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Candidate Genes, Pathways and Mechanisms for Bipolar (Manic–Depressive) and Related Disorders: an Expanded Convergent Function

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Candidate Genes, Pathways and Mechanisms for Bipolar (Manic–Depressive) and Related Disorders: an Expanded Convergent Function Molecular Psychiatry (2004), 1007–1029 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $30.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Candidate genes, pathways and mechanisms for bipolar (manic–depressive) and related disorders: an expanded convergent functional genomics approach CA Ogden1,2,3, ME Rich1,2,3, NJ Schork2, MP Paulus2,3, MA Geyer2,3, JB Lohr2,3, R Kuczenski2,3 and AB Niculescu1,2,3 1Laboratory of Neurophenomics, University of California, San Diego, CA, USA; 2Department of Psychiatry, University of California, San Diego, CA, USA; 3VA San Diego Healthcare System VISN-22 MIRECC, San Diego, CA, USA Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant—methamphetamine, and a mood stabilizer—valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neuro- trophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology. Molecular Psychiatry (2004) 9, 1007–1029. doi:10.1038/sj.mp.4001547 Published online 17 August 2004 Keywords: bipolar; microarray; convergent functional genomics; methamphetamine; valproate; pain Bipolar (manic–depressive) disorders are character- there has been limited success so far in terms of ized by alternating episodes of elevated and de- reproducible findings. The linkage peaks supported pressed mood. Severe episodes have psychotic by the most recent meta-analyses of genome scan features similar to some of the symptoms of schizo- data4,5 are fairly broad, with hundreds of genes in phrenia, that is, positive psychotic symptoms (hallu- each peak. A method of prioritizing candidate genes cinations, delusions) in mania, and negative for individual analysis of association with illness is psychotic symptoms (lack of motivation, psychomo- critical. We have previously described initial proof of tor retardation) in depression. The genetic basis of principle for one such approach that we have termed bipolar disorder and schizophrenia are well docu- Convergent Functional Genomics.6 The approach mented, with an incidence of about 1% in the general integrates gene expression data from a relevant population. Having a first-degree relative with the animal model with human linkage data, as a way of illness increases the likelihood of developing the crossvalidating findings and coming up with a short illness by about 10-fold. Traditionally, linkage analy- list of high-probability candidate genes that deserve sis and positional cloning approaches have been used individual scrutiny in a prioritized manner. Here, we to try to identify the genes involved. This has led to report the first comprehensive analysis using an the identification of a series of loci in the genome that expanded Convergent Functional Genomics approach exhibit linkage with the illness. Several of these loci as a way of unraveling the genetic code of bipolar and are identified in both bipolar disorder and schizo- related disorders. phrenia studies, suggesting the possibility of shared Single-dose methamphetamine treatment in hu- genes between these disorders.1–3 As these disorders mans and animals mimics many of the behavioral are likely polygenic, non-Mendelian with variable signs and symptoms of bipolar disorder—mania penetrance, and the clinical phenotypes are complex, features during the activation phase (elevated mood, increased energy, hyperlocomotion, perseverative behavior, hypersexuality), and depressive features Correspondence: Dr AB Niculescu III, MD, PhD. Current address: during the withdrawal phase (low mood, low energy, Institute of Psychiatric Research, Department of Psychiatry, decreased locomotion, passivity, anhedonia)6–12 Indiana University School of Medicine, 791 Union Dr., Indiana- (Figure 1a). Amphetamine challenge led to a signifi- polis, IN 46202-4887, USA. E-mail: [email protected] Received 26 February 2004; revised 25 May 2004; accepted 26 cantly greater behavioral response in euthymic bipo- May 2004 lar disorder patients than in healthy subjects,13 Candidate genes and mechanisms for bipolar disorders CA Ogden et al 1008 a b Positive psychotic symptoms Reproducible Genes Chipping M e t t Mania h n a e m m V t p a h a e l Pooling e p r t t r a o e m a n t i e i n m e t r a e w t a e i t t m