No evidence for linkage between chromosome 5 markers and schizophrenia

Linkage between chromosome 5 markers and schizophrenia has been proposed for a small number of Icelandic and English families. Three subsequent reports have failed to replicate this report. To increase the number of tested kindreds, we collected seven North American families with schizophrenia and genotyped them at 4 loci that span the region 5p13-5q11-14, including the two markers used in the single positive linkage report. The data were analyzed with models of affection status similar to those utilized in the positive report. We observed no evidence of linkage between these markers and psychiatric disorders, regardless of the definition of affection status. Additionally, we can exclude most of the region for linkage with schizophrenia in these families. This and other negative reports of linkage between schizophrenia and chromosome 5 markers suggest that genetic defects in this region are rarely, if ever, etiologically related to schizophrenia.     

Genetic analysis of psychiatric disorders in humans

Psychiatric disorders place a large burden not only on affected individuals and their families but also on societies and health services. Current treatment is only effective in a proportion of the patients, so considerable effort has been put into the development of new medications. The susceptibility to all major psychiatric disorders is, at least in part, genetic. Knowledge of the genes that underlie this susceptibility may lead to the identification of new drug targets and the development of more effective treatments. Therefore, numerous genetic studies in search for the genes involved in psychiatric disorders have been performed. Although results of both linkage and association studies have been inconsistent, several promising gene regions and candidate genes have been identified recently. In this article, we will review the strategies that proved to be successful in detecting genes for psychiatric disorders and we will provide some recommendations to increase the probability of detecting susceptibility genes in genetic studies of different designs.     

Genetics and genomics of behavioral and psychiatric disorders

Psychiatric conditions are to some degree under genetic influences. Despite the application of advanced genetic and molecular biological technologies, the genetic bases of the human behavioral traits and psychiatric diseases remains largely unresolved. Conventional genetic linkage approaches have not yielded definitive results, possibly because of the absence of objective diagnostic tests, the complex nature of human behavior or the incomplete penetrance of psychiatric traits. However, recent studies have revealed some genes of interest using multifaceted approaches to overcome these challenges. The approaches include using families in which specific behaviors segregate as a mendelian trait, utilization of endophenotypes as biological intermediate traits, identification of psychiatric disease phenotypes in genomic disorders, and the establishment of mouse models.     

Premenstrual mood changes in affective disorders.

Mood changes during the premenstrual phase have been the focus of considerable research in recent years. Although there has been significant progress in the diagnosis and etiology of major affective disorders, the relation between these disorders and menstrual changes remains controversial. There have been contradictory reports and speculations on women''s susceptibility to psychiatric disorders during the premenstrual phase. We describe three patients with a history of mood swings associated with menstruation in whom major affective disorders developed, necessitating intensive psychiatric treatment or admission to hospital. Among women who manifest menstrual mood changes, manic-depressive illness may develop only in a subgroup with genetic predisposition. In such cases the possibility of postpartum mania or depression should be kept in mind in follow-up.     

Review. Genetics of addictions: strategies for addressing heterogeneity and polygenicity of substance use disorders

Addictions are common psychiatric disorders that exert high cost to the individual and to society. Addictions are a result of the interplay of multiple genetic and environmental factors. They are characterized by phenotypic and genetic heterogeneity as well as polygenicity, implying a contribution of different neurobiological mechanisms to the clinical diagnosis. Therefore, treatments for most substance use disorders are often only partially effective, with a substantial proportion of patients failing to respond. To address heterogeneity and polygenicity, strategies have been developed to identify more homogeneous subgroups of patients and to characterize genes contributing to their phenotype. These include genetic linkage and association studies as well as functional genetic analysis using endophenotypes and animal behavioural experimentation. Applying these strategies in a translational context aims at improving therapeutic response by the identification of subgroups of addiction patients for individualized, targeted treatment strategies. This article aims to discuss strategies addressing heterogeneity and polygenicity of substance use disorders by presenting results of recent research on genetic and environmental components of addiction. It will also introduce the European IMAGEN study that aims to integrate methodical approaches discussed in order to identify the genetic and neurobiological basis of behavioural traits relevant to the development of addictions.     

Candidate gene studies in the 21st century: meta-analysis, mediation, moderation

The results of a large body of candidate gene studies of behavioural and psychiatric phenotypes have been largely inconclusive, with most findings failing to replicate reliably. A variety of approaches that augment the 'traditional' candidate gene approach are discussed, including the use of meta-analysis to combine findings from existing published reports, the investigation of mediating variables (including the use of intermediate phenotypes or endophenotypes) and the awareness of possible moderating influences (such as sex or ethnicity) and gene–environment interactions on genetic associations, possibly via epigenetic mechanisms. Advances in genotyping technology will also allow the routine use of haplotype analysis and linkage disequilibrium mapping. Examples of how these approaches may improve our understanding of how genetic associations with behavioural and psychiatric phenotypes obtain are given.     

A Novel Analytical Framework for Dissecting the Genetic Architecture of Behavioral Symptoms in Neuropsychiatric Disorders

Background

For diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms.

