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Association Study of Wnt Signaling Pathway Genes in Bipolar Disorder
Peter P. Zandi, PhD, MHS;
Pamela L. Belmonte, PhD;
Virginia L. Willour, PhD;
Fernando S. Goes, MD;
Judith A. Badner, MD, PhD;
Sylvia G. Simpson, MD;
Elliot S. Gershon, MD;
Francis J. McMahon, MD;
J. Raymond DePaulo Jr, MD;
James B. Potash, MD;
Bipolar Disorder Phenome Group; National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium*
Arch Gen Psychiatry. 2008;65(7):785-793.
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.
Author Affiliations: Department of Mental Health, Johns Hopkins School of Public Health (Dr Zandi) and Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine (Drs Belmonte, Willour, Goes, DePaulo, and Potash), Baltimore, Maryland; Department of Psychiatry, University of Chicago, Chicago, Illinois (Drs Badner and Gershon); Department of Psychiatry, University of Colorado Health Sciences Center, Denver (Dr Simpson); and Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland (Dr McMahon).
*Authors/Group Information: The following members of the Bipolar Phenome Group take authorship responsibility: J. Steele , J. Pearl , L. Kassem , and V. Lopez , Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, NIMH, National Institutes of Health, Bethesda, Maryland; D. MacKinnon , E. Miller , and J. Toolan , Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland; and T. Schulze , Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany (Drs Zandi, Simpson, McMahon, and Potash are also members of this group). The following members of the NIMH Genetics Initiative Bipolar Disorder Consortium take authorship responsibility: William Byerley, MD , University of California–San Francisco, San Francisco; William Coryell, MD , University of Iowa, Iowa City; John Kelsoe, MD , University of California–Davis, Davis; John Rice, PhD , Washington University at St Louis, St Louis, Missouri; and John Nurnberger, MD, PhD , Indiana University, Indianapolis.
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