The relationship between the pharmacology of antiepileptic drugs and human gene variation: an overview

Individual differences in clinical responsiveness to antiepileptic drugs are due to a complex interaction between environmental factors and genetic variation. Considerable interest has arisen in exploiting advances in molecular genetics to improve drug therapy for epilepsy and many other diseases; however, practical application of pharmacogenetics has been difficult to realize. Attempts to define gene variants that are associated with therapeutic (or adverse) effects of antiepileptic drugs rely currently on the prior identification of candidate genes and the subsequent evaluation of the distribution of allelic variants between individuals who have a "good" versus a "poor" clinical response. Many factors can adversely affect interpretation of such data, and careful consideration must be given to the design of genetic association studies involving candidate genes. Candidate genes may be identified in a number of ways; however, for studies of drugs, application of knowledge derived from basic pharmacology can suggest focused and testable hypotheses that are based on the fundamental principles of drug action. Thus, studies of genetic variation as they relate to proteins involved in antiepileptic drug kinetics and dynamics will identify key polymorphisms in endogenous molecules that determine degrees of drug efficacy and toxicity. Delineation of these effects in the coming years will promote enhanced success in the treatment of epilepsy.     

The genetic background of Parkinson's disease: current progress and future prospects

Almost two decades of genetic research in Parkinson's disease (PD) have remarkably increased our knowledge regarding the genetic basis of PD with numerous genes and genetic loci having been found to cause familial PD or affect the risk for PD. Approximately 5–10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors. Nowadays, six genes, alpha synuclein, LRRK2, VPS35, Parkin, PINK1 and DJ‐1, have definitely been associated with an autosomal dominant or recessive PD mode of inheritance. The advent of genome‐wide association studies (GWAS) and the implementation of new technologies, like next generation sequencing (NGS) and exome sequencing has undoubtedly greatly aided the identification on novel risk variants for sporadic PD. In this review, we will summarize the current progress and future prospects in the field of PD genetics.     

Genetics of age-related hearing loss

Age-related hearing loss (ARHL) has recently been confirmed as a common complex trait, that is, it is heritable with many genetic variants each contributing a small amount of risk, as well as environmental determinants. Historically, attempts to identify the genetic variants underlying the ARHL have been of limited success, relying on the selection of candidate genes based on the limited knowledge of the pathophysiology of the condition, and linkage studies in samples comprising related individuals. More recently genome-wide association studies have been performed, but these require very large samples having consistent and reliable phenotyping for hearing loss (HL), and early attempts suffered from lack of reliable replication of their findings. Replicated variants shown associated with ARHL include those lying in genes GRM7, ISG20, TRIOBP, ILDR1, and EYA4. The availability of large biobanks and the development of collaborative consortia have led to a breakthrough over the last couple of years, and many new genetic variants associated with ARHL are becoming available, through the analysis publicly available bioresources and electronic health records. These findings along with immunohistochemistry and mouse models of HL look set to help disentangle the genetic architecture of ARHL, and highlight the need for standardization of phenotyping methods to facilitate data sharing and collaboration across research networks.     

Imaging genetics of schizophrenia

Recent years have seen an explosive growth of interest in the application of imaging genetics to understand neurogenetic mechanisms of schizophrenia. Imaging genetics applies structural and functional neuroimaging to study subjects carrying genetic risk variants that relate to a psychiatric disorder. We review selected aspects of this literature, starting with a widely studied candidate gene--the catechol-O-methyltransferase gene (COMT)--discussing other candidate genes in the dopaminergic system, and then discussing variants with genome-wide support. In future perspectives, approaches to characterize epistatic effects, the identification of new risk genes through forward-genetic approaches using imaging phenotypes, and the study of rare structural variants are considered.     

