A Novel Analytical Framework for Dissecting the Genetic Architecture of Behavioral Symptoms in Neuropsychiatric Disorders

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.

A genome‐wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32

“…We detected a suggestive linkage signal at chromosome 2q13‐14, a region previously implicated in a number of studies to be associated with BP [Abou Jamra et al, ; DeLisi et al, ; Deo et al, ; Etain et al, ; Labbe et al, ; Lewis et al, ; Mathieu et al, ; McGough et al, ; Papiol et al, ]. Although we did not obtain genome‐wide significance threshold for linkage, several individual SNPs within this region showed evidence of association (Table ).…”

Enhanced Persistency of Resting and Active Periods of Locomotor Activity in Schizophrenia

“…One promising strategy to build animal models of mental illness is translating human behavior into animals [37], [38]. However, the translation of human behavioral abnormalities is quite difficult because of the absence of an established method to evaluate humans quantitatively.…”

Comprehensive neurocognitive endophenotyping strategies for mouse models of genetic disorders

“…Optimally, a wide reaching behavioral assessment should be performed, ranging from an analysis of basic sensory function to tasks evaluating general memory--a process analogous to neurological/neuropsychological testing in patient populations ( e.g. , SHIRPA; Hatcher et al , 2001; Rogers et al , 1997, 1999, 2001; other protocols; Ahmed, 2010; Deo et al , 2010; Kendler and Neale, 2010; Kuang et al , 2010; Matsuo et al , 2010; Ryan et al , 2008, 2010; Takao et al , 2010; Taylor et al , 2010; Tennant and Jones, 2009; Wang et al , 2009; Zang et al , 2009). With such a battery, any confounding factors related to strain background may be identified and controlled for by comparison of the model with littermate or strain-related controls, as it is important to determine whether any major behavioral phenotypes are present in the mouse model at the outset of experimentation.…”