Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia

Blackwood, Douglas; Glabus, Michael F.; Dunan, Julie; O’Carroll, Ronan; Muir, Walter; Ebmeier, Klaus P.

doi:10.1192/bjp.175.4.357

Cited by 60 publications

(20 citation statements)

References 64 publications

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“…P300 amplitude reduction may not be specifically related to an increased risk for alcohol dependence as reduction in amplitude has been found in association with other psychiatric disorders. A family study that recorded auditory event-related potentials from members of 20 multiplex families with schizophrenia found P300 latency delayed and amplitude reduced in schizophrenics in comparison to controls and in about half of the asymptomatic relatives, though not all families were characterized by this pattern [Blackwood et al, 1999]. A segregation analysis using ERP characteristics found P300 latency as a marker for predisposition to schizophrenia [Sham et al, 1994].…”

Section: Discussionmentioning

confidence: 99%

A genome wide search for alcoholism susceptibility genes

Hill

Shen

Zezza

et al. 2004

American J of Med Genetics Pt B

115

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Alcoholism is currently one of the most serious public health problems in the US. Lifetime prevalence rates are relatively high with one in five men and one in 12 women meeting criteria for this condition. Identification of genetic loci conferring an increased susceptibility to developing alcohol dependence could strengthen prevention efforts by informing individuals of their risk before abusive drinking ensues. Families identified through a double proband methodology have provided an exceptional opportunity for gene-finding because of the increased recurrence risks seen in these sibships. A total of 360 markers for 22 autosomes were spaced at an average distance of 9.4 cM and genotyping performed for 330 members of these multiplex families. Extensive clinical data, personality variation, and event-related potential characteristics were available for reducing heterogeneity and detecting robust linkage signals. Multipoint linkage analysis using different analytic strategies give strong support for loci on chromosomes 1, 2, 6, 7, 10, 12, 14, 16, and 17.

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Section: Discussionmentioning

confidence: 99%

A genome wide search for alcoholism susceptibility genes

Hill

Shen

Zezza

et al. 2004

American J of Med Genetics Pt B

115

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“…This is as a result of the welldocumented deficits in particular cognitive tasks involving learning and memory in individuals with schizophrenia, bipolar disorder and unipolar major depression. [60][61][62] Presynaptic changes in kainate receptor-dependent plasticity have been described at hipocampal mossy fibre synapses, 63,64 suggesting that the expected reduction in GRIK4 protein levels in the karyotypically abnormal patient might be expected to modify kainate receptor channel properties, and their contribution to LTP, by altering subunit stoichiometry.…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

et al. 2006

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In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P = 0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P = 0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P = 0.0430, s.e. 0.0064 and P = 0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.

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“…P300 shows reduced amplitude and increased latency in patients with schizophrenia and their relatives (Blackwood et al, 1991;Freedman and Squires-Wheeler, 1994) and also in families of patients with bipolar disorder (Pierson et al, 2000). In patients with schizophrenia, P300 changes correlate with cognitive impairment including verbal memory and verbal fluency deficits (Souza et al, 1995;Shajahan et al, 1997a;Blackwood et al, 1999) and are accompanied by altered regional cerebral blood flow measured by SPECT (Shajahan et al, 1997b). Eye movement abnormalities have been widely studied in schizophrenia (Levy et al, 1994), and Arolt et al (1996) identified a chromosome 6 locus for an eye tracking endophenotype.…”

Section: Intermediate Phenotypes (Endophenotypes)mentioning

confidence: 98%

Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia

Blackwood

Muir

2004

neurotox res

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Genetic factors play an important part in the development of schizophrenia and bipolar disorder, and linkage analyses in families have successfully identified several chromosomal regions containing candidate genes. A single large pedigree has been described in which schizophrenia and depression segregate with a balanced chromosomal translocation involving the long arm of chromosome 1 and the short arm of chromosome 11. The gene named DISC1, disrupted at the chromosome 1 breakpoint, is a novel candidate gene that may have a role in the pathogenesis of schizophrenia. The cellular location and function of the protein coded by DISC1 is currently being investigated. The phenotype associated with DISC1 in the t (1;11) translocation family includes schizophrenia, schizoaffective disorder, recurrent major depression and bipolar disorder. Hence this locus is one of several now reported apparently showing linkage to both schizophrenia and bipolar disorder. The study of intermediate phenotypes or "endophenotypes" may clarify the relations between phenotype and genotype. Auditory event related potentials are EEG based physiological measures widely studied in schizophrenia. In particular the cognitive evoked potential, the P300 response generated during an "odd-ball" two-tone discrimination task consistently shows reduced amplitude in schizophrenia compared to controls. In members of the family with the t (1;11) translocation, P300 amplitude was reduced in relatives who carried the translocation compared to relatives with a normal karyotype. Furthermore the amplitude reduction was independent of the presence or absence of symptoms because asymptomatic translocation carriers showed similar P300 amplitude reduction as was found in translocation carriers who were diagnosed with schizophrenia, bipolar disorder or unipolar depression. The results confirm that subjects with schizophrenia who carry the t (1;11) translocation have similar phenotype to unrelated subjects with schizophrenia and a normal karyotype. Furthermore P300 amplitude may be a useful intermediate phenotype detecting the neuropathology of schizophrenia in "at risk" individuals even in the absence of clinical symptoms.

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Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia

Abstract: Medication- and symptom-free relatives had altered regional perfusion intermediate between subjects with schizophrenia and controls. Impaired perfusion, verbal memory and P300 appear to be related traits associated with an increased risk of illness.

Cited by 60 publications

References 64 publications

A genome wide search for alcoholism susceptibility genes

A genome wide search for alcoholism susceptibility genes

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia

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