Genome‐wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications

Recent advances in molecular genetics have enabled assessments of the associations among genetic variants (e.g., single‐nucleotide polymorphisms) and susceptibility for complex diseases, including psychiatric disorders. Specifically, genome‐wide association studies (GWAS), meta‐analyses of the GWAS summary statistics, and mega‐analyses (which use raw data, not summary statistics) of GWAS have provided revolutionary results and have identified numerous susceptibility genes or single‐nucleotide polymorphisms. By using several tens of thousands of subjects, >40 genes have been identified as being associated with susceptibility for bipolar disorder so far. The purpose of this systematic review was to summarize the recent findings of bipolar disorder GWAS and discuss their clinical implications.     

Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10⁻⁴). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.     

Genetics of bipolar disorder

Family and twin studies have consistently documented that bipolar disorder (BPD) is familial and heritable, but efforts to identify specific susceptibility genes have been complicated by the disorder’s genetic and phenotypic complexity. Genetic linkage studies have implicated numerous chromosomal regions, but findings have been inconsistent. As with other complex disorders, it has become clear that linkage analysis lacks the power and precision to identify susceptibility loci for BPD. Candidate gene association studies have implicated several specific genes, but these studies have been limited by our incomplete understanding of the disorder’s biology, and there have been few robustly replicated results. Within the past 2 years, a major advance in the genetics of complex disease has become feasible in the form of genome-wide association studies. Such studies, which require large sample sizes, have already proven successful in identifying susceptibility variants for a range of common medical disorders. Genome-wide association studies have begun to appear for BPD, and more are in progress. By providing an unbiased approach, this technology may reveal novel biological mechanisms underlying BPD.     

Recent molecular genetic studies and methodological issues in suicide research

Suicide behavior (SB) spans a spectrum ranging from suicidal ideation to suicide attempts and completed suicide. Strong evidence suggests a genetic susceptibility to SB, including familial heritability and common occurrence in twins. This review addresses recent molecular genetic studies in SB that include case-control association, genome gene-expression microarray, and genome-wide association (GWA). This work also reviews epigenetics in SB and pharmacogenetic studies of antidepressant-induced suicide.SB fulfills criteria for a complex genetic phenotype in which environmental factors interact with multiple genes to influence susceptibility. So far, case-control association approaches are still the mainstream in SB genetic studies, although whole genome gene-expression microarray and GWA studies have begun to emerge in recent years. Genetic association studies have suggested several genes (e.g., serotonin transporter, tryptophan hydroxylase 2, and brain-derived neurotrophic factor) related to SB, but not all reports support these findings. The case-control approach while useful is limited by present knowledge of disease pathophysiology. Genome-wide studies of gene expression and genetic variation are not constrained by our limited knowledge. However, the explanatory power and path to clinical translation of risk estimates for common variants reported in genome-wide association studies remain unclear because of the presence of rare and structural genetic variation. As whole genome sequencing becomes increasingly widespread, available genomic information will no longer be the limiting factor in applying genetics to clinical medicine. These approaches provide exciting new avenues to identify new candidate genes for SB genetic studies. The other limitation of genetic association is the lack of a consistent definition of the SB phenotype among studies, an inconsistency that hampers the comparability of the studies and data pooling.In summary, SB involves multiple genes interacting with non-genetic factors. A better understanding of the SB genes by combining whole genome approaches with case-control association studies, may potentially lead to developing effective screening, prevention, and management of SB.     

Gene-environment correlations: a review of the evidence and implications for prevention of mental illness

Family studies have demonstrated genetic influences on environmental exposure: the phenomenon of gene-environment correlation (rGE). A few molecular genetic studies have confirmed the results, but the identification of rGE in studies that measure genes and environments faces several challenges. Using examples from studies in psychology and psychiatry, we integrate the behavioral and molecular genetic literatures on rGE, describe challenges in identifying rGE and discuss the implications of molecular genetic findings of rGE for future research on gene-environment interplay and for attempts to prevent disease by reducing environmental risk exposure. Genes affect environments indirectly, via behavior and personality characteristics. Associations between individual genetic variants and behaviors are typically small in magnitude, and downstream effects on environmental risk are further attenuated by behavioral mediation. Genotype-environment associations are most likely to be detected when the environment is behaviorally modifiable and highly specified and a plausible mechanism links gene and behavior. rGEs play an important causal role in psychiatric illness. Although research efforts should concentrate on elucidating the genetic underpinnings of behavior rather than the environment itself, the identification of rGE may suggest targets for environmental intervention even in highly heritable disease. Prevention efforts must address the possibility of confounding between rGE and gene-environment interaction (G x E).     

