Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia

Cathryn M. Lewis; Douglas F. Levinson; Lesley H. Wise; Lynn E. DeLisi; Richard E. Straub; Iiris Hovatta; Nigel M. Williams; Sibylle G. Schwab; Ann E Pulver; Stephen V. Faraone; Linda M. Brzustowicz; Charles A. Kaufmann; David L. Garver; Hugh M.D. Gurling; Eva Lindholm; Hilary Coon; Hans W. Moises; William Byerley; Sarah H. Shaw; Andrea Mesen; Robin Sherrington; F. Anthony O'Neill; Dermot Walsh; Kenneth S. Kendler; Jesper Ekelund; Tiina Paunio; Jouko Lönnqvist; Leena Peltonen; Michael C. O'Donovan; Michael J. Owen; Dieter B. Wildenauer; Wolfgang Maier; Gerald Nestadt; Jean Louis Blouin; Stylianos E. Antonarakis; Bryan J. Mowry; Jeremy M. Silverman; Raymond R. Crowe; C. Robert Cloninger; Ming T. Tsuang; Dolores Malaspina; Jill M. Harkavy-Friedman; Dragan M. Svrakic; Anne S. Bassett; Jennifer Holcomb; Gursharan Kalsi; Andrew McQuillin; Jon Brynjolfson; Thordur Sigmundsson; Hannes Petursson; Elena Jazin; Tomas Zoëga; Tomas Helgason

doi:10.1086/376549

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia

Cathryn M. Lewis, Douglas F. Levinson, Lesley H. Wise, Lynn E. DeLisi, Richard E. Straub, Iiris Hovatta, Nigel M. Williams, Sibylle G. Schwab, Ann E Pulver, Stephen V. Faraone, Linda M. Brzustowicz, Charles A. Kaufmann, David L. Garver, Hugh M.D. Gurling, Eva Lindholm, Hilary Coon, Hans W. Moises, William Byerley, Sarah H. Shaw, Andrea MesenRobin Sherrington, F. Anthony O'Neill, Dermot Walsh, Kenneth S. Kendler, Jesper Ekelund, Tiina Paunio, Jouko Lönnqvist, Leena Peltonen, Michael C. O'Donovan, Michael J. Owen, Dieter B. Wildenauer, Wolfgang Maier, Gerald Nestadt, Jean Louis Blouin, Stylianos E. Antonarakis, Bryan J. Mowry, Jeremy M. Silverman, Raymond R. Crowe, C. Robert Cloninger, Ming T. Tsuang, Dolores Malaspina, Jill M. Harkavy-Friedman, Dragan M. Svrakic, Anne S. Bassett, Jennifer Holcomb, Gursharan Kalsi, Andrew McQuillin, Jon Brynjolfson, Thordur Sigmundsson, Hannes Petursson, Elena Jazin, Tomas Zoëga, Tomas Helgason

School of Medicine

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

910 Scopus citations

Abstract

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R_avg) and then weighted for sample size (√N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P_AvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P_ord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (P_AvgRnk < .000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P_AvgRnk and P_ord < .05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P_ord < .05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Original language	English (US)
Pages (from-to)	34-48
Number of pages	15
Journal	American journal of human genetics
Volume	73
Issue number	1
DOIs	https://doi.org/10.1086/376549
State	Published - Jul 1 2003

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1086/376549

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Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, L. E., Straub, R. E., Hovatta, I., Williams, N. M., Schwab, S. G., Pulver, A. E., Faraone, S. V., Brzustowicz, L. M., Kaufmann, C. A., Garver, D. L., Gurling, H. M. D., Lindholm, E., Coon, H., Moises, H. W., Byerley, W., Shaw, S. H., ... Helgason, T. (2003). Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. American journal of human genetics, 73(1), 34-48. https://doi.org/10.1086/376549

Lewis, CM, Levinson, DF, Wise, LH, DeLisi, LE, Straub, RE, Hovatta, I, Williams, NM, Schwab, SG, Pulver, AE, Faraone, SV, Brzustowicz, LM, Kaufmann, CA, Garver, DL, Gurling, HMD, Lindholm, E, Coon, H, Moises, HW, Byerley, W, Shaw, SH, Mesen, A, Sherrington, R, O'Neill, FA, Walsh, D, Kendler, KS, Ekelund, J, Paunio, T, Lönnqvist, J, Peltonen, L, O'Donovan, MC, Owen, MJ, Wildenauer, DB, Maier, W, Nestadt, G, Blouin, JL, Antonarakis, SE, Mowry, BJ, Silverman, JM, Crowe, RR, Cloninger, CR, Tsuang, MT, Malaspina, D, Harkavy-Friedman, JM, Svrakic, DM, Bassett, AS, Holcomb, J, Kalsi, G, McQuillin, A, Brynjolfson, J, Sigmundsson, T, Petursson, H, Jazin, E, Zoëga, T & Helgason, T 2003, 'Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia', American journal of human genetics, vol. 73, no. 1, pp. 34-48. https://doi.org/10.1086/376549

