Genetic Evidence Reveals Clues to Roots of Bipolar Disorder

Genetic epidemiologist Peter Zandi, Ph.D., M.P.H., M.H.S., has a roadmap to the truth, but the truth is playing awfully hard to get.

Zandi, an assistant professor in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health, is one of many researchers around the world trying to identify the specific common genetic variations that underlie the propensity of bipolar disorder to run in families.

“Bipolar disorder shows much etiological and clinical heterogeneity,” said Zandi in an interview. “It presents with a variety of clinical features and comorbidities, and that probably reflects some genetic heterogeneity.” Now, he and colleagues from other institutions have published a study of genes that act on a cellular pathway known to be involved in the origins and treatment of bipolar disorder.

Their most recent efforts, published in the July Archives of General Psychiatry, not only represent another step along the path to understanding the genetics underlying mental illness, but also shed light on the routes researchers choose for the journey and how far they have to go. The research was supported by the National Institute of Mental Health and several private foundations.

“We started with the hypothesis that certain genes may be relevant to bipolar disorder and focused on them,” said Zandi. These 34 candidate genes are associated with the Wnt signaling pathways. All genes are expressed in the brain and are located in chromosomal regions associated with bipolar disorder or schizophrenia in previous genetic linkage studies.

“We looked for genes that encode for proteins that might be important in this pathway to see if variations may be related to susceptibility in developing bipolar disorder,” said Zandi.

Wnt proteins are found in species ranging from Drosophila to humans. They are involved in intracellular signaling pathways and in development. Several lines of research have associated Wnt proteins with bipolar disorder. For one thing, they play important roles in neuroplasticity, cell survival, and adult neurogenesis, impairments that seem related to bipolar disorder. Also, monozygotic twins discordant for bipolar disorder express Wnt signaling pathway genes differentially.

Drugs used to treat bipolar disorder interact with the Wnt pathway as well.

Lithium inhibits the enzyme GSk-3β, a critical part of the Wnt pathway, explained Todd Gould, M.D., an assistant professor of psychiatry at the University of Maryland School of Medicine in Baltimore, in an interview. That association became stronger recently when researchers found that other inhibitors of GSk-3β mimicked lithium's action and that raising levels of GSk-3β reversed lithium's effects.

“Since then, we've seen more biological evidence not only that lithium inhibits GSk-3β and activates Wnt pathways, but also that these pathways respond to valproate, antipsychotics, and some antidepressants,” said Gould, who was not involved in Zandi's study. These associations have already drawn early interest from drug companies, he said.

Zandi's consortium of researchers recruited 317 families from three ongoing projects: the National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Consortium; a collaboration among the University of Chicago, Johns Hopkins University, and the NIMH Intramural Program; and the Clinical Neurogenetics collection. There were 1,118 participants, comprising 237 quads (two parents with two affected offspring) and 80 trios (two parents with one affected offspring).

They found that the single nucleotide polymorphism (SNP) producing the most significant response lay in the gene PPARD, located on chromosome 6p21. PPARD is expressed at high levels in the embryonic brain and thus may play a part in differentiating cells during neurodevelopment, wrote the authors. Furthermore, this SNP closely matched the response of another SNP identified in the bipolar cohort of the Wellcome Trust Case-Control Consortium Genome-Wide Association Study. Further genotyping of 13 additional tagging SNPs found four that were significantly associated with bipolar disorder, all lying in a single haplotype block on the gene.

“We then wanted to see if the variations in the SNPs matched clinical features of the disease,” said Zandi. The two best SNPs in the PPARD gene were significantly linked to the illness with an odds ratio of 1.46. However, that risk rose to an odds ratio of 3.36 in participants with poor functioning, as measured on the GAS scale.

“The increased evidence of association for PPARD among those with poor functioning is consistent with a potential role for Wnt dysfunction in severe bipolar disorder,” wrote Zandi and colleagues.

“We knew that worse functioning aggregated in families with bipolar disorder, so our findings bolster the thinking that functioning may be tied to genes,” he said.

Their findings suggest that several changes along the main Wnt pathway are needed to significantly influence susceptibility to bipolar disorder, given that it is a genetically complex disease.

“I'm excited to see this paper,” said Gould. “It's the best genetic evidence in humans linking Wnt to bipolar disorder.”

Genome-wide studies will be useful as Zandi and other researchers try to replicate these findings.

The candidate-gene approach depends on picking the right candidates but may miss a disease-related SNP elsewhere. Genome-wide association studies look for genetic origins of disease from another direction.

“You're not looking at specific genetic variants in candidates,” said Zandi. “Rather, you test throughout the genome, unconstrained by any prior hypothesis.”

Both approaches will be needed to delineate the multigenetic origins of complex diseases like bipolar disorder.

“We don't know a lot about the underlying neurobiology of bipolar, so there may be genes we don't know about or won't find through candidate studies like this,” said Gould. “But it is also important to interrogate genes with the candidate approach.”

An abstract of “Association Study of Wnt Signaling Pathway Genes in Bipolar Disorder” is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/65/7/785>.▪