Correspondence regarding German psychiatric genetics and Ernst Rüdin.
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Eugenics↗
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Results for “Psychiatric genetics”
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Vth World Congress of Psychiatric Genetics. Santa Fe, New Mexico, October 19-23, 1997. Abstracts.
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Animals↗
6th World Congress on Psychiatric Genetics. Bonn, Germany, October 6-10, 1998. Abstracts.
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Animals↗
The genetic epidemiology of psychiatric disorders: a current perspective.
Psychiatric genetic epidemiology has, as a field, undergone considerable change in the last two decades. My goal here is to provide a brief, selective and inevitably personal overview of where the field has come from, where it is now and where it might be going. Methodologic issues will be emphasized, particularly those of an "epidemiologic" nature. I will organize this review around three of the major methods used in psychiatric genetics: family studies, twin studies and linkage studies.
Epidemiology↗
Initiation and adaptation: a paradigm for understanding psychotropic drug action.
OBJECTIVE: This article describes a paradigm--initiation and adaptation--within which to conceptualize the drug-induced neural plasticity that underlies the long-term actions of psychotropic drugs in the brain. METHOD: Recent advances in neurobiology are reviewed. RESULTS: Recent developments in cellular and molecular neurobiology provide new conceptual and experimental tools for understanding the mechanisms by which psychotropic drugs produce long-lived alterations in brain function. Because of the availability of more robust animal models, the mechanisms by which drugs of abuse produce dependence are better understood than the mechanisms by which antidepressants, antipsychotics, and lithium produce their therapeutic effects. Nonetheless, the fundamental types of mechanisms appear to be similar: chronic drug administration drives the production of adaptations in postreceptor signaling pathways, including regulation of neural gene expression. Whether the results are deleterious or therapeutic depends on the precise neural systems targeted by a particular drug. CONCLUSIONS: Biological investigation in psychiatry has often focused too narrowly on synaptic pharmacology, especially on neurotransmitter turnover and neurotransmitter receptors. This review focuses on molecular and cellular changes in neural function that are produced as adaptations to chronic administration of addictive drugs such as psychostimulants and therapeutic drugs such as antidepressants. To understand normal brain function, psychopathology, and the actions of psychiatric treatments, and to exploit the eventual findings of psychiatric genetics, psychiatric research must now extend its efforts beyond the synapse, to an understanding of cellular and molecular neurobiology (in particular, postreceptor signal transduction) as well as to a better understanding of the architecture and function of neural systems. A paradigm is presented to help understand the long-term effects of psychotropic drugs, including the latency in onset of their therapeutic actions.
Animals↗
Genetics of psychiatric disease.
Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA) disorders, while relatives of schizophrenia (SZ) probands are at increased risk for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed susceptibility loci for BIP disorder for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of SZ kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13, both of which are implicated in susceptibility to BIP disorder. Similarly, confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong statistical evidence for a 13q32 BIP susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two group of disorders may not be so distinct as current nosology suggests.
Bipolar Disorder↗
Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation.
IMPORTANCE: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. OBJECTIVE: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. DESIGN SETTING AND PARTICIPANTS: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. EXPOSURES: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). MAIN OUTCOMES AND MEASURES: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. RESULTS: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (β = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls (β = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (β = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. CONCLUSIONS AND RELEVANCE: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.
Journal Article↗
Genetic susceptibility to psychiatric disorders.
Genetics contributes susceptibility to most psychiatric conditions and the understanding of these genetic factors is increasing rapidly. Because of such breakthroughs and their implications for patient care, professional nursing organizations support the incorporation of genetics into nursing curricula and the attainment of a working knowledge of genetics by all nurses. In this article, the basics of psychiatric genetics are presented to provide a foundation for the understanding of current and future findings in the field as well as information about family history assessment and appropriate references that the practitioner may find helpful.
Biological Psychiatry↗
Recent progress in psychiatric genetics-some hope but no hype.
The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.
Epistasis, Genetic↗
Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases.
IMPORTANCE: Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE: Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN SETTING AND PARTICIPANTS: Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES: Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS: The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE: Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking.
Journal Article↗
Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds.
Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets associated with a single or multiple disorders that implicate glutamate signaling. Drug prioritization indicated genetic support for psychotropic medications, including several top-ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders, providing novel opportunities for improving patient outcomes. Depicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next, a series of molecular trait analyses is conducted to generate and rank a list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome-wide association studies, MR = Mendelian randomization, coloc = colocalization.
Humans↗
At issue: genes, experience, and chance in schizophrenia--positioning for the 21st century.
Genetic factors make important contributions to the etiologies of schizophrenia. The mode of familial inheritance remains unknown, but it is highly likely that multiple genes and idiosyncratic environmental factors are involved. Rapidly evolving genetic technologies have been applied in the genetic analysis of schizophrenia, and several genomic regions have been posited as harboring susceptibility genes. Currently, the strongest evidence implicates chromosomes 6 and 8, but these linkages are not yet confirmed. In this article we discuss genetic risk factors, gene-environment interaction, the feasibility of genetic testing, psychiatric genetic counseling, and the dangers of genetic discrimination as they apply to schizophrenia. We also address and correct specific misconceptions about the genetics of schizophrenia held by many in the scientific community and in the media, and discuss a blueprint for future genetic research and informed dissemination of findings to the public and to lawmakers.
Diseases in Twins↗
Phenotype definitions: some hidden issues in psychiatry.