@article{b6f08de8981f413aa17899d37e8a541e,

title = "Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia",

abstract = "Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size (√N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk < .000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord < .05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord < .05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.",

author = "Lewis, {Cathryn M.} and Levinson, {Douglas F.} and Wise, {Lesley H.} and DeLisi, {Lynn E.} and Straub, {Richard E.} and Iiris Hovatta and Williams, {Nigel M.} and Schwab, {Sibylle G.} and Pulver, {Ann E} and Faraone, {Stephen V.} and Brzustowicz, {Linda M.} and Kaufmann, {Charles A.} and Garver, {David L.} and Gurling, {Hugh M.D.} and Eva Lindholm and Hilary Coon and Moises, {Hans W.} and William Byerley and Shaw, {Sarah H.} and Andrea Mesen and Robin Sherrington and O'Neill, {F. Anthony} and Dermot Walsh and Kendler, {Kenneth S.} and Jesper Ekelund and Tiina Paunio and Jouko L{\"o}nnqvist and Leena Peltonen and O'Donovan, {Michael C.} and Owen, {Michael J.} and Wildenauer, {Dieter B.} and Wolfgang Maier and Gerald Nestadt and Blouin, {Jean Louis} and Antonarakis, {Stylianos E.} and Mowry, {Bryan J.} and Silverman, {Jeremy M.} and Crowe, {Raymond R.} and Cloninger, {C. Robert} and Tsuang, {Ming T.} and Dolores Malaspina and Harkavy-Friedman, {Jill M.} and Svrakic, {Dragan M.} and Bassett, {Anne S.} and Jennifer Holcomb and Gursharan Kalsi and Andrew McQuillin and Jon Brynjolfson and Thordur Sigmundsson and Hannes Petursson and Elena Jazin and Tomas Zo{\"e}ga and Tomas Helgason",

note = "Funding Information: This work was funded by NIMH grant R01-MH61602 (to D.F.L.). The genome scan projects were supported, in part, by NIMH grant R01-MH44245, Axys Pharmaceuticals and Schizophrenia A National Emergency (SANE) (support to L.E.D.); NIMH grants R01-MH45390 (to R.E.S.), R01-MH41953 (to K.S.K.), and R01-MH52537 (to C. J. MacLean); the Academy of Finland and the MacDonald Foundation, USA (support to L.P.); the Medical Research Council of the U.K. (support to M.J.O.); Deutsche Forschungsgemeinschaft grant SFB 400 and German-Israeli Foundation for Scientific Research (support to D.B.W.); NIMH grant R01-MH4558 and Novartis Pharmaceuticals (1995–1998) (support to A.E.P.); NIMH grants R01-MH45097, K02-01207, K24-MH64197 (to D.F.L.); National Health and Medical Research Council of Australia (NHMRC) grants 910234, 941087, and 971095, the Rebecca L. Cooper Medical Research Foundation, the Queensland Department of Health, and the NHMRC Network for Brain Research into Mental Disorders (support to B.J.M.); NIMH grants 1 R01-MH41874-01, 5 U01-MH46318, and 1 R37-MH43518 (to M.T.T.), U01-MH46289 and R01-MH44292 (to C.A.K.), and U01-MH46276 (to C.R.C.); the Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression (to C.A.K.); Millennium Pharmaceuticals, sponsored by Wyeth-Ayerst Pharmaceuticals (NIMH project); Canadian Institutes of Health Research grant MT-1225, the Ontario Mental Health Foundation, the Bill Jeffries Schizophrenia Endowment Fund, the Ian Douglas Bebensee Foundation (support to A.B.); NIMH grants K08-MH01392 and R01-MH62440, Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression, and the EJLB Foundation Scholar Research Programme (support to L.M.B.); the Center for Inherited Disease Research (Canada project); the Veterans Administration Merit Review award (to D.L.G.); MRC project grant G880473N, The European Science Foundation, SANE, the Iceland Department of Health, the General Hospital Reykjavik, the Joseph Levy Charitable Foundation, Wellcome Trust grant 055379, The Priory Hospital, the Neuroscience Research Charitable Trust, the University of Iceland and the Icelandic Science Council, and G{\'e}n{\'e}thon (Paris) (support to H.M.D.G.); Deutsche Forschungsgemeinschaft (support to H.W.M.); and NIMH grants R01-MH42643, K02-MH01089, and R01-MH56098 (to W.B.). The authors gratefully acknowledge the many additional collaborators who contributed to these projects. Finally we acknowledge the families without whose patience and assistance, in the face of the many burdens of coping with familial schizophrenia, progress in this field would be impossible. ",

year = "2003",

month = jul,

day = "1",

doi = "10.1086/376549",

language = "English (US)",

volume = "73",

pages = "34--48",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Genome scan meta-analysis of schizophrenia and bipolar disorder, part II

T2 - Schizophrenia

AU - Lewis, Cathryn M.