Results and Methodology

We introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21.

Conclusions

The findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression.     

The pseudoautosomal regions of the human sex chromosomes

In human females, both X chromosomes are equivalent in size and genetic content, and pairing and recombination can theoretically occur anywhere along their entire length. In human males, however, only small regions of sequence identity exist between the sex chromosomes. Recombination and genetic exchange is restricted to these regions of identity, which cover 2.6 and 0.4 Mbp, respectively, and are located at the tips of the short and the long arm of the X and Y chromosome. The unique biology of these regions has attracted considerable interest, and complete long-range restriction maps as well as comprehensive physical maps of overlapping YAC clones are already available. A dense genetic linkage map has disclosed a high rate of recombination at the short arm telomere. A consequence of the obligatory recombination within the pseudoautosomal region is that genes show only partial sex linkage. Pseudoautosomal genes are also predicted to escape X-inactivation, thus guaranteeing an equal dosage of expressed sequences between the X and Y chromosomes. Gene pairs that are active on the X and Y chromosomes are suggested as candidates for the phenotypes seen in numerical X chromosome disorders, such as Klinefelter's (47,XXY) and Turner's syndrome (45,X). Several new genes have been assigned to the Xp/Yp pseudoautosomal region. Potential associations with clinical disorders such as short stature, one of the Turner features, and psychiatric diseases are discussed. Genes in the Xq/Yq pseudoautosomal region have not been identified to date.     

New insights from the last decade of research in psychiatric genetics: discoveries,challenges and clinical implications

Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision-making. Long recognized to be heritable, recent evidence shows that psychiatric disorders are influenced by thousands of genetic variants acting together. Most of these variants are commonly occurring, meaning that every individual has a genetic risk to each psychiatric disorder, from low to high. A series of large-scale genetic studies have discovered an increasing number of common and rare genetic variants robustly associated with major psychiatric disorders. The most convincing biological interpretation of the genetic findings implicates altered synaptic function in autism spectrum disorder and schizophrenia. However, the mechanistic understanding is still incomplete. In line with their extensive clinical and epidemiological overlap, psychiatric disorders appear to exist on genetic continua and share a large degree of genetic risk with one another. This provides further support to the notion that current psychiatric diagnoses do not represent distinct pathogenic entities, which may inform ongoing attempts to reconceptualize psychiatric nosology. Psychiatric disorders also share genetic influences with a range of behavioral and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes and cardiovascular disease, suggesting shared genetic etiology of potential clinical importance. Current polygenic risk score tools, which predict individual genetic susceptibility to illness, do not yet provide clinically actionable information. However, their precision is likely to improve in the coming years, and they may eventually become part of clinical practice, stressing the need to educate clinicians and patients about their potential use and misuse. This review discusses key recent insights from psychiatric genetics and their possible clinical applications, and suggests future directions.     

Predictive Psychiatric Genetic Testing in Minors: An Exploration of the Non-Medical Benefits

Predictive genetic testing for susceptibility to psychiatric conditions is likely to become part of standard practice. Because the onset of most psychiatric diseases is in late adolescence or early adulthood, testing minors could lead to early identification that may prevent or delay the development of these disorders. However, due to their complex aetiology, psychiatric genetic testing does not provide the immediate medical benefits that current guidelines require for testing minors. While several authors have argued non-medical benefits may play a crucial role in favour of predictive testing for other conditions, little research has explored such a role in psychiatric disorders. This paper outlines the potential non-medical benefits and harms of psychiatric genetic testing in minors in order to consider whether the non-medical benefits could ever make such testing appropriate. Five non-medical themes arise in the literature: psychological impacts, autonomy/self-determination, implications of the biomedical approach, use of financial and intellectual resources, and discrimination. Non-medical benefits were prominent in all of them, suggesting that psychiatric genetic testing in minors may be appropriate in some circumstances. Further research needs to empirically assess these potential non-medical benefits, incorporate minors in the debate, and include normative reflection to evaluate the very purposes and motivations of psychiatric genetic testing in minors.     

Polygenic risk for psychiatric disorders correlates with executive function in typical development

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome‐wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.     

Use of a Quantitative Trait to Map a Locus Associated with Severity of Positive Symptoms in Familial Schizophrenia to Chromosome 6p

A number of recent linkage studies have suggested the presence of a schizophrenia susceptibility locus on chromosome 6p. We evaluated 28 genetic markers, spanning chromosome 6, for linkage to schizophrenia in 10 moderately large Canadian families of Celtic ancestry. Parametric analyses of these families under autosomal dominant and recessive models, using broad and narrow definitions of schizophrenia, produced no significant evidence for linkage. A sib-pair analysis using categorical disease definitions also failed to produce significant evidence for linkage. We then conducted a separate sibpair analysis using scores on positive-symptom (psychotic), negative-symptom (deficit), and general psychopathology-symptom scales as quantitative traits. With the positive symptom-scale scores, the marker D6S1960 produced P = 1.2 x 10(-5) under two-point and P = 5.4 x 10(-6) under multipoint analyses. Using simulation studies, we determined that these nominal P values correspond to empirical P values of .034 and .0085, respectively. These results suggest that a schizophrenia susceptibility locus on chromosome 6p may be related to the severity of psychotic symptoms. Assessment of behavioral quantitative traits may provide increased power over categorical phenotype assignment for detection of linkage in complex psychiatric disorders.     

Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and psychiatric disease conditions

A high level of Interleukin-1beta (IL1B), a key mediator of inflammation, is expressed in the brain, particularly in the hippocampus, which plays a pivotal role in memory and mood regulation. In the brain, IL1B exerts a myriad of effects such as neuronal proliferation, differentiation, apoptosis, and long-term potentiation. Considering its pleiotropic effects in the brain, IL1B has been implicated in the pathogenesis of various psychiatric disorders as well as cognitive function in normal individuals. Thus, IL1B has been considered a candidate gene for the study of psychiatric diseases as well as brain function in normal individuals. The polymorphisms of IL1B have been described in relation to various expression levels in response to stimulation. This review describes previous studies on the genetic effects of IL1B, which relate it to psychiatric diseases such as major depressive disorder, bipolar disorder, schizophrenia, and Alzheimer’s disease, as well as cognitive function in normal individuals. Although many reports have indicated a possible role of the genetic effects of IL1B or its phenotypes in psychiatric diseases, some reports were unable to confirm these findings. IL1B release is mediated by an inflammatory response or psychological stress, leading to a cascade of immune reactions involving numerous immune components. To further explore the genetic effects of IL1B on mental diseases and brain function, gene–gene and gene–environment interactions should also be considered.     

Physical linkage of a GABAA receptor subunit gene to the DXS374 locus in human Xq28.

We report the physical linkage of the gene encoding one of the subunits of the GABAA receptor (GABRA3) to the polymorphic locus DXS374 on the human X chromosome at Xq28. X-linked manic depression and other psychiatric disorders have been mapped to this region, and thus GABRA3 is a potential candidate gene for these disorders. DXS374--and therefore GABRA3--lies distal to the fragile X locus at a recombination fraction of approximately .15.     

Dissecting cause and effect in the pathogenesis of psychiatric disorders: genes, environment and behaviour

It has long been established that the development of psychiatric illness results from a complex interplay between genetic and environmental factors. Postmortem and genetic linkage studies have identified a number of promising candidate genes which have been reinforced by replication and functional studies. However, the fact that concordance rates for monozygotic twins rarely approach 100% highlights the involvement of environmental factors. Whilst epidemiological studies of psychiatric cohorts have demonstrated potential risk factors, such studies are clearly limited and in many cases the potential mechanism linking a given risk factor with pathogenesis remains unclear. A very powerful method of elucidating the mechanisms underlying gene-environment interactions is the use of appropriate animal models of psychiatric pathology. Whilst animals cannot be used to map the entire complexity of diseases such as schizophrenia, dissecting the symptom profile into more simply encapsulated traits or endophenotypes has proved to be a successful approach. Such endophenotypes provide a measurable link between aetiological factors and phenotypic outcome. Given the potential for the careful control and modification of an experimental animal's environment, the combination of studies of candidate genes with investigations of environmental factors is an effective heuristic tool, allowing examination of behavioural endophenotypes in conjunction with cellular and molecular outcomes. This review will consider the extant genetic, molecular, pharmacological and lesion-based models of psychiatric disorders, and the relevant methods of environmental manipulation appearing in the literature. We will discuss studies where such models have been combined, and the potential for future experimentation in this area.     

Genomewide linkage disequilibrium mapping of severe bipolar disorder in a population isolate

Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype.     

Schizophrenia: genes at last?

Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders.     

Anchoring of canine linkage groups with chromosome-specific markers

A high-resolution genetic map with polymorphic markers spaced frequently throughout the genome is a key resource for identifying genes that control specific traits or diseases. The lack of rigorous selection against genetic disorders has resulted in many breeds of dog suffering from a very high frequency of genetic diseases, which tend to be breed-specific and usually inherited as autosomal recessive or apparently complex genetic traits. Many of these closely resemble human genetic disorders in their clinical and pathologic features and are likely to be caused by mutations in homologous genes. To identify loci important in canine disease genes, as well as traits associated with morphological and behavioral variation, we are developing a genetic map of the canine genome. Here we report on an updated version of the canine linkage map, which includes 341 mapped markers distributed over the X and 37 autosomal linkage groups. The average distance between markers on the map is 9.0 cM, and the linkage groups provide estimated coverage of over 95% of the genome. Fourteen linkage groups contain either gene-associated or anonymous markers localized to cosmids that have been assigned to specific canine chromosomes by FISH. These 14 linkage groups contain 150 microsatellite markers and allow us to assign 40% of the linkage groups to specific canine chromosomes. This new version of the map is of sufficient density and characterization to initiate mapping of traits of interest. Received: 23 February 1999 / Accepted: 28 April 1999     

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.