Schizophrénie et génétique : concepts et évidences

The relationship between the field of genetics and the social sciences has been fraught with difficulties. The philosophers were the first to predict that it would not be an easy matter, and genetics was used in psychiatry not as an aid to persons recognized as being vulnerable, but with the aim of putting a term to degeneration within the population (the theory of Morel). The hesitancy shown by psychiatrists toward this area of research can thus be well understood. However, genetics is first of all a powerful and original means of investigating psychic suffering. A certain number of misunderstandings explain why psychiatrists (French psychiatrists in particular, and to a greater degree than the patients themselves) show some reserve regarding genetic research into mental illnesses. Three concepts that are often poorly understood have been detailed in this article (genetic determinism, heritability, familial aggregation), then illustrated for schizophrenia through a review of familial studies and several candidate genes. The implications and limits of genetics as applied to schizophrenia should thus be better defined.     

De novo mutation in schizophrenia

Several studies in the last 5 years have shown that newly arising (de novo) mutations contribute to the genetics of schizophrenia (SZ). This will replenish genetic variants removed by natural selection and could, in part, explain why SZ prevalence has remained stable in the general population despite low fecundity. The strongest evidence to date for the association between SZ and de novo mutation comes from studies of de novo copy number variation (CNV), where the rate of de novo CNV mutation is shown to be increased in cases when compared with controls, and genes disrupted by these mutations are enriched for those encoding proteins involved in synaptic function and development. Previous estimates have shown high levels of negative selection operating against SZ associated CNVs, and we provide an updated estimate of these levels of selection using the most recently published data. Recent studies involving next-generation sequencing technology have provided preliminary evidence that de novo single-nucleotide mutations might also increase risk of SZ. However, these are very small in scale, and the results can only be considered as preliminary.     

Nature and nurture in neuropsychiatric genetics: where do we stand?

Both genetic and nongenetic risk factors, as well as interactions and correlations between them, are thought to contribute to the etiology of psychiatric and behavioral phenotypes. Genetic epidemiology consistently supports the involvement of genes in liability. Molecular genetic studies have been less successful in identifying liability genes, but recent progress suggests that a number of specific genes contributing to risk have been identified. Collectively, the results are complex and inconsistent, with a single common DNA variant in any gene influencing risk across human populations. Few specific genetic variants influencing risk have been unambiguously identified. Contemporary approaches, however, hold great promise to further elucidate liability genes and variants, as well as their potential inter-relationships with each other and with the environment. We will review the fields of genetic epidemiology and molecular genetics, providing examples from the literature to illustrate the key concepts emerging from this work.     

Heterogeneity and the genetics of autism

The objective of this review is to summarize recent data on the genetics of autism, highlight the evidence for genetic heterogeneity and extend the implications of these findings for the identification of susceptibility genes in this disorder. Family studies have shown that autism runs in families and twin studies indicate that the basis of that familial aggregation is genetic. As a result the prospects for the identification of susceptibility genes using either linkage or association studies are quite good. However, recent evidence is accumulating suggesting that the disorder is genetically heterogeneous; higher functioning individuals with autism may arise from separate genetic mechanisms that lower functioning ones. If true, this will make the detection of linkage and association much more difficult.     

Brain imaging genetics in ADHD and beyond – Mapping pathways from gene to disorder at different levels of complexity

Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.     

The next challenge for psychiatric genetics: characterizing the risk associated with identified genes.