Three hidden problems in phenotype definition in psychiatric genetic studies are described. 1. Data on physical conditions in family members are not routinely collected in genetic studies of psychiatric disorders. These data may reveal cosegregation with psychiatric disorders which can be included in genetic analysis when defining the phenotype. Data on physical conditions can be obtained by a combination of medical checklists, medical history, and medical records. 2. Detailed clinical narrative summaries should be prepared on family members even if the narratives are not part of the diagnostic data included in centralized cell repositories for future distribution to qualified genetic investigators. Means for retaining the narratives for future use, while protecting patient confidentiality, should be sought. The narratives include detailed information on the context, severity, and sequence of the symptoms and can provide phenotype descriptions for reconsideration of diagnosis in the future. 3. The selection of early onset psychiatric disorders for genetic studies does not automatically mean that affected children should be included in genetic studies for some psychiatric disorders. Screening for genetic studies among child psychiatric patients and inclusion of children as affected in pedigrees should proceed with caution until more data are available from longitudinal studies on the continuity between childhood and adult psychiatric disorders.
Adult↗
[Introduction to genetic psychiatry: progress in uncovering genetic susceptibility to psychiatric disorders].
The recent progress in human genetics suggests major benefits in clinical practice, including psychiatry. This article introduces the research methodology used in psychiatric genetics and explains how it is applied, for a better understanding of the challenges facing psychiatric genetics and the strategies being used to overcome them. We will review the evidence of genetic factors in psychiatric disorder etiology as well as the specificity or non-specificity of their expression. We will discuss problems associated with the approximate nature of diagnostic methods, the incomplete penetrance and the genetic heterogeneity of psychiatric disorders, the presence of phenocopies and our uncertainty concerning the mode of inheritance of psychiatric disorders. Finally, we will provide an overview of the most promising results and set out priorities for future studies.
Genetic Markers↗
[Research approaches in the behavioral genetics of psychiatric disorders].
Multi-factorial inheritance combines genetic and environmental effects. Each factor contributes a relatively small part to the overall phenotype. Multi-factorial multi-genetic illnesses are usually divided into two categories: 1. Continuous variation of the normal distribution--phenotypes that can be measured within the normal scale (i.e. blood pressure). A normal distribution is obtained and the mean is in the middle. 2. Multi-factorial threshold trait--a threshold separates between the existence or absence of the phenotype. The curve of distribution obtained only predicts sensitivity for the illness rather than it's existence, since the illness appears only beyond a specific threshold, which represents a specific combination of defected genes. Mental illnesses (psychoses, affective disorders and neuroses) are multi-factorial illnesses, affected at a level of approximately 50% by inheritance. These diseases are not inherited in a simple Mendelian way, and, most probably, many genes are involved. Today, there is still no biochemical or molecular marker for any of the mental illnesses, and diagnosis of patients is obtained according to behavioral accepted scales. The aim of behavioral genetics is to understand the interaction between genes and behavioral variability among individuals. Most behaviors are complex, and when a genetic influence is observed, we can not point at a single responsible gene. Behavioral genetics targets to identify multiple genes and to understand the contribution of each of them to a specific behavioral trait. Methods to study multi-gene diseases include linkage analysis, family studies, twin and adoption studies, search for candidate genes affected by drug therapy of the patients, analysis of candidate genes using knockout mice and SNP's, methods that identify the effect of specific genes on behavior by QTL, and gene expression using DNA differential display and DNA microarray chips. The present review summarizes and exemplifies these issues.
Genetics, Behavioral↗
Genetic counseling in psychiatry.
While psychiatrists may commonly discuss family history in clinical practice, there has been little systematic research documenting the role and effectiveness of genetic counseling for psychiatric disorders. In the coming years, the expected identification of susceptibility genes for psychiatric disorders may bring new opportunities and expectations from patients and families for the clinical translation of research findings in psychiatric genetics. We review evidence for possible increasing demand for genetic counseling, particularly if specific genes related to psychiatric disorders are identified. We then explore both the potential role of genetic counseling for psychiatric disorders and the issues involved in conveying genetic information in the clinical setting. Further research regarding the effectiveness of counseling interventions, as well as additional efforts directed at genetics education for clinicians, will be needed if emerging advances in genetic research are to be incorporated into clinical practice.
Genetic Counseling↗
The thyroid: genetic and psychiatric relations.
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Genetic Therapy↗
A guide to the genetics of psychiatric disease.
The road to scientific discovery begins with an awareness of what is unknown. Research in science can in some ways be like putting together the pieces of a puzzle without having the benefit of the box-top picture of the completed puzzle. The "picture" in science is an understanding of how nature works in a particular instance, and it takes many separate pieces of the "puzzle" to put this understanding together. These pieces are always of different kinds of data, often obtained using different approaches and techniques. The challenge of the researcher is to picture or hypothesize each of the missing pieces before actually having them in hand, so they can be sought and tested in the laboratory. This "picturing" is actually having a clear idea of what you don't know: having a clear image of the "shape" of the missing piece. This is easy when the puzzle surrounding the missing piece is already in hand, but more difficult with less of it constrained by what is already known. In putting paper puzzles together, the shape of the pieces is not the only limitation that needs to be satisfied. There is also the picture to satisfy, that is, the picture usually has to make sense. In science these constraints can be manifold, and usually the quality of the research is judged by the number of ways a piece of data integrates into and brings together the rest of the puzzle. The multidimensionality of scientific questions makes it virtually essential that as many different pieces of the puzzle as possible be obtained. The more that is not known about the puzzle, the more pieces you need. Thus it is with the genetics of psychiatric diseases. In this guide, we will explore as many of the domains of the genetic puzzle as we are aware of. We will learn a bit of the language of each and how they fit into the puzzle with at least one anecdote to serve as an example. Mapping unknown territory is always a process, but we hope this guide will increase the reader's awareness of what is unknown.
Alzheimer Disease↗