Psychiatric Disorders - Reading.pdf

Psychiatric Disorders - Reading 19 December 2023 14:37 Source Notes Psychiatric genetics and the structure of psychopathology Background: The study explores the relationship between psychiatric disorders and genetic variations, and its implications for the classification of psychopathology. It discu...

Psychiatric Disorders - Reading 19 December 2023 14:37 Source Notes Psychiatric genetics and the structure of psychopathology Background: The study explores the relationship between psychiatric disorders and genetic variations, and its implications for the classification of psychopathology. It discusses the challenges faced by psychiatry in validating descriptive syndromes and defining boundaries between disorders and normal variation. The study highlights the recent advances in genomic research and collaborative efforts like the Psychiatric Genomics Consortium. (Smoller et al., 2018) Methods: The study utilizes large-scale collaborative efforts and genomic research to identify common and rare genetic variations associated with neuropsychiatric disorders. It emphasizes the need for very large studies and mega-analyses to identify these genetic variations. The study also discusses the importance of longitudinal population-based cohorts with genomic data for understanding disorder risk and gene-environment interplay. Results: The study reveals that psychiatric disorders are highly polygenic, influenced by hundreds to thousands of common variants of small effect and rare single-nucleotide variants (SNVs) and copy number variations (CNVs). It suggests that genetic influences on psychopathology transcend the diagnostic boundaries of the clinical DSM nosology. The study also highlights the overlaps between psychiatric disorders and measures of brain structure, indicating shared genetic influences Critical Analysis and conclusions: Strengths: ○ The study provides a comprehensive overview of the relationship between psychiatric disorders and genetic variations, incorporating recent advances in genomic research. ○ It highlights the importance of large-scale collaborative efforts and the need for very large studies to identify genetic variations. ○ The study emphasizes the significance of longitudinal population-based cohorts with genomic data for understanding disorder risk and gene-environment interplay. Limitations: ○ The study acknowledges that genetic data alone may not lead to empirically derived diagnoses, but it can aid in the revision or formulation of diagnostic criteria in the future. ○ The study suggests that genetic data will incrementally help the DSM evolve, rather than revolutionize the clinical psychiatric nosology. ○ The study acknowledges that while genetic research has begun to elucidate the underlying structure of psychopathology, there are still many unanswered questions. ○ It emphasizes the need for larger studies incorporating DNA sequencing, environmental exposures, and phenomewide analyses to gain a more granular understanding of the genetic etiology and phenotypic spectrum of mental illness In summary, this study provides valuable insights into the relationship between psychiatric disorders and genetic variations. It highlights the polygenic nature of these disorders and the need for large-scale collaborative efforts to identify genetic variations. The study also emphasizes the importance of considering environmental risk factors and taking a developmental perspective in understanding the etiology and structure of psychopathology. However, it acknowledges that genetic data alone may not lead to empirically derived diagnoses and that further research is needed to fully understand the genetic etiology and phenotypic spectrum of mental illness. A joint history of the nature of genetic variation and the nature of schizophrenia (Kendler, 2015) Background: The essay traces the history of concepts of genetic variation and schizophrenia from Darwin and Mendel to the present. The debate between the Biometricians and the Mendelians about the nature of gene action is discussed. The central limit theorem and the concept of multiple genes of small effect are introduced as potential explanations for the patterns of resemblance in relatives sought by the Biometricians The reconnection between psychiatric and biometrical genetics in the 1960s is highlighted, leading to the polygenic theory of schizophrenia Method: The essay discusses the use of biometrical methods and statistical approaches to study gene action in schizophrenia The lack of success of linkage studies in identifying common single major loci (SML) for schizophrenia is mentioned Genome-wide association studies (GWAS) and sequencing studies are introduced as methods that provided positive evidence for polygenes in schizophrenia The use of Genome-Wide Complex Trait Analysis (GCTA) and approximate Bayesian polygenic analysis in GWAS is described Results: GWAS of schizophrenia revealed that a large proportion of the genetic liability to schizophrenia results from hundreds, if not thousands, of individual risk variants, both common and rare The population distribution of genetic risk for schizophrenia is likely to be approximately normal, with some small bumps in the high liability tail The correlation between the contribution of variants to schizophrenia risk and the length of the chromosome supports a highly polygenic model The largest GWAS estimated that 8300 independent, mostly common SNPs contribute to risk for schizophrenia Critical analysis and conclusion: The historical effort to ground the categorical nature of