BACKGROUND: As advances in genetics further our ability to identify genes influencing psychiatric disorders, the next challenge facing psychiatric genetics is to characterize the risk associated with specific genetic variants in order to better understand how these susceptibility genes are involved in the pathways leading to illness. METHODS: To further this goal, findings from behavior genetic analyses about how genetic influences act can be used to guide hypothesis testing about the effects associated with specific genes. RESULTS: Using the phenotype of alcohol dependence as an example, this paper provides an overview of how the integration of behavioral and statistical genetics can advance our knowledge about the genetics of psychiatric disorders. Areas currently being investigated in behavior genetics include careful delineation of phenotypes, to examine the heritability of various aspects of normal and abnormal behavior; developmental changes in the nature and magnitude of genetic and environmental effects; the extent to which different behaviors are influenced by common genes; and different forms of gene-environment correlation and interaction. CONCLUSIONS: Understanding how specific genes are involved in these processes has the potential to significantly enhance our understanding of the development of psychiatric disorders.     

Copy Number Variants: A New Molecular Frontier in Clinical Psychiatry

Molecular genetic research, building on genetic epidemiology, has provided the field of psychiatry with a host of exciting advances. It is now clear beyond any reasonable doubt that genetic inheritance influences liability to develop almost every major psychiatric disorder. Rapid progress in identifying genes contributing to psychiatric liability, recently accelerated by the advent of approaches such as genome-wide association studies and chromosomal microarray analysis, raises a critical question for psychiatric practice and training: how will molecular genetics alter the practice of psychiatry for front-line clinicians? The premise of the present review is that our growing knowledge regarding the roles of copy number variants in behavioral disorders will soon require revision of standards of evaluation and care for psychiatric patients.     

Milestones in PD genetics

Over the last 25 years, genetic findings have profoundly changed our views on the etiology of Parkinson's disease. Linkage studies and positional cloning strategies have identified mutations in a number of genes that cause several monogenic autosomal‐dominant or autosomal‐recessive forms of the disorder. Although most of these Mendelian forms of Parkinson's disease are rare, whole‐genome association studies have more recently provided convincing evidence that low‐penetrance variants in at least some of these, but also in several other genes, play a direct role in the etiology of the common sporadic disease as well. In addition, rare variants with intermediate‐effect strengths in genes such as Gaucher's disease–associated glucocerebrosidase A have been discovered as important risk factors. “Next‐generation” sequencing technologies are expected by some to identify many more of these variants. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings may provide the “genetic entry points” to identify molecular targets and readouts necessary to design rational disease‐modifying treatments. © 2011 Movement Disorder Society     

Preferences for Genetic and Behavioral Health Information: The Impact of Risk Factors and Disease Attributions

Increased availability of genetic risk information may lead the public to give precedence to genetic causation over behavioral/environmental factors, decreasing motivation for behavior change. Few population-based data inform these concerns. We assess the association of family history, behavioral risks, and causal attributions for diseases and the perceived value of pursuing information emphasizing health habits or genes. 1,959 healthy adults completed a survey that assessed behavioral risk factors, family history, causal attributions of eight diseases, and health information preferences. Participants’ causal beliefs favored health behaviors over genetics. Interest in behavioral information was higher than in genetic information. As behavioral risk factors increased, inclination toward genetic explanations increased; interest in how health habits affect disease risk decreased. Those at greatest need for behavior change may hold attributions that diminish interest in information for behavior change. Enhancing understanding of gene-environment influences could be explored to increase engagement with health information.     

Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models

Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability, or attention‐deficit hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features. Genetically engineered mice have provided a technical means to ascertain precise genetic mechanisms of association between copy number variants and dimensional aspects of mental illnesses. Molecular, cellular, and neuronal phenotypes can be detected as potential mechanistic substrates for various behavioral constructs of mental illnesses. However, mouse models come with many technical pitfalls. Genetic background is not well controlled in many mouse models, leading to rather obvious interpretative issues. Dose alterations of many copy number variants and single genes within copy number variants result in some molecular, cellular, and neuronal phenotypes without a behavioral phenotype or with a behavioral phenotype opposite to what is seen in humans. In this review, I discuss technical and interpretative pitfalls of mouse models of copy number variants and highlight well‐controlled studies to suggest potential neuronal mechanisms of dimensional aspects of mental illnesses. Mouse models of copy number variants represent toeholds to achieve a better understanding of the mechanistic bases of dimensions of neuropsychiatric disorders and thus for development of mechanism‐based therapeutic options in humans.