Evaluation of a susceptibility gene for schizophrenia

Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples

Michael E. Talkowski, Howard Seltman, Anne S. Bassett, Linda M. Brzustowicz, Xiangning Chen, Kodavali V. Chowdari, David A. Collier, Quirino Cordeiro, Aiden P. Corvin, Smita N. Deshpande, Michael F. Egan, Michael Gill, Kenneth S. Kendler, George Kirov, Leonard L. Heston, Pat Levitt, David A. Lewis, Tao Li, Karoly Mimics, Derek W. Morris & 16 others Nadine Norton, Michael C. O'Donovan, Michael J. Owen, Christian Richard, Prachi Semwal, Janet L. Sobell, David Malcolm St Clair, Richard E. Straub, B. K. Thelma, Homero Vallada, Daniel R. Weinberger, Nigel M. Williams, Joel Wood, Feng Zhang, Bernie Devlin, Vishwajit L. Nimgaonkar

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background. Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotidepolymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles.
Methods: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).
Results: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations.
Conclusions. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Original languageEnglish
Pages (from-to)152-162
Number of pages11
JournalBiological Psychiatry
Volume60
Issue number2
Early online date21 Apr 2006
DOIs
Publication statusPublished - 15 Jul 2006

Keywords

  • rGS4
  • schizophrenia
  • meta-analysis
  • association
  • polymorphism
  • linkage
  • family-based association
  • at-risk haplotype
  • transmission/disequilibrium test
  • linkage analysis
  • dysbindin gene
  • receptor
  • neuregulin-1 gene
  • ser9gly variant
  • no association
  • 6P22.3 gene

Cite this

Talkowski, M. E., Seltman, H., Bassett, A. S., Brzustowicz, L. M., Chen, X., Chowdari, K. V., ... Nimgaonkar, V. L. (2006). Evaluation of a susceptibility gene for schizophrenia: Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. Biological Psychiatry, 60(2), 152-162. https://doi.org/10.1016/j.biopsych.2006.02.015

Evaluation of a susceptibility gene for schizophrenia : Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. / Talkowski, Michael E.; Seltman, Howard; Bassett, Anne S.; Brzustowicz, Linda M.; Chen, Xiangning; Chowdari, Kodavali V.; Collier, David A.; Cordeiro, Quirino; Corvin, Aiden P.; Deshpande, Smita N.; Egan, Michael F.; Gill, Michael; Kendler, Kenneth S.; Kirov, George; Heston, Leonard L.; Levitt, Pat; Lewis, David A.; Li, Tao; Mimics, Karoly; Morris, Derek W.; Norton, Nadine; O'Donovan, Michael C.; Owen, Michael J.; Richard, Christian; Semwal, Prachi; Sobell, Janet L.; St Clair, David Malcolm; Straub, Richard E.; Thelma, B. K.; Vallada, Homero; Weinberger, Daniel R.; Williams, Nigel M.; Wood, Joel; Zhang, Feng; Devlin, Bernie; Nimgaonkar, Vishwajit L.

In: Biological Psychiatry, Vol. 60, No. 2, 15.07.2006, p. 152-162.

Research output: Contribution to journalArticle

Talkowski, ME, Seltman, H, Bassett, AS, Brzustowicz, LM, Chen, X, Chowdari, KV, Collier, DA, Cordeiro, Q, Corvin, AP, Deshpande, SN, Egan, MF, Gill, M, Kendler, KS, Kirov, G, Heston, LL, Levitt, P, Lewis, DA, Li, T, Mimics, K, Morris, DW, Norton, N, O'Donovan, MC, Owen, MJ, Richard, C, Semwal, P, Sobell, JL, St Clair, DM, Straub, RE, Thelma, BK, Vallada, H, Weinberger, DR, Williams, NM, Wood, J, Zhang, F, Devlin, B & Nimgaonkar, VL 2006, 'Evaluation of a susceptibility gene for schizophrenia: Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples', Biological Psychiatry, vol. 60, no. 2, pp. 152-162. https://doi.org/10.1016/j.biopsych.2006.02.015
Talkowski, Michael E. ; Seltman, Howard ; Bassett, Anne S. ; Brzustowicz, Linda M. ; Chen, Xiangning ; Chowdari, Kodavali V. ; Collier, David A. ; Cordeiro, Quirino ; Corvin, Aiden P. ; Deshpande, Smita N. ; Egan, Michael F. ; Gill, Michael ; Kendler, Kenneth S. ; Kirov, George ; Heston, Leonard L. ; Levitt, Pat ; Lewis, David A. ; Li, Tao ; Mimics, Karoly ; Morris, Derek W. ; Norton, Nadine ; O'Donovan, Michael C. ; Owen, Michael J. ; Richard, Christian ; Semwal, Prachi ; Sobell, Janet L. ; St Clair, David Malcolm ; Straub, Richard E. ; Thelma, B. K. ; Vallada, Homero ; Weinberger, Daniel R. ; Williams, Nigel M. ; Wood, Joel ; Zhang, Feng ; Devlin, Bernie ; Nimgaonkar, Vishwajit L. / Evaluation of a susceptibility gene for schizophrenia : Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. In: Biological Psychiatry. 2006 ; Vol. 60, No. 2. pp. 152-162.
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abstract = "Background. Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotidepolymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. Methods: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). Results: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Conclusions. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.",
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T1 - Evaluation of a susceptibility gene for schizophrenia

T2 - Genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples

AU - Talkowski, Michael E.

AU - Seltman, Howard

AU - Bassett, Anne S.

AU - Brzustowicz, Linda M.

AU - Chen, Xiangning

AU - Chowdari, Kodavali V.

AU - Collier, David A.

AU - Cordeiro, Quirino

AU - Corvin, Aiden P.

AU - Deshpande, Smita N.

AU - Egan, Michael F.

AU - Gill, Michael

AU - Kendler, Kenneth S.

AU - Kirov, George

AU - Heston, Leonard L.

AU - Levitt, Pat

AU - Lewis, David A.

AU - Li, Tao

AU - Mimics, Karoly

AU - Morris, Derek W.

AU - Norton, Nadine

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Richard, Christian

AU - Semwal, Prachi

AU - Sobell, Janet L.

AU - St Clair, David Malcolm

AU - Straub, Richard E.

AU - Thelma, B. K.

AU - Vallada, Homero

AU - Weinberger, Daniel R.

AU - Williams, Nigel M.

AU - Wood, Joel

AU - Zhang, Feng

AU - Devlin, Bernie

AU - Nimgaonkar, Vishwajit L.

PY - 2006/7/15

Y1 - 2006/7/15

N2 - Background. Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotidepolymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. Methods: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). Results: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Conclusions. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

AB - Background. Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotidepolymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. Methods: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). Results: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Conclusions. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

KW - rGS4

KW - schizophrenia

KW - meta-analysis

KW - association

KW - polymorphism

KW - linkage

KW - family-based association

KW - at-risk haplotype

KW - transmission/disequilibrium test

KW - linkage analysis

KW - dysbindin gene

KW - receptor

KW - neuregulin-1 gene

KW - ser9gly variant

KW - no association

KW - 6P22.3 gene

U2 - 10.1016/j.biopsych.2006.02.015

DO - 10.1016/j.biopsych.2006.02.015

M3 - Article

VL - 60

SP - 152

EP - 162

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 2

ER -