Current Psychiatry Reviews - Volume 6, Issue 2, 2010

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Neurological and behavioral disorders are often difficult to study: In many cases they are the culmination of years of subtle biological processes, and the nervous system is inherently complex. Thus, researchers have been eager to exploit new, genome-scale technologies that promise fresh avenues to understanding these disorders. Here we review these technologies and present examples of neurological and behavioral findings that they have engendered. These technologies include oligonucleotide arrays, which are widely used for several purposes. Among these are genome-wide association studies (GWASs) and gene expression profiling-the simultaneous assessment of the transcript levels of all genes. Other genome-scale approaches to investigation of neurological and behavioral disorders rely on the high-throughput, parallel measurement of small molecules (metabolomics) and proteins (proteomics). Finally, next-generation DNA sequencing is poised to revolutionize neurological and behavioral research. It will provide global perspectives on the role of rare genetic variants in neurological and behavioral disorders. It will also revolutionize genome-wide assessment of protein- DNA interactions and partly supplant oligonucleotide arrays for transcriptional profiling. Genome-scale technologies have already affected neurological and behavioral research, and, in the near future, the effects of further technological advances will be profound.

There is a vast literature on the genetic basis for Major Depressive Disorder, a topic which only continues to expand. Several genes have been examined in the context of MDD. Some of these genetic studies have been replicated but most have not. One possible rationale for this lack of replication is an increasing recognition that gene-environment interactions play a crucial role in determining the risk of developing MDD. In this review, we highlight the findings from a Genome Wide Association study as well as linkage studies of depression and discuss the implications of these results. We then summarize some of the most important genetic variations identified in depression, including conclusions from published meta-analyses, with an emphasis on gene-environment interactions. Finally we discuss both the need for and complexity of conducting gene-environment studies in MDD, as well as limitations inherent in current approaches.

OCD is a psychiatric disorder with a lifetime prevalence of 1-3% and is a significant cause of disability worldwide. Family studies indicate that OCD has a significant hereditable component, with relatives of OCD cases being 4 times more likely to develop the disorder than the general population. Linkage studies in OCD have generally been underpowered and have failed to reach the statistical threshold for genome-wide significance, but they have nevertheless been useful for revealing potential regions of interest for future candidate gene studies. Candidate gene studies in OCD have thus far focused on genes involved in the serotonergic, dopaminergic, and glutamatergic pathways. These studies have been for the most part inconclusive, and failures to replicate have been the norm until very recently. The only genetic association replicated by multiple groups is with a glutamate transporter gene (SLC1A1). Genome-wide association studies in OCD are in progress, but final results have not yet been reported. As with the study of many other psychiatric disorders, an improved understanding of OCD will only be achieved [1] with larger collaborative efforts involving more probands, [2] the use of probands and controls drawn from epidemiologically-based populations rather than clinical samples, [3] developing a more precise phenotypic description of OCD and [4] measuring important environmental influences that affect OCD pathogenesis and severity.

Alzheimer disease (AD) is the most common neurodegenerative disease that afflicts mankind. Tremendous efforts have been made in investigating the genetic underpinnings and molecular pathophysiology of this illness. The heritability of AD is estimated to be around 60% and about 5% of AD cases are familial with early-onset caused by gene mutations. Several genes including APP, PSEN1, PSEN2 and APOE e4 have been identified to be causative or associated with AD. This is an overview of AD from the perspective of some of the latest high throughput technological platforms, including genome-wide association studies (GWAS), transcriptomics, proteomics, metabolomics and epigenetics. These approaches are introduced briefly followed by discussion of some of the more significant endeavors and findings. These results, including putative gene loci, differentially expressed genes, epigenetic effects etc., may provide some of the pieces of the AD puzzle. However a systems approach towards the diverse findings from various platforms will most likely give us a quantum leap in the understanding of AD that should lead to breakthroughs in diagnosis, tracking the disease progress, drug discovery and development.

