Genetic Basis Of Psychiatric Disorders Research Articles

Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk.

Despite the strong genetic basis of psychiatric disorders, the underlying molecular mechanisms remain largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translational to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. However, quantifying the pathogenic contribution of noncoding variants impacting RBP target sites is challenging. Here, we leverage a deep learning approach that can accurately predict RBP target site dysregulation effects of mutations, and discover that RBP dysregulation is a principal contributor to psychiatric disorder risk. RBP dysregulation explains a substantial amount of heritability not captured by large-scale molecular QTL studies, and has a stronger impact than common coding region variants. We share genome-wide profiles of RBP dysregulation, which we use to identify DDHD2 as a candidate schizophrenia risk gene. This resource provides a novel analytical framework to connect the full range of RNA regulation to complex disease.

Investigating assumptions of vulnerability: A case study of the exclusion of psychiatric inpatients as participants in genetic research in low- and middle-income contexts.

Psychiatric genetic research investigates the genetic basis of psychiatric disorders with the aim of more effectively understanding, treating, or, ultimately, preventing such disorders. Given the challenges of recruiting research participants into such studies, the potential for long-term benefits of such research, and seemingly minimal risk, a strong claim could be made that all non-acute psychiatric inpatients, including forensic and involuntary patients, should be included in such research, provided they have capacity to consent. There are tensions, however, regarding the ethics of recruiting psychiatric inpatients into such studies. In this paper our intention is to elucidate the source of these tensions from the perspective of research ethics committee interests and decision-making. We begin by defining inpatient status and outline some of the assumptions surrounding the structures of inpatient care. We then introduce contemporary conceptions of vulnerability, including Florencia Luna’s account of vulnerability which we use as a framework for our analysis. While psychiatric inpatients could be subject to consent-related vulnerabilities, we suggest that a particular kind of exploitation-related vulnerability comes to the fore in the context of our case study. Moreover, a subset of these ethical concerns takes on particular weight in the context of genetic research in low- and middle-income countries. At the same time, the automatic exclusion of inpatients from research elicits justice-related vulnerabilities.

Genetics and genetic counseling in psychiatry: Results from an opinion survey of professionals and users.

BackgroundThe heritability of several psychiatric disorders is high, and specific at‐risk variants have been identified. Therefore, genetic counseling and genetic testing can be prescribed to some psychiatric patients, but these services are not standardized for most of the population. The aims of the study were to gather opinions from mental health professionals and users regarding (a) the genetics of psychiatric disorders and (b) the usefulness of a genetic counseling unit in psychiatry.MethodsThe survey was conducted in the province of Tarragona (Spain), and we analyzed 152 valid questionnaires from professionals and 959 from users.ResultsSixty‐one percent of professionals strongly believed that psychiatric disorders have a genetic basis, and 59% rated a genetic counseling unit in psychiatry as very or extremely useful. However, only a few professionals reported that patients asked them about the genetics of their diseases (12%) or the possibility of transmitting the disease to offspring (19%). Forty‐seven percent of users strongly believed that psychiatric disorders have a genetic basis, 30% responded that they talked with their families about the genetics of their diseases, and 43% were worried about transmitting the disease to offspring; however, only 14% reported that their psychiatrist had talked to them about this topic. Remarkably, 80% of users would consider a genetic counseling unit very or extremely useful.ConclusionsThe present study showed that mental health professionals were more aware of the genetic basis of psychiatric disorders than users, and both considered the implementation of a genetic counseling service very useful.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 – 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 – rs2086256 – rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

Integrated analysis supports ATXN1 as a schizophrenia risk gene

Protein-protein interaction (PPI) is informative in identifying hidden disease risk genes that tend to interact with known risk genes usually working together in the same disease module. With the use of an integrated approach combining PPI information with pathway and expression analysis as well as genome-wide association study (GWAS), we intended to find new risk genes for schizophrenia (SCZ). We showed that ATXN1 was the only direct PPI partner of the know SCZ risk gene ZNF804A, and it also had direct PPIs with other 18 known SCZ risk genes. ATXN1 serves as one of the hub genes in the PPI network containing many known SCZ risk genes, and this network is significantly enriched for the MAPK signaling pathway. Further gene expression analysis indicated that ATXN1 is highly expressed in prefrontal cortex, and SCZ patients had significantly decreased expression compared with healthy controls. Finally, the published GWAS data supports an association of ATXN1 with SCZ as well as other psychiatric disorders though not reaching genome-wide significance. These convergent evidences support ATXN1 as a promising risk gene for SCZ, and the integrated approach serves as a useful tool for dissecting the genetic basis of psychiatric disorders.

