-90-8825PP, NHRI -EX91,92-9113PP from the National Health Research Institute, Taiwan, and support from the Genomic Medicine Research Program of Psychiatric Disorders, National Taiwan University Hospital; the VA Linkage Study was supported by funds from the Department of Veterans Affairs Cooperative Studies Program; the US/Mexico/Central America study was supported by a collaborative NIMH grant (‘Genetics of Schizophrenia in Latino Populations’) (MH60881 and MH60875) to ME [University of Texas Health Science Center at San Antonio], R Mendoza [University of California at Los Angeles-Harbor], HR [University of Costa Rica, San Jose, Costa Rica], A Ontiveros [Instituto de Informacion de Investigacion en Salud Mental, Monterrey, Mexico], HN [Medical and Family Research Group, Carracci SC, Mexico City, Mexico], and R Munoz [Family Health Centers of San Diego, CA].

PY - 2009/8

Y1 - 2009/8

N2 - A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for aggregate genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

AB - A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for aggregate genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

KW - Genetic predisposition to disease

KW - Genome

KW - Human

KW - Humans

KW - Linkage (genetics)

KW - Meta-analysis

KW - Schizophrenia/genetics

UR - http://www.scopus.com/inward/record.url?scp=67651160485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651160485&partnerID=8YFLogxK

U2 - 10.1038/mp.2008.135

DO - 10.1038/mp.2008.135

M3 - Article

C2 - 19349958

AN - SCOPUS:67651160485

SN - 1359-4184

VL - 14

SP - 774

EP - 785

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 8

ER -

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

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