Schizophrenia is a serious mental illness and clinical diagnosis over the past century had been based on recognition of a certain pattern of thinking, perception and behavior. Although mostly people accept that the disease is a complex phenotypic presentation with a strong hereditary predisposition, the exact pathophysiology of schizophrenia has not been clearly elucidated. Rapid advancements in genomics, epigenomics, transcriptomics, proteomics and lipidomics had been made in the search for molecular biomarkers in schizophrenia which could potentially aid clinicians in understanding and subtyping psychosis. It could assist in diagnosis and selection of appropriate antipsychotic therapy, it also provides early indicators of clinical response. In this review, we discuss relevant literature with regards to these advancements, their challenges and their potential clinical impact.

Addictions are chronic relapsing/remitting disorders with enormous repercussions at the individual and societal level. Heritabilities of addictions range from 0.39 to 0.72. Therefore it is essential to identify genetic vulnerability factors to clarify etiology and to develop individualized prevention and treatment strategies. Complex disorders are characterized by the interplay of genetic and environmental factors. We review genomic approaches that are being integrated to advance our understanding of that interface. For addictions involving abused substances, gene-environment interactions can occur at the pharmacokinetic and pharmacodynamic level via modulations of neuronal pathways involved in behavioral control, reward and stress resiliency. Animal models allow the manipulation of environment and genes to reveal associations between addiction-related behaviors and neurobiological phenotypes that are inaccessible in humans. Genome-wide analyses, including whole-genome linkage and association, allow for hypothesis-free mapping of disease-causing loci and measurement of effects of environmental exposure. Deep sequencing is augmenting the catalog of rare variants essential to understand the genetic heterogeneity of addiction. Recently intermediate phenotypes have provided a bridge between functional alleles and complex phenotypes and offer the same opportunity in genome-wide analyses. Environmental effects may be captured in part via epigenetic modifications and changes in gene expression. The analysis of these effects is a long-lasting challenge, but immediate benefits may be realized.

The most common psychiatric disorders that are co-morbid with temporal lobe epilepsy (TLE) are depressive, anxiety, psychotic and personality disorders. This review examines the role of the hippocampus in TLE and associated co-morbidities, and compares the patterns of gene expression in the hippocampus in TLE with patterns in the hippocampus and associated neocortical areas in major depressive disorder and schizophrenia. They may help to provide some insights into the molecular pathophysiology that underlies the psychiatric co-morbidities associated with TLE. Studies to date suggest that hippocampal atrophy is associated with TLE as well as depression and schizophrenia. However, the cause of the atrophy varies: in TLE it is associated with neuronal loss whereas in schizophrenia and major depressive disorder (MDD) there is little or no neuronal loss. Significant gliosis accompanies neuronal loss in TLE, but there is only moderate gliosis in depression and no observable gliosis in schizophrenia. Concordant with astrocytosis there are many astrocyte related genes unregulated in TLE but not in schizophrenia and depression. Down-regulation of mechanisms for the clearance of glutamate is associated with TLE and depression, while activation of immune and inflammatory response genes is seen in TLE and schizophrenia. Down-regulation of genes associated with myelination is common to depression and schizophrenia but not TLE. Synaptic function, ion transport and receptor function genes are down-regulated in TLE and the prefrontal cortex in schizophrenia, whereas neurotransmitter function related genes are up-regulated in the prefrontal cortex in depression.

There are numerous examples of the enduring effects of early experience on neural function. In this paper we review the emerging evidence for epigenetics as a candidate mechanism for such effects. Epigenetics refers to a set of functionally relevant modifications to the genome that do not involve a change in nucleotide sequence. Such modifications include chemical marks that regulate the transcription of the genome. There is now evidence that environmental events can directly modify these marks, and thus gene transcription. Studies with rodent models suggest that environmental signals can act during both early development and in adult life to activate intracellular pathways that directly remodel the ‘epigenome’, leading to changes in gene expression and neural function. Parallel studies with clinically-relevant samples suggest comparable processes are related to psychiatric health. These studies define a biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in behavior, cognition and physiology.