Association study of Wnt signaling pathway genes in bipolar disorder

Peter P. Zandi, Pamela L. Belmonte, Virginia L. Willour, Fernando S. Goes, Judith A. Badner, Sylvia G. Simpson, Elliot S. Gershon, Francis J. McMahon, J. Raymond DePaulo, James B. Potash, J. Steele, J. Pearl, L. Kassem, V. Lopez, D. MacKinnon, E. Miller, J. Toolan, T. Schulze, William Byerley, William CoryellJohn Kelsoe, John Rice, John Nurnberger

Research output: Contribution to journalArticle

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Abstract

Context: The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. Objective: To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. Design: Two hundred twenty-seven tagging single-nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. Setting: Nine academic medical centers in the United States. Participants: Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. Main Outcome Measures: Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/∼fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). Results: In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P<.001). This remained significant at P=.05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P<.01), the most significant being rs9462082 (P<.001). Exploratory analyses revealed significant evidence (P<.01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63). Conclusions: We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments. copy;2008 American Medical Association, All rights reserved.

Original languageEnglish
Pages (from-to)785-793
Number of pages9
JournalArchives of General Psychiatry
Volume65
Issue number7
DOIs
StatePublished - Jul 2008

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Wnt Signaling Pathway
Bipolar Disorder
Single Nucleotide Polymorphism
Genes
Odds Ratio
Confidence Intervals
Public Health Schools
Disease Susceptibility
American Medical Association
Haplotypes
Embryonic Development
Outcome Assessment (Health Care)
Growth

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Zandi, P. P., Belmonte, P. L., Willour, V. L., Goes, F. S., Badner, J. A., Simpson, S. G., ... Nurnberger, J. (2008). Association study of Wnt signaling pathway genes in bipolar disorder. Archives of General Psychiatry, 65(7), 785-793. https://doi.org/10.1001/archpsyc.65.7.785

Association study of Wnt signaling pathway genes in bipolar disorder. / Zandi, Peter P.; Belmonte, Pamela L.; Willour, Virginia L.; Goes, Fernando S.; Badner, Judith A.; Simpson, Sylvia G.; Gershon, Elliot S.; McMahon, Francis J.; DePaulo, J. Raymond; Potash, James B.; Steele, J.; Pearl, J.; Kassem, L.; Lopez, V.; MacKinnon, D.; Miller, E.; Toolan, J.; Schulze, T.; Byerley, William; Coryell, William; Kelsoe, John; Rice, John; Nurnberger, John.

In: Archives of General Psychiatry, Vol. 65, No. 7, 07.2008, p. 785-793.

Research output: Contribution to journalArticle

Zandi, PP, Belmonte, PL, Willour, VL, Goes, FS, Badner, JA, Simpson, SG, Gershon, ES, McMahon, FJ, DePaulo, JR, Potash, JB, Steele, J, Pearl, J, Kassem, L, Lopez, V, MacKinnon, D, Miller, E, Toolan, J, Schulze, T, Byerley, W, Coryell, W, Kelsoe, J, Rice, J & Nurnberger, J 2008, 'Association study of Wnt signaling pathway genes in bipolar disorder', Archives of General Psychiatry, vol. 65, no. 7, pp. 785-793. https://doi.org/10.1001/archpsyc.65.7.785
Zandi PP, Belmonte PL, Willour VL, Goes FS, Badner JA, Simpson SG et al. Association study of Wnt signaling pathway genes in bipolar disorder. Archives of General Psychiatry. 2008 Jul;65(7):785-793. https://doi.org/10.1001/archpsyc.65.7.785
Zandi, Peter P. ; Belmonte, Pamela L. ; Willour, Virginia L. ; Goes, Fernando S. ; Badner, Judith A. ; Simpson, Sylvia G. ; Gershon, Elliot S. ; McMahon, Francis J. ; DePaulo, J. Raymond ; Potash, James B. ; Steele, J. ; Pearl, J. ; Kassem, L. ; Lopez, V. ; MacKinnon, D. ; Miller, E. ; Toolan, J. ; Schulze, T. ; Byerley, William ; Coryell, William ; Kelsoe, John ; Rice, John ; Nurnberger, John. / Association study of Wnt signaling pathway genes in bipolar disorder. In: Archives of General Psychiatry. 2008 ; Vol. 65, No. 7. pp. 785-793.
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abstract = "Context: The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. Objective: To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. Design: Two hundred twenty-seven tagging single-nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. Setting: Nine academic medical centers in the United States. Participants: Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. Main Outcome Measures: Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/∼fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). Results: In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P<.001). This remained significant at P=.05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P<.01), the most significant being rs9462082 (P<.001). Exploratory analyses revealed significant evidence (P<.01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95{\%} confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95{\%} CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95{\%} CI, 1.23-2.63). Conclusions: We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments. copy;2008 American Medical Association, All rights reserved.",
author = "Zandi, {Peter P.} and Belmonte, {Pamela L.} and Willour, {Virginia L.} and Goes, {Fernando S.} and Badner, {Judith A.} and Simpson, {Sylvia G.} and Gershon, {Elliot S.} and McMahon, {Francis J.} and DePaulo, {J. Raymond} and Potash, {James B.} and J. Steele and J. Pearl and L. Kassem and V. Lopez and D. MacKinnon and E. Miller and J. Toolan and T. Schulze and William Byerley and William Coryell and John Kelsoe and John Rice and John Nurnberger",
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T1 - Association study of Wnt signaling pathway genes in bipolar disorder

AU - Zandi, Peter P.

AU - Belmonte, Pamela L.

AU - Willour, Virginia L.

AU - Goes, Fernando S.

AU - Badner, Judith A.

AU - Simpson, Sylvia G.

AU - Gershon, Elliot S.

AU - McMahon, Francis J.

AU - DePaulo, J. Raymond

AU - Potash, James B.

AU - Steele, J.

AU - Pearl, J.

AU - Kassem, L.

AU - Lopez, V.

AU - MacKinnon, D.

AU - Miller, E.

AU - Toolan, J.

AU - Schulze, T.

AU - Byerley, William

AU - Coryell, William

AU - Kelsoe, John

AU - Rice, John

AU - Nurnberger, John

PY - 2008/7

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N2 - Context: The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. Objective: To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. Design: Two hundred twenty-seven tagging single-nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. Setting: Nine academic medical centers in the United States. Participants: Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. Main Outcome Measures: Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/∼fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). Results: In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P<.001). This remained significant at P=.05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P<.01), the most significant being rs9462082 (P<.001). Exploratory analyses revealed significant evidence (P<.01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63). Conclusions: We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments. copy;2008 American Medical Association, All rights reserved.

AB - Context: The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. Objective: To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. Design: Two hundred twenty-seven tagging single-nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. Setting: Nine academic medical centers in the United States. Participants: Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. Main Outcome Measures: Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/∼fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). Results: In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P<.001). This remained significant at P=.05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P<.01), the most significant being rs9462082 (P<.001). Exploratory analyses revealed significant evidence (P<.01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63). Conclusions: We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments. copy;2008 American Medical Association, All rights reserved.

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