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, Ann 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 & 62 others G. R. Abecasis, B. Lerer, Daniele Daniele 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, Gerald 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 journalArticle

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 languageEnglish (US)
Pages (from-to)774-785
Number of pages12
JournalMolecular Psychiatry
Volume14
Issue number8
DOIs
StatePublished - Aug 2009

Fingerprint

Meta-Analysis
Schizophrenia
Genome
Chromosomes
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 1
Pedigree

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Ng, M. Y. M., Levinson, D. F., Faraone, S. V., Suarez, B. K., Delisi, L. E., Arinami, T., ... 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

Meta-analysis of 32 genome-wide linkage studies of schizophrenia. / Ng, M. Y M; Levinson, D. F.; Faraone, S. V.; Suarez, B. K.; Delisi, L. E.; Arinami, T.; Riley, B.; Paunio, T.; Pulver, Ann 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.; Garver, D. L.; Abecasis, G. R.; Lerer, B.; Fallin, Daniele Daniele; Gurling, H. M D; Gejman, P. V.; Lindholm, E.; Moises, H. W.; Byerley, W.; Wijsman, E. M.; Forabosco, P.; Tsuang, M. T.; Hwu, H. G.; Okazaki, Y.; Kendler, K. S.; Wormley, B.; Fanous, A.; Walsh, D.; O'Neill, F. A.; Peltonen, L.; Nestadt, Gerald; Lasseter, V. K.; Liang, K. Y.; Papadimitriou, G. M.; Dikeos, D. G.; Schwab, S. G.; Owen, M. J.; O'Donovan, M. C.; Norton, N.; Hare, E.; Raventos, H.; Nicolini, H.; Albus, M.; Maier, W.; Nimgaonkar, V. L.; Terenius, L.; Mallet, J.; Jay, M.; Godard, S.; Nertney, D.; Alexander, M.; Crowe, R. R.; Silverman, J. M.; Bassett, A. S.; Roy, M. A.; Mérette, C.; Pato, C. N.; Pato, M. T.; Roos, J. Louw; Kohn, Y.; Amann-Zalcenstein, D.; Kalsi, G.; McQuillin, A.; Curtis, D.; Brynjolfson, J.; Sigmundsson, T.; Petursson, H.; Sanders, A. R.; Duan, J.; Jazin, E.; Myles-Worsley, M.; Karayiorgou, M.; Lewis, C. M.

In: Molecular Psychiatry, Vol. 14, No. 8, 08.2009, p. 774-785.

Research output: Contribution to journalArticle

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, DD, 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
Ng MYM, Levinson DF, Faraone SV, Suarez BK, Delisi LE, Arinami T et al. Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Molecular Psychiatry. 2009 Aug;14(8):774-785. https://doi.org/10.1038/mp.2008.135
Ng, M. Y M ; Levinson, D. F. ; Faraone, S. V. ; Suarez, B. K. ; Delisi, L. E. ; Arinami, T. ; Riley, B. ; Paunio, T. ; Pulver, Ann 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. ; Garver, D. L. ; Abecasis, G. R. ; Lerer, B. ; Fallin, Daniele Daniele ; Gurling, H. M D ; Gejman, P. V. ; Lindholm, E. ; Moises, H. W. ; Byerley, W. ; Wijsman, E. M. ; Forabosco, P. ; Tsuang, M. T. ; Hwu, H. G. ; Okazaki, Y. ; Kendler, K. S. ; Wormley, B. ; Fanous, A. ; Walsh, D. ; O'Neill, F. A. ; Peltonen, L. ; Nestadt, Gerald ; Lasseter, V. K. ; Liang, K. Y. ; Papadimitriou, G. M. ; Dikeos, D. G. ; Schwab, S. G. ; Owen, M. J. ; O'Donovan, M. C. ; Norton, N. ; Hare, E. ; Raventos, H. ; Nicolini, H. ; Albus, M. ; Maier, W. ; Nimgaonkar, V. L. ; Terenius, L. ; Mallet, J. ; Jay, M. ; Godard, S. ; Nertney, D. ; Alexander, M. ; Crowe, R. R. ; Silverman, J. M. ; Bassett, A. S. ; Roy, M. A. ; Mérette, C. ; Pato, C. N. ; Pato, M. T. ; Roos, J. Louw ; Kohn, Y. ; Amann-Zalcenstein, D. ; Kalsi, G. ; McQuillin, A. ; Curtis, D. ; Brynjolfson, J. ; Sigmundsson, T. ; Petursson, H. ; Sanders, A. R. ; Duan, J. ; Jazin, E. ; Myles-Worsley, M. ; Karayiorgou, M. ; Lewis, C. M. / Meta-analysis of 32 genome-wide linkage studies of schizophrenia. In: Molecular Psychiatry. 2009 ; Vol. 14, No. 8. pp. 774-785.
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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.",
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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, Ann 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, Daniele Daniele

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, Gerald

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.

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

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