Suchergebnisse

The current status of child and adolescent psychiatric genetics appears promising in light of the initiation of genome-wide association studies (GWAS) for diverse polygenic disorders and the molecular elucidation of monogenic Rett syndrome, for which recent functional studies provide hope for pharmacological treatment strategies. Within the last 50 years, tremendous progress has been made in linking genetic variation to behavioral phenotypes and psychiatric disorders. We summarize the major findings of the Human Genome Project and dwell on largely unsuccessful candidate gene and linkage studies. GWAS for the first time offer the possibility to detect single nucleotide polymorphisms and copy number variants without a priori hypotheses as to their molecular etiology. At the same time it is becoming increasingly clear that very large sample sizes are required in order to enable genome wide significant findings, thus necessitating further large-scaled ascertainment schemes for the successful elucidation of the molecular genetics of childhood and adolescent psychiatric disorders. We conclude by reflecting on different scenarios for future research into the molecular basis of early onset psychiatric disorders. This review represents the introductory article of this special issue of the European Child and Adolescent Psychiatry.

Summary: There is good evidence from recent studies that depression is familial, and that a substantial proportion of the variation in liability is explained by genes. Suicidal behavior, including completed suicide, also seems to cluster in families. First-degree relatives of individuals who have committed suicide (included dizygotic twins) have more than twice the risk of the general population. For identical co-twins of suicides, the relative risk increases to about 11. Applying a simple structural equation model to the published data suggests a heritability for completed suicide of about 43% (95% confidence intervals 25-60). It is not known at present whether the genes predisposing to suicide are identical with those predisposing to affective disorder, but since only about half of those committing suicide have a diagnosis of depression, it seems probable that the overlap is incomplete. The mode of inheritance of suicidal behavior is almost certain to be complex, involving many genes. There have already been some initial studies of allelic association with polymorphisms in candidate genes such as those involved in serotonergic transmission. Further progress is likely to come from candidate gene and linkage disequilibrium studies that are capable of detecting multiple genes of small effect.

Irving I. Gottesman played an important role for psychiatric genetic research in Denmark through more than 40 years of collaboration with Danish scientists, resulting in important twin and family studies based upon the unique national registers available in Denmark.

This paper examines the role of complexity in descriptions of the aetiology of common psychiatric disorders. While scientists attest to the discovery of an underlying reality of complex inheritance — the so-called 'witches' brew' of genetic and non-genetic factors — we argue that 'complexity' also performs rhetorical work. In our analysis of scientific review papers (1999—2008), we find a relatively stable genre of accountability in which descriptions of complexity appear to neutralize past failures by incorporating different and sometimes competing methodological perspectives. We identify two temporal strategies: retrospective accounting, which reconstructs a history of psychiatric genetics that deals with the recent failures, citing earlier twin studies as proof of the heritability of common psychiatric disorders; and prospective accounting, which engages in the careful reconstruction of expectations by balancing methodological limitations with moderated optimism. Together, these strategies produce a simple-to-complex narrative that belies the ambivalent nature of complexity. We show that the rhetorical construction of complexity in scientific review papers is oriented to bridging disciplinary boundaries, marshalling new resources and reconstructing expectations that justify delays in gene discovery and risk prediction.

Background:There continues to be significant investment in the detection of genotype × environment interaction (G × E) in psychiatric genetics. The implications of the method of assessment for the genetic analysis of psychiatric disorders are examined for simulated twin data on symptom scores and environmental covariates.Methods: Additive and independent genetic and environmental risks were simulated for 10,000 monozygotic (MZ) and 10,000 dizygotic (DZ) twin pairs and the 'subjects' administered typical simulated checklists of clinical symptoms and environmental factors. A variety of standard tests for G × E were applied to the simulated additive risk scores, sum scores derived from the checklists and transformed sum scores.Results:All analyses revealed no evidence for G × E for latent risk but marked evidence for G × E and other effects of modulation in the sum scores. These effects were all removed by transformation. An integrated genetic and psychometric model, accounting for both the causes of latent liability and a theory of measurement, was fitted to a sample of the simulated sum-score data and showed that there was no significant modulation of the parameters of the genetic model by environmental covariates (i.e., no G × E).Conclusions:Claims to detect G × E based on analytical methods that ignore the theory of measurement must be subjected to greater scrutiny prior to publication.

This paper seeks to make a contribution to the discussion on what clinical work consists of in biomedicine. It draws on the comparison between two clinical practices: (1) cancer genetics of breast/ovarian and colon cancers; and (2) psychiatric genetics of autism and its related syndromes. We argue that the clinic does not reflect genetic reductionism, nor does it entail a straightforward return to the previous clinical tradition. We show that the clinic is affected by three changes in the practices that we studied. The first change concerns clinical settings: clinical work is now performed by 'bioclinical collectives', gathering researchers and clinicians from various disciplines and activities, and conjointly searching biology and pathology. The second change concerns the content of clinical work that we propose to call 'clinic of mutations'. This clinic involves the intense work of collecting and comparing multiple and heterogeneous data to document the biological nature and the clinical relevance of mutations, whose status is ambiguous and whose effects are uncertain. The third change concerns the dynamics of clinical work, which is now overlapping with research. As a consequence, the elaboration of a judgment and a medical decision is no longer a matter of simply making a diagnosis or prognosis. Rather it consists in accounting for nosographic domains and descriptive and interpretive models of diseases, into which mutations may plausibly play a role. We conclude with a discussion of the form of objectivity underlying clinical work in biomedicine. Our contention is that in the current post-genomic era, thinking of genetic markers as objective proofs of a disease or a risk of disease is definitely inappropriate. Rather, the clinic has to constantly produce the meaning and relevance of mutations and biomedical entities that tend to proliferate and regularly invade the clinical settings.

<b><i>Background:</i></b> Psychiatric genetics has had limited success in translational efforts. A thorough understanding of the present state of translation in this field will be useful in the facilitation and assessment of future translational progress. <b><i>Purpose:</i></b> A narrative literature review was conducted. Combinations of 3 groups of terms were searched in EBSCOhost, Google Scholar, and PubMed. The review occurred in multiple steps, including abstract collection, inclusion/exclusion criteria review, coding, and analysis of included papers. <b><i>Results:</i></b> One hundred and fourteen articles were analyzed for the narrative review. Across those, 4 bottlenecks were noted that, if addressed, may provide insights and help improve and increase translation in the field of psychiatric genetics. These 4 bottlenecks are emphasizing linear translational frameworks, relying on molecular genomic findings, prioritizing certain psychiatric disorders, and publishing more reviews than experiments. <b><i>Conclusions:</i></b> These entwined bottlenecks are examined with one another. Awareness of these bottlenecks can inform stakeholders who work to translate and/or utilize psychiatric genetic information. Potential solutions include utilizing nonlinear translational frameworks as well as a wider array of psychiatric genetic information (e.g., family history and gene-environment interplay) in this area of research, expanding which psychiatric disorders are considered for translation, and when possible, conducting original research. Researchers are urged to consider how their research is translational in the context of the frameworks, genetic information, and psychiatric disorders discussed in this review. At a broader level, these efforts should be supported with translational efforts in funding and policy shifts.