The Science of The Psychiatric Genomics Consortium (Part 2)

Overall Abstract On the advice of the Jerusalem organizers, the Psychiatric Genomics Consortium (PGC) is submitting two symposia which are meant to occur on the same afternoon. The PGC, now in its ninth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 900+ investigators from 40+ countries and >400K subjects. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. Due to our open-source approach, there are 75+ papers that use PGC results, and numerous groups are using our findings to direct basic and applied research (including therapeutic development). Large amounts of new data will be available to the PGC in the next five years. We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify “actionable” variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. In Part 2, we provide more informationn about the current status and future plans for additional key PGC groups: OCD and TS (Knowles), PTSD (Liberzon), schizophrenia (O'Donovan), substance use disorders (Gelertner), pathway analysis (Breen), and cross-disorder findings (Smoller).

The Science of The Psychiatric Genomics Consortium (Part 1)

Overall Abstract On the advice of the Jerusalem organizers, the Psychiatric Genomics Consortium (PGC) is submitting two symposia which are meant to occur on the same afternoon. The PGC, now in its ninth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 900+ investigators from 40+ countries and >400K subjects. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. Due to our open-source approach, there are 75+ papers that use PGC results, and numerous groups are using our findings to direct basic and applied research (including therapeutic development). Large amounts of new data will be available to the PGC in the next five years. We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify “actionable” variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. In Part 1, we provide a big picture overview of where we've been and where we are (Sklar) followed by a description of the just awarded PGC3 grant (Sullivan). This is followed by updates of the current status and future plans for the key PGC groups: ADHD and ASD (Borglum from iPSYCH), bipolar disorder (Kelsoe), eating disorders (Bulik), and MDD (Levinson).

Psychiatric Genomics Consortium: Past And Present

The Psychiatric Genomics Consortium (http://pgc.unc.edu), now in its eighth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 800+ investigators from 36 countries and >400K subjects. The PGC has attracted a cadre of outstanding scientists whose careers center on our work.During the first phase of our efforts, we completed mega-analyses for ADHD, AUT, BD, MDD, and SCZ and preliminary cross-disorder analysis (cases defined as either BIP, MDD or SCZ). In total, the PGC has published 17 main papers plus 31 secondary analysis/methods development papers including a landmark Nature paper identifying 108 loci for schizophrenia (SCZ). Due to our open-source approach, there are 75+ papers that use PGC results, and we know of numerous groups that are using our findings to direct basic and applied research (including therapeutic development).We will describe the results of the two phases of our efforts to date, including recent efforts extending GWAS to >120,000 new individuals across multiple disorders using a custom microarray, PsychCHIP.

Genome-wide association studies in psychiatry: what have we learned?

Genome-wide association studies (GWAS) have been the focus of considerable effort in psychiatry. These efforts have markedly increased knowledge of the genetic basis of psychiatric disorders, and yielded empirical data on genetic architecture critical to addressing long-standing debates in the field. There is a now a clear path to increased knowledge of the 'parts lists' for these disorders.

AS23-04 - The phenotype - the still unknown quantity in psychiatric genetics?

Research into the genetic basis of psychiatric disorders has reached a turning point. Genome-wide association studies (GWAS), encompassing several thousand samples, have produced replicated evidence for some novel susceptibility genes; however, the genetic variants implicated so far account for only a fraction of disease liability, a phenomenon not limited to psychiatric phenotypes but characteristic of all complex genetic traits studied to date. It appears that pure genomic approaches, such as GWAS alone, will not suffice to unravel the genetic basis of psychiatric phenotypes. Apart from sophisticated genomic, epigenomic, and neurobiological approaches, the comprehensive study of the phenotype will be a hallmark of 21 st century psychiatric genetics. The analysis of cross-sectional, categorical disease phenotypes by traditional statistical tools alone will have to be replaced by novel approaches modeling the complexity of psychiatric phenotypes. A framework is presented that encompasses strategies (1) to ascertain longitudinal phenotypes, (2) to systematically and prospectively assess environmental influences on phenotypic presentations, (3) to delineate phenotypes for pharmacogenetic studies, and (3) to define robust genotype-phenotype signatures or patterns using novel data-mining tools.

Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses

In this article, we review some of the data that contribute to our understanding of the genetic architecture of psychiatric disorders. These include results from evolutionary modelling (hence no data), the observed recurrence risk to relatives and data from molecular markers. We briefly discuss the common-disease common-variant hypothesis, the success (or otherwise) of genome-wide association studies, the evidence for polygenic variance and the likely success of exome and whole-genome sequencing studies. We conclude that the perceived dichotomy between 'common' and 'rare' variants is not only false, but unhelpful in making progress towards increasing our understanding of the genetic basis of psychiatric disorders. Strong evidence has been accumulated that is consistent with the contribution of many genes to risk of disease, across a wide range of allele frequencies and with a substantial proportion of genetic variation in the population in linkage disequilibrium with single-nucleotide polymorphisms (SNPs) on commercial genotyping arrays. At the same time, most causal variants that segregate in the population are likely to be rare and in total these variants also explain a significant proportion of genetic variation. It is the combination of allele frequency, effect size and functional characteristics that will determine the success of new experimental paradigms such as whole exome/genome sequencing to detect such loci. Empirical results suggest that roughly half the genetic variance is tagged by SNPs on commercial genome-wide chips, but that individual causal variants have a small effect size, on average. We conclude that larger experimental sample sizes are essential to further our understanding of the biology underlying psychiatric disorders.

Meta-Analysis of the Cognitive Effects of the Catechol- O-Methyltransferase Gene Val158/108Met Polymorphism

Cognitive endophenotypes may further our understanding of the genetic basis of psychiatric disorders, and the catechol-O-methyltransferase (COMT) gene is a promising candidate gene for both cognitive function and disorder. We conducted a meta-analysis of reported associations between the COMT Val158/108Met polymorphism and measures of memory and executive function. The PubMed database was searched for studies relating cognitive functions and the COMT Val158/108Met polymorphism. This enabled meta-analyses of six cognitive phenotypes (Trail Making task, verbal recall, verbal fluency, IQ score, n-back task, and Wisconsin Card Sorting Test). Data were extracted by two reviewers and included cognitive scores by COMT genotype, publication year, diagnostic status, ancestry, proportion of male participants, and whether genotype frequencies were consistent with Hardy-Weinberg equilibrium. We found no association between COMT genotype and the majority of phenotypes. There was evidence of association with IQ score (d = .06), which did not differ significantly by ancestry, sex, average sample age, or patient status. For the n-back task, there was no robust evidence for genetic association, but the effect size was significantly larger in patient (d = .40) than nonpatient (d = -.27) populations, larger in both samples with fewer male subjects, and those of greater average age. There was also evidence of publication bias and decreasing effect sizes with later publication. Despite initially promising results, the COMT Val158/108Met polymorphism appears to have little if any association with cognitive function. Publication bias may hamper attempts to understand the genetic basis of psychological functions and psychiatric disorders.

Le conseil génétique en psychiatrie

There are several lines of evidence supporting the role of genetic factors in major psychiatric disorders. The evidence is mainly provided by family and twin studies. These have documented the familiality of disorders such as autism, schizophrenia, bipolar disorder or major depression. These data are relevant in providing information about familial risk of illness. Nevertheless, the available information is still limited and this probably justifies the little attention paid to genetic counselling for psychiatric disorders. However, probably related to the recent high profile of genetics, clinicians are now confronted with questions from patients and their families regarding risks of disorders for themselves and/or their relatives. Despite the difficulty to precise the risk of recurrence for psychiatric disorders and since having a family history of the disorder is currently the best predictor for the development of these disorders, it is noteworthy that the American Psychiatric Association guidelines for the treatment of bipolar disorder suggest that genetic counselling is helpful for patients who are considering having children. 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 counselling, particularly if specific genes related to psychiatric disorders are identified. We also explore both the potential role of genetic counselling for psychiatric disorders and the issues involved in conveying genetic information in the clinical setting. The psychiatry genetics is currently in its infancy, but with accelerating advances in understanding the genetic basis of psychiatric disorders, psychiatrists will certainly be called upon to incorporate genetic information into clinical practice.