Molecular genetics of psychopathologies: A search for simple answers to complex problems

Ginsburg, Benson E.; Werick, Theresa M.; Escobar, Javier I.; Kugelmass, Sol; Treanor, John J.; Wendtland, Leigh

doi:10.1007/bf02359388

Cited by 40 publications

(32 citation statements)

References 51 publications

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“…Amidst growing doubts in the capacity of the broad diagnostic category to serve as a reliable phenotype for gene discovery, [193][194][195][196] the concept of endophenotype (intermediate, elementary, alternative, or correlated phenotype) offered a novel perspective on subtyping schizophrenia that could be either an alternative or a complement to symptom-based phenotypes. The term, originating in early 20th century plant and insect genetics, was introduced into schizophrenia genetics by Gottesman and Shields.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

Subtyping schizophrenia: implications for genetic research

2006

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Phenotypic variability and likely extensive genetic heterogeneity have been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. The inconsistent results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype suggest that the current broad concept of schizophrenia does not demarcate a homogeneous disease entity. Approaches involving subtyping and stratification by covariates to reduce heterogeneity have been successful in the genetic study of other complex disorders, but rarely applied in schizophrenia research. This article reviews past and present attempts at delineating schizophrenia subtypes based on clinical features, statistically derived measures, putative genetic indicators, and intermediate phenotypes, highlighting the potential utility of multidomain neurocognitive endophenotypes.

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Section: Molecular Psychiatrymentioning

confidence: 99%

Subtyping schizophrenia: implications for genetic research

2006

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“…Traditionally the definition of the phenotype has been based on categorical diagnoses which do not guarantee biological homogeneity and have been considered reductive of the amount of information available from the whole symptomatologic presentation of patients. [30][31][32] Moreover, converging evidence indicates that susceptibility genes only elicit limited symptomatologic effects on psychiatric syndromes. [33][34][35] We have, therefore, developed a phenotype definition that is based on four symptomatological factors: Excitement, Depression, Delusion and Disorganization.…”

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confidence: 99%

“…36 This is an alternative to the traditional use of psychiatric diagnoses to define the affected phenotype for genetic studies. 30,31 However, the use of symptoms for phenotype definition may be considered a limitation as symptomatologic presentation may vary across illness episodes. We used a lifetime scoring perspective including ever-presented symptoms to reduce this bias, and follow-up studies evidenced that episodes are substantially stable over time.…”

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confidence: 99%

Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

et al. 2000

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The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses. Molecular Psychiatry (2000) The D2 receptor is the major binding site of many typical and atypical neuroleptic drugs and its gene has been cloned and mapped to 11q22-23.2 Itokawa et al 3 reported a polymorphism causing a structural change from Serine to Cysteine at codon 311 of DRD2 (S311C); this substitution occurs in the third intracellular loop of the receptor. Preliminary results showed that DRD2 rarer TaqI variants were associated with higher levels of the monoamine metabolites homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in lumbar cerebrospinal fluid in controls. 4 S311C has been proposed as Correspondence: A Serretti MD,

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“…However, finding individual susceptibility loci using diagnosis as a phenotype may be problematic. [21][22][23] Whereas schizophrenia is broadly heritable as a complex clinical entity, its symptoms show significant inter-and intra-individual variation, both cross-sectionally and over time, 24 and may not provide robust phenotypes for genetic study. Moreover, the genotypes underlying schizophrenia tend to remain clinically unexpressed in the majority (80-90%) of first-degree relatives.…”

Section: Introductionmentioning

confidence: 99%

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

et al. 2003

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As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/ DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic firstdegree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS43.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

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Molecular genetics of psychopathologies: A search for simple answers to complex problems

Cited by 40 publications

References 51 publications

Subtyping schizophrenia: implications for genetic research

Subtyping schizophrenia: implications for genetic research

Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia

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