schizophrenia in genetic theory has failed The essay highlights the parallels between the historical debates about the nature of genetic variation and the current debates about the nature of schizophrenia The use of Fisher's model of many segregating genes of small effect to explain the pattern of continuous variation and correlation in relatives seen by the Biometricians is discussed The essay suggests that the merging of Mendelian and Biometrical models in molecularly verified polygene models may diminish debates about who are the geneticists The intuitive model of schizophrenia spectrum disorders as milder conditions on the same continuum of genetic risk as schizophrenia is supported by statistical evidence Strengths: ○ The essay provides a comprehensive historical overview of the concepts of genetic variation and schizophrenia, tracing their development from Darwin and Mendel to the present. ○ The inclusion of excerpts from relevant studies and publications adds credibility to the analysis. ○ The essay highlights the importance of both biometrical and molecular genetic approaches in understanding the nature of schizophrenia. ○ The discussion of Fisher's model and the use of GWAS and sequencing studies adds depth to the analysis. Conclusion PSYC0036 Genes and Behaviour Page 1 Conclusion ○ Overall, the essay provides a valuable historical perspective on the nature of genetic variation and its relationship to schizophrenia. ○ It highlights the shift from a dichotomous view of gene action to a more nuanced understanding of polygenic risk. ○ The strengths lie in the comprehensive overview and inclusion of relevant studies, while the limitations include a lack of detailed statistical analysis and discussion of potential confounders. ○ Further research is needed to explore the specific genetic variants and mechanisms underlying schizophrenia and to understand how these variants interact with environmental factors. ○ Additionally, future studies could investigate the implications of the polygenic nature of schizophrenia for personalized medicine and treatment approaches. ○ It is important to note that while the essay provides a historical perspective and synthesizes existing research, it does not provide a definitive answer to all questions about the nature of genetic variation and schizophrenia. ○ The field of psychiatric genetics is complex and evolving, and new discoveries and theories may emerge in the future. Genetic and Environmental Influences on the Developmental Course of AttentionDeficit/Hyperactivity Disorder Symptoms From Childhood to Adolescence (Pingault et al., 2015) Background: ADHD is a neurodevelopmental disorder with substantial genetic influences. However, there's limited research on the developmental trajectory of ADHD symptoms, which could significantly inform clinical practice, prognosis, and intervention strategies. This study aims to investigate the impact of genetic and environmental influences on the developmental course of ADHD symptom domains (hyperactivity/impulsivity and inattention) in a large population-based sample of twins from childhood to adolescence. Methods: Participants: 8395 twin pairs from the Twins Early Development Study. Measures: ADHD symptom subscale from the Conners’ Parent Rating Scales–Revised, assessing hyperactivity/impulsivity and inattention at ages 8, 11, 14, and 16 years. Statistical Analysis: ○ Latent growth curve models were used to examine developmental trajectories. ○ Genetic and environmental influences were assessed using ACE (additive genetic influence, common environment, nonshared environment) and ADE (nonadditive genetic influence) models. Results: Phenotypic Trends: Hyperactivity/impulsivity decreased steadily, while inattention showed a less pronounced decline, with some individuals experiencing increasing symptoms. Genetic Influences: Both domains were influenced by genetics, with different patterns: predominantly additive genetic effects for hyperactivity/impulsivity and a combination of additive and nonadditive genetic effects for inattention. Developmental Course: Genetic influences largely independent of baseline symptoms affected the developmental course of both domains. The decline in symptoms and its variations were significantly genetically driven. Critical Analysis and conclusions: Strengths: ○ Longitudinal Population-Based Study: Followed twins from childhood to adolescence. ○ Consistent Assessment: Used the same measure across multiple time points, enabling the modeling of systematic change with age. ○ Differentiated Symptom Domains: Analysed separate symptom domains (hyperactivity/impulsivity and inattention). Limitations: ○ Rater-Related Bias: Relied on maternal ratings, which might introduce bias. ○ Age Range: Lack of adulthood data and instruments for the transition to adulthood. ○ Generalizability: Findings based on population-level symptoms, not clinical diagnoses. Implications: ○ Clinical Relevance: Understanding the genetic basis for symptom persistence informs clinicians about markers of vulnerability, facilitating closer monitoring and tailored interventions. ○ Genetic Variants: Identifying genetic variants associated with symptom trajectories could aid in predicting persistence or remission of symptoms. Conclusions Overall, the study sheds light on the genetic influences shaping the developmental course of ADHD symptoms. The findings suggest a need for further research into genetic variants associated with symptom trajectories and their implications for clinical practice and intervention strategies. PSYC0036 Genes and Behaviour Page 2