AU - Levinson, Douglas F.

AU - Wise, Lesley H.

AU - DeLisi, Lynn E.

AU - Straub, Richard E.

AU - Hovatta, Iiris

AU - Williams, Nigel M.

AU - Schwab, Sibylle G.

AU - Pulver, Ann E

AU - Faraone, Stephen V.

AU - Brzustowicz, Linda M.

AU - Kaufmann, Charles A.

AU - Garver, David L.

AU - Gurling, Hugh M.D.

AU - Lindholm, Eva

AU - Coon, Hilary

AU - Moises, Hans W.

AU - Byerley, William

AU - Shaw, Sarah H.

AU - Mesen, Andrea

AU - Sherrington, Robin

AU - O'Neill, F. Anthony

AU - Walsh, Dermot

AU - Kendler, Kenneth S.

AU - Ekelund, Jesper

AU - Paunio, Tiina

AU - Lönnqvist, Jouko

AU - Peltonen, Leena

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Wildenauer, Dieter B.

AU - Maier, Wolfgang

AU - Nestadt, Gerald

AU - Blouin, Jean Louis

AU - Antonarakis, Stylianos E.

AU - Mowry, Bryan J.

AU - Silverman, Jeremy M.

AU - Crowe, Raymond R.

AU - Cloninger, C. Robert

AU - Tsuang, Ming T.

AU - Malaspina, Dolores

AU - Harkavy-Friedman, Jill M.

AU - Svrakic, Dragan M.

AU - Bassett, Anne S.

AU - Holcomb, Jennifer

AU - Kalsi, Gursharan

AU - McQuillin, Andrew

AU - Brynjolfson, Jon

AU - Sigmundsson, Thordur

AU - Petursson, Hannes

AU - Jazin, Elena

AU - Zoëga, Tomas

AU - Helgason, Tomas

N1 - Funding Information: This work was funded by NIMH grant R01-MH61602 (to D.F.L.). The genome scan projects were supported, in part, by NIMH grant R01-MH44245, Axys Pharmaceuticals and Schizophrenia A National Emergency (SANE) (support to L.E.D.); NIMH grants R01-MH45390 (to R.E.S.), R01-MH41953 (to K.S.K.), and R01-MH52537 (to C. J. MacLean); the Academy of Finland and the MacDonald Foundation, USA (support to L.P.); the Medical Research Council of the U.K. (support to M.J.O.); Deutsche Forschungsgemeinschaft grant SFB 400 and German-Israeli Foundation for Scientific Research (support to D.B.W.); NIMH grant R01-MH4558 and Novartis Pharmaceuticals (1995–1998) (support to A.E.P.); NIMH grants R01-MH45097, K02-01207, K24-MH64197 (to D.F.L.); National Health and Medical Research Council of Australia (NHMRC) grants 910234, 941087, and 971095, the Rebecca L. Cooper Medical Research Foundation, the Queensland Department of Health, and the NHMRC Network for Brain Research into Mental Disorders (support to B.J.M.); NIMH grants 1 R01-MH41874-01, 5 U01-MH46318, and 1 R37-MH43518 (to M.T.T.), U01-MH46289 and R01-MH44292 (to C.A.K.), and U01-MH46276 (to C.R.C.); the Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression (to C.A.K.); Millennium Pharmaceuticals, sponsored by Wyeth-Ayerst Pharmaceuticals (NIMH project); Canadian Institutes of Health Research grant MT-1225, the Ontario Mental Health Foundation, the Bill Jeffries Schizophrenia Endowment Fund, the Ian Douglas Bebensee Foundation (support to A.B.); NIMH grants K08-MH01392 and R01-MH62440, Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression, and the EJLB Foundation Scholar Research Programme (support to L.M.B.); the Center for Inherited Disease Research (Canada project); the Veterans Administration Merit Review award (to D.L.G.); MRC project grant G880473N, The European Science Foundation, SANE, the Iceland Department of Health, the General Hospital Reykjavik, the Joseph Levy Charitable Foundation, Wellcome Trust grant 055379, The Priory Hospital, the Neuroscience Research Charitable Trust, the University of Iceland and the Icelandic Science Council, and Généthon (Paris) (support to H.M.D.G.); Deutsche Forschungsgemeinschaft (support to H.W.M.); and NIMH grants R01-MH42643, K02-MH01089, and R01-MH56098 (to W.B.). The authors gratefully acknowledge the many additional collaborators who contributed to these projects. Finally we acknowledge the families without whose patience and assistance, in the face of the many burdens of coping with familial schizophrenia, progress in this field would be impossible.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size (√N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk < .000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord < .05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord < .05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

AB - Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size (√N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk < .000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord < .05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord < .05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

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U2 - 10.1086/376549

DO - 10.1086/376549

M3 - Article

C2 - 12802786

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SN - 0002-9297

VL - 73

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EP - 48

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia

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