23 October 2012. Though psychiatric diseases are uniquely human, they have aspects that can be fruitfully modeled in animals, according to Tuesday’s plenary speakers at the 20th World Congress of Psychiatric Genetics held in Hamburg, Germany, 14-18 October. Kerstin Lindblad-Toh of Uppsala University in Sweden and the Broad Institute in Cambridge, Massachusetts, described her work seeking the genetic basis of aberrant behaviors in dogs. These behaviors can be seen as extreme versions of desirable traits for which dogs have been bred (e.g., proficiency at hunting can manifest as compulsive tail chasing), and may reflect a pathological combination of genetic variants that are desirable individually. The genetic homogeneity within a breed helps researchers efficiently zero in on risk factors, requiring a survey of merely 170,000 single nucleotide polymorphisms (SNPs) in hundreds of dogs, compared to one million SNPs in tens of thousands of humans for comparable analyses. Lindblad-Toh reported that a genomewide association study (GWAS) of canine compulsive disorder has identified multiple loci, including a cell adhesion gene called CDH2, which she is now following up on in mouse models and in humans with obsessive-compulsive disorder.
From a drug development perspective, Bryan Roth of the University of North Carolina in Chapel Hill argued that current animal models were useful in that they predicted drug response (Conn and Roth, 2008), in contrast with recent commentary (Hyman, 2012). He also said that pharmaceutical companies mistakenly overlook these established models of drug response when testing novel compounds, which could have contributed to their exit from psychiatric drug development. With medicinal chemistry capable of producing nearly any kind of compound, Roth argued that the real challenge lies in identifying the relevant targets, and that “promiscuous” drugs, like clozapine, which hit multiple molecular targets, would be key (Roth et al., 2004). “Single target agents are not going to work for psychiatric disease,” he said. “This is just the way complex diseases are.”
Further tuning the effects of these drugs with agents that bias the downstream machinations of these receptors may enhance their therapeutic effects, Roth said, referring to the dopamine D2 receptor compounds that selectively activate the β-arrestin pathway recently developed by him and his colleagues (Allen et al., 2011; see SRF related news story).
The NEWMEDS consortium
The animal model theme continued in a symposium Wednesday afternoon, which featured talks from the NEWMEDS consortium, a collaboration between European Union academic centers and European drug companies seeking new methods that can expedite drug development for depression and schizophrenia. One such method is a mouse engineered to carry a copy number variant (CNV)—the 15q13.3 deletion associated with schizophrenia, autism, and epilepsy (see SRF schizophrenia genetics overview). Jacob Nielsen of H. Lundbeck A/S in Valby, Denmark, described these mice, showing that expression of genes within this region, including CHRNA7, was knocked down 50 percent without impinging on expression of bordering genes. The mice had decreased survival, and their body weight increased with age. Their brain morphology appeared largely normal, but an extensive battery of tests uncovered a surprising resistance to seizure induction, increased stress-induced aggression, and a memory deficit as revealed by the Morris water maze. Michelle Birknow of Lundbeck detailed electroencephalography (EEG) findings in these mice, which mimicked abnormalities in auditory-evoked potentials and auditory-evoked γ oscillations found in schizophrenia. The mice did not, however, exhibit a decrease in prepulse inhibition, a measure of sensory gating that is altered in some people with schizophrenia.
The NEWMEDS consortium also includes deCODE Genetics in Iceland, which means access to genotypes of a large sample from the general population. This has turned up CNVs in people who appear rather normal, including those carrying 15q11.2 deletions and duplications—a surprise, said Hreinn Stefánsson of deCODE Genetics, because in the literature these same CNVs are associated with intellectual disability, as well as autism and schizophrenia. In trying to describe the “phenotypic stamp” of physical and cognitive features common to these CNVs, the group is finding subtle differences in reading and math abilities in these deletion carriers. Brain scans of 15q11.2 CNV carriers point to dose-dependent structural changes in gray matter and white matter, as reported by Andreas Meyer-Lindenberg of the Central Institute of Mental Health in Mannheim, Germany. Imaging unaffected carriers can strengthen the link between any CNV and the brain, because it can reveal brain changes solely due to genetics without the potential confounds that come from living with a severe mental illness.
PAKed with CNVs
In a session on Monday, Aiden Corvin of Trinity College in Dublin, Ireland, gave an update on a 146.5 kb duplication of two exons in a gene called p21 protein-activated kinase 7 (PAK7). Originally detected in schizophrenia cases, the kinase was enriched in a bipolar disorder sample as well, Corvin reported. Combining the samples revealed more PAK7 duplications in cases than in controls, suggesting its involvement in broader psychosis. Of the PAK7 duplication carriers with schizophrenia, 12 of 13 had normal cognitive development, but poor clinical outcome. PAK7 is a serine-threonine kinase involved in dendrite formation and synapse function, and though it is barely expressed in the brain overall, its expression increases when synapses change their strength.
Taking a cue from genes hit by de novo single nucleotide mutations in schizophrenia (see SRF related news story and SRF news story), Franziska Degenhardt of the University of Bonn, Germany, and colleagues searched schizophrenia samples and controls for CNVs in these genes. A small duplication in RB1CC1, a brain-expressed “cancer” gene, was one that turned up in excess in schizophrenia with an odds ratio of 5. RB1CC1 may have more to do with cognition, Degenhardt said, because one duplication carrier did worse on cognitive tests than did people with schizophrenia who do not carry the duplication.
Mind the gaps
Despite its heralded "completion," the human genome reference contains 30 Mb-worth of gaps in the sequence. Twenty-one of these gaps overlap with the location of a schizophrenia-related deletion at 1q21.1, leaving researchers in the dark about what exactly these deletion carriers are missing. In a session on Tuesday, Giulio Genovese of the Broad Institute described how he filled in some of these missing pieces using admixture mapping, which takes advantage of the different patterns of sequences found in mixed populations such as African-Americans. This revealed a gene called HYDIN2 in one of the gaps, and Genovese argued that other genes are likely to be found in these gaps because the large segments of repeating sequences that make it hard to map these regions also make them prone to CNV creation.—Michele Solis.