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Molecular Genetic Studies of Psychopathology

Molecular Genetic Studies of Psychopathology

Molecular genetic studies of most major forms of psychopathology have become a major area of contemporary etiological research. Approaches to f inding genes that underlie psychiatric disorders have included both association studies of the role of specific candidate genes, as well as genome scans of anonymous DNA markers by using linkage analysis.

Generally speaking, such studies have produced mixed findings for almost all psychiatric disorders; some studies report exciting positive findings, and others report failures to replicate. There are many reasons for these mixed f indings and failures to replicate, but one of these deserves special attention, in our opinion. Molecular genetic analyses of psychiatric disorders might be more successful if continuous symptom dimensions or related traits are analyzed either along with, or instead of, the categorical disorder phenotype (viz., the diagnosis). Consider the case of the genetics of schizophrenia as a specific example. Recent results suggest that linkage analyses based on more specific phenotypic indicators than the schizophrenia diagnosis alone may be more successful than a search for linkage among individuals diagnosed with schizophrenia but with disparate syndromes and ymptoms. For example, Brzustowicz et al. hypothesized that different aspects of the schizophrenic phenotype may be influenced by different genes. Their evaluation of genetic markers on the short arm of chromosome 6 revealed no evidence for linkage by using categorical schizophrenia diagnostic definitions (i.e., narrow, broad, and very broad). Examining linkage for positive symptom, negative symptom, and general psychopathology symptom scales, however, yielded significant evidence for linkage for the positive symptom scale only. The specificity of these results suggests that the positive and negative dimensions of schizophrenia may have different susceptibility loci, in which case schizotypy may be genetically related to schizophrenia through a common diathesis pertaining to negative symptoms. Similarly, Serretti, Macciardi, and Smeraldi hypothesized that the influence of dopamine D2 receptor gene (DRD2) variants should be analyzed at the symptom dimension, rather than syndrome, level. They based their reasoning on the results of a previous study that found a stronger association between DRD2 and schizophrenia in those subjects without negative symptoms identified four factors of psychotic symptoms. Subjects with the S311C variant of DRD2 presented with higher scores on the Disorganization factor than those without this particular variant. Moreover, none of the other factors (Excitement, Depression, Delusion) was associated with the S311C variant. These results also suggest that different aspects of the schizophrenic phenotype may be influenced by different underlying genetic vulnerabilities. The results of multivariate behavior genetic studies of disorders also have important implications for molecular genetic studies of those disorders. It is important to know, for example, whether candidate genes that influence one disorder (e.g., ADHD) also influence other related disorders (e.g., ODD and CD). Multivariate behavior genetic analyses of such disorders can help guide molecular genetic research by determining to what extent the substantial phenotypic overlap among them is due to common genetic influences compared with common environmental influences. Multivariate behavior genetic analyses also can suggest whether all of the genetic influences on these disorders are shared in common or whether each of the disorders exhibits genetic influences that are unique compared to those on the others. If the latter is true, a search for candidate genes that influence ODD and CD uniquely would be fruitful, whereas if the former is true, one would need merely to search for candidate genes for ADHD to f ind those that also influence childhood antisocial behavior.

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