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Mapping genes for Bipolar Disorder

The primary focus of the lab is positional cloning studies of bipolar disorder. By examining the pattern of transmission of DNA markers in families with the illness we hope to identify genomic regions that contain susceptibility genes. This strategy, termed genetic linkage, has led to the identification of several chromosomal regions that may contain genes. We have collected over 400 families with bipolar disorder for this work. These families were collected primarily as part of two collaborations.

UCSD, UBC, U. Cincinnati families

We have previously coordinated a collaboration between UCSD, the University of British Columbia and the University of Cincinnati. Together, at these three sites over 200 families were studied. We are currently conducting a genome survey of 52 of these families. Several years ago we completed a genome survey of the first 20 of these families. This identified two distinct regions on chromosome 22 as containing genes for bipolar disorder. It also provided confirmation of several other regions reportedly linked to bipolar disorder including 13q, 10p, 16p and 21q.

NIMH Consortium for the Genetics of Bipolar Disorder

Over the past four years the lab has been a collaborator in an eight-site consortium to collect affected sib pairs with bipolar disorder for genetic linkage studies. This consortium has been sponsored by NIMH and just completed the collection of over 700 families with bipolar disorder. This is the largest such collection ever assembled and will have great power for mapping genes. Already two novel regions have been identified on 6q and 17.

Some specific genes and regions we are studying

G protein receptor kinase 3 (GRK3)

This is one of our most interesting and exciting results. This gene regulates the efficiency of synaptic transmission by mediating the process of homologous desensitization. When a receptor is stimulated by a neurotransmitter at high levels or for a prolonged period of time, it rapidly becomes less sensitive to that neurotransmitter as part of the systems adaptation. This is mediated in part by the GRK3 genes whose expression is turned on under such circumstances. The protein then migrates to the cell surface where it phosphorylates the receptor. As indicated by its name, this occurs only for G protein coupled receptors (GPCR), but GPCR's comprise the majority of receptors in the brain. When the GPCR is phosphorylated, it undergoes a conformational change that facilitates the binding of another protein arrestin. The binding of this protein causes the GPCR to be decoupled from the G protein complex thereby reducing its efficiency of signal transduction. Subsequently, it also triggers the removal of the receptor from the cell surface by endocytosis.

This gene was first implicated by our genome survey of our first 20 families. In this study, we found evidence for linkage spanning about 15 Mb on chromosome 22q. There appeared to be two distinct peaks one at 22q11 and one at 22q11. At that time, this work was dramatically aided by the Sanger Centre publishing the complete sequence of chromosome 22. The 22q11 peak turned out to be exactly at the GRK3 locus. Thanks to Richard Hauger in our department for first raising the idea that the GRK genes would make excellent candidate genes for bipolar disorder.

Support for GRK3 also came from an independent direction. We have for some time been using amphetamine administration in rats as an animal model for bipolar disorder. We gave a single dose of methamphetamine to rats and then examined the expression of 8,000 genes in prefrontal cortex and amygdala using Affymetrix GeneChips. Out of all these genes, the one with the highest increase in expression in response to amphetamine was (to our great surprise) GRK3! This was an amazing shocker to us at the time. One of those extraordinary and exciting moments of discovery in science that don't come along too often. These results indicated that not only did GRK3 map to the right position in our linkage studies, but its function was also central to the response to amphetamine and our model of mania. This work was done by Bob Niculescu in our lab. He was also central in developing the idea of convergent functional genomics.

Further stronger evidence for the role of GRK3 in bipolar disorder came from experiments conducted by Tom Barrett in the lab. Tom identified families with the strongest evidence of linkage to the GRK3 locus who would be most likely to be transmitting a mutation in the GRK3 gene. He then sequenced much of the gene in an effort to find disease causing mutations or just anonymous markers. This was a big job! He sequenced all coding regions and most of the non-coding regions. He found no coding sequence variants, but he did find six sequence variants in the promoter of the gene. These SNPs were in such a position so as to possibly influence the regulation of when the gene was turned on and off. Tom then examined these SNPs in about 150 families from the UCSD/UBC/UC  and NIMH sets using the transmission disequilibrium test (TDT). This analysis indicated genetic association to two of these SNPs. We were then fortunate to be able to collaborate with Jim Kennedy at the U. of Toronto and to study another set of 250 triad families with bipolar disorder. Our results for one of the SNPs (P-5) was replicated in this sample!

Together these data argue that a regulatory mutation in or near the GRK3 promoter causes this gene to fail to be expressed when dopamine stimulates receptors in the brain. These receptors then fail to be desensitized in the normal fashion. This results in an effective supersensitivity to dopamine. This is exciting because post-synaptic dopamine receptor supersensitivity has been hypothesized for many decades based on many other lines of research. We are now working on definitively identifying the functional mutation and proving that it affects transcriptional regulation. We also want to replicate our results again in a larger sample. 

The dopamine transporter (DAT)

22q13

Bipolar disorder and MCKD

Temperament and other quantitative traits in bipolar disorder

Genetic predictors of longitudinal outcome and treatment response in mood disorders

Animal Models of Mania and Psychosis

Under construction!