RESUMEN

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

Asunto(s)

Canales de Calcio Tipo L/genética , Factores de Transcripción de Tipo Kruppel/genética , Sustancia Blanca/fisiología , Adulto , Alelos , Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Canales de Calcio Tipo L/metabolismo , Imagen de Difusión Tensora , Epistasis Genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Sustancia Blanca/metabolismo , Sustancia Blanca/ultraestructura

RESUMEN

The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.

Asunto(s)

Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Encéfalo/fisiopatología , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Ancirinas/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Trastorno Bipolar/psicología , Canales de Calcio Tipo L/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Femenino , Neuroimagen Funcional , Genes , Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/psicología , Genoma , Estudio de Asociación del Genoma Completo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Lectinas Tipo C/genética , Masculino , Mutación/genética , Proteínas del Tejido Nervioso/genética , Neurocano , Neurogranina/genética , Fenotipo , Polimorfismo Genético , Trastornos Psicóticos/fisiopatología , Factores de Riesgo , Psicología del Esquizofrénico , Factor de Transcripción 4 , Factores de Transcripción/genética

Asunto(s)

Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Canales de Calcio Tipo L/genética , Emociones/fisiología , Polimorfismo Genético/genética , Adulto , Trastorno Bipolar/patología , Encéfalo/patología , Familia , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Método de Montecarlo , Vías Nerviosas/patología

RESUMEN

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.

Asunto(s)

Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Proteínas del Tejido Nervioso/genética , Corteza Prefrontal/fisiopatología , Esquizofrenia/genética , Adulto , Sustitución de Aminoácidos/genética , Trastorno Bipolar/epidemiología , Comorbilidad/tendencias , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Corteza Prefrontal/metabolismo , Esquizofrenia/epidemiología

Asunto(s)

Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/fisiología , Serina/genética , Aprendizaje Verbal/fisiología , Factores de Edad , Mapeo Encefálico , Cisteína/genética , Femenino , Lateralidad Funcional/genética , Genotipo , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Corteza Prefrontal/anatomía & histología