Abstract
BackgroundFor diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms.Results and MethodologyWe introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21.ConclusionsThe findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression.
Highlights
Emil Kraepelin’s descriptions of psychiatric diagnoses at the turn of the 20th century were groundbreaking and remain influential to this day
Kraepelin’s dichotomous classification of manic-depressive insanity and dementia praecox provides a simple way for conceptualizing an often complex clinical picture and has been extended to include a categorical classification system utilized for a vast array of psychiatric illnesses [1]
We present an analytical framework for detection of genetic factors contributing to specific subsets of behavioral symptoms
Summary
Emil Kraepelin’s descriptions of psychiatric diagnoses at the turn of the 20th century were groundbreaking and remain influential to this day. Kraepelin’s dichotomous classification of manic-depressive insanity (bipolar disorder) and dementia praecox (schizophrenia) provides a simple way for conceptualizing an often complex clinical picture and has been extended to include a categorical classification system utilized for a vast array of psychiatric illnesses [1] The validity of such a categorical classification system has been challenged, as providing an unsatisfactory model of mental illness [2,3,4,5]. For diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms
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