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 Jr; James B Potash

doi:10.1001/archpsyc.65.7.785

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Association study of Wnt signaling pathway genes in bipolar disorder

Journal article

Open access

Peer reviewed

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 Jr and James B Potash

Archives of general psychiatry, Vol.65(7), pp.785-793

07/2008

DOI: 10.1001/archpsyc.65.7.785

PMCID: PMC3170992

PMID: 18606951

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Abstract

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. To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. 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. Nine academic medical centers in the United States. Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. 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). 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). 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.

Glycoproteins - genetics

Haplotypes

Diagnostic and Statistical Manual of Mental Disorders

Follow-Up Studies

Humans

Genotype

Signal Transduction - genetics

Bipolar Disorder - diagnosis

Bipolar Disorder - genetics

Chromosomes, Human, Pair 6 - genetics

Wnt Proteins - genetics

Polymorphism, Single Nucleotide - genetics

Wnt3 Protein

PPAR delta - genetics

Details

Title: Subtitle: Association study of Wnt signaling pathway genes in bipolar disorder
Creators: Peter P Zandi - Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Hampton House, Room 857, 624 N Broadway, Baltimore, MD 21205, USA. pzandi@jhsph.edu
Pamela L Belmonte
Virginia L Willour
Fernando S Goes
Judith A Badner
Sylvia G Simpson
Elliot S Gershon
Francis J McMahon
J Raymond Depaulo Jr
James B Potash
Resource Type: Journal article
Publication Details: Archives of general psychiatry, Vol.65(7), pp.785-793
DOI: 10.1001/archpsyc.65.7.785
PMID: 18606951
PMCID: PMC3170992
NLM abbreviation: Arch Gen Psychiatry
ISSN: 0003-990X
eISSN: 1538-3636
Publisher: American Medical Association; United States
Grant note: K01 MH072866 / NIMH NIH HHS R01 MH059535 / NIMH NIH HHS R01 MH059556 / NIMH NIH HHS Z01 MH002810 / Intramural NIH HHS R01 MH-042243 / NIMH NIH HHS K01 MH072866-01 / NIMH NIH HHS R01 MH059545 / NIMH NIH HHS R01 MH059533 / NIMH NIH HHS R01 MH059548 / NIMH NIH HHS K01 MH-072866 / NIMH NIH HHS R01 MH061613 / NIMH NIH HHS R01 MH059534 / NIMH NIH HHS R01 MH-061613 / NIMH NIH HHS R01 MH059553 / NIMH NIH HHS R01 MH042243 / NIMH NIH HHS R01 MH060068 / NIMH NIH HHS R01 MH059567 / NIMH NIH HHS
Language: English
Date published: 07/2008
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984070263602771

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