h h 6 independent p d e 2 mice 2 mice 2 mice 2 mice 2 mice 2 mice n r m de novo a t a w h biological t a e l M experiments Depression 2 mice / treatment / experiment Negative psychotic symptoms cd Internal Lines External Lines of Evidence of Evidence Methamphetamine Valproate II Reproducibly Changed Reproducibly Changed Meth AND Human IV IV Valproate Genetic I Responsive (1) Linkage (4) III III Co-Treatment Reproducibly No Change Gene Stopped By expression Human Post- Co- changes from Mortem Treatment (2) target brain evidence (5) regions I. Overlap between Methamphetamine Changed, Valproate Changed genes, and No Change in Co-Treatment experiments II. Overlap between Methamphetamine Changed and Valproate Changed Genes III. Methamphetamine Changed or Valproate Changed Genes and No Change in CoTreatment experiments IV. Methamphetamine Changed or Valproate Changed Genes Changed in more Biologically than one target relevant (6) brain region (3) Figure 1 Design of experiments and data analysis: (a) pharmacological treatment paradigm, (b) experimental design, (c) Venn diagram categorizing genes changed by the various drug treatments, and their classification into Categories I–IV, (d) multiple converging independent internal and external lines of evidence for crossvalidation of findings. suggesting that amphetamines act on at least some of sion in response to either of the drugs are necessarily the pathways involved in bipolar disorder. germane to the pathophysiology of bipolar and related Valproate, an anticonvulsant mood stabilizer, is one disorders. It is likely that some of them have to do of the current mainstays of treatment for bipolar with other effects of the drugs, and with their disorder, and has been shown to interfere with and individual side effects. We hence used three internal treat the development of full-blown manic sympto- criteria for crossvalidation (Figure 1d). We reasoned, matology. For mania, the spectrum of efficacy of first, that the genes that changed in expression in valproate is broader than for other mood stabilizers.14 response to both drugs are more likely to be core to In essence, in our approval we are using drug the pathophysiological process, and are higher prob- effects on gene expression as tools to tag genes that ability candidate genes. Second, cotreatment with the may have pathophysiological relevance. Changes of two drugs, one a bipolar inducing, and the other one a gene expression in response to each of the two drugs, bipolar disorder-treating drug, could arguably show methamphetamine and valproate might be of interest interference effects (Figure 2), and some genes that in and of themselves, and in terms of candidate gene would be changed by single drug treatment would be generation and convergent functional genomics. ‘‘nipped in the bud’’ and not show changes in However, not all genes that show changes in expres- expression by cotreatment. Those genes would also Molecular Psychiatry Candidate genes and mechanisms for bipolar disorders CA Ogden et al 1009 a 300 METH 200 VPA 100 Co-Treatment changed genes 0 number of significantly Prefrontal Amygdala Caudate Nucleus Ventral Cortex Putamen Accumbens Tegmentum Prefrontal Cortex b Amygdala Caudate Putamen 300 250 Nucleus Accumbens 200 Ventral Tegmentum 150 100 50 changed genes 0 number of significantly significantly number of METH VPA Prefrontal Cortex c Amygdala 5 Caudate Putamen 4 Nucleus Accumbens 3 Ventral Tegmentum 2 1 0 number genes of Category I Candidate Genes d Category Brain I II Meth III VPA III Meth IV VPA IV Totals Region Prefrontal Cortex 5 0 12 14 20 10 61 Amygdala 1 9 8 68 9 136 231 Caudate Putamen 2 23 28 25 75 209 362 Nucleus Accumbens 1 3 9 0 8 6 27 Ventral Tegmentum 0 8 0 4 16 21 49 Figure 2 Number of genes reproducibly changed: METH—methamphetamine; VPA—valproate. (a) Comparative effects of methamphetamine, valproate, and cotreatment with both drugs in different target brain regions, showing interference effects of cotreatment. (b) Brain region-specific differences of drug treatment with methamphetamine and valproate on gene expression. (c) Distribution of Category I candidate genes across brain regions. (d) Number of reproducibly changed genes in Categories I–IV. be deemed higher probability candidate genes than physiology.13,15–17 We reasoned that if a gene is genes that still change during cotreatment. Third, we changed in more than one of these brain regions, it comprehensively surveyed gene expression
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