DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia

Szeszko, Philip R.; Hodgkinson, Colin A.; Robinson, Delbert G.; DeRosse, Pamela; Bilder, Robert M.; Lencz, Todd; Burdick, Katherine E.; Napolitano, Barbara; Betensky, Julia D.; Kane, John M.; Goldman, David; Malhotra, Anil K.

doi:10.1016/j.biopsycho.2007.10.011

Cited by 87 publications

(78 citation statements)

References 52 publications

(66 reference statements)

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“…Several groups have found SNPs or other lesions in the DISC1 gene, and several linkage studies have associated the DISC1 locus with schizophrenia in cohorts that are not enriched for the DISC1 translocation (Callicott et al, 2005;Chakirova et al, 2011;Eastwood et al, 2010;Szeszko et al, 2008;Takahashi et al, 2009) (reviewed by Roberts (2007)). The DISC1 protein has multiple functions that likely underlie cognitive function.…”

Section: Data From Disc1 Postmortem Studiesmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Data From Disc1 Postmortem Studiesmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

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“…We show that transcripts encoding truncated DISC1 proteins in transfected HEK293 cells are expressed at significantly higher levels in the cerebral cortex during normal human fetal development than later in life, are enriched in the hippocampus of patients with schizophrenia, and are related to the previously identified risk-associated polymorphisms (20)(21)(37)(38)(39)(40). Our data suggest that a molecular mechanism by which variation in DISC1 impacts risk for psychiatric illness involves specific alternative gene processing.…”

mentioning

confidence: 67%

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Nakata

Lipska

Hyde

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

161

146

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Disrupted-In-Schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (⌬3), exons 7 and 8 (⌬7⌬8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms ⌬7⌬8, Esv1, and ⌬3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of ⌬3 and ⌬7⌬8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1⌬7⌬8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.alternative splicing ͉ genetic ͉ hippocampus ͉ psychiatric illness S chizophrenia is a common mental disorder with a lifetime prevalence of Ϸ 1% (1). It has been assumed, on the basis of evidence from twin, family, and adoption studies, that genetic factors play a strong etiologic role in schizophrenia (2, 3). The genetic predisposition is likely to be determined by a complex network of interactions between genes and environmental risk factors (4).The Disrupted-In-Schizophrenia-1 (DISC1) gene was identified as a potential susceptibility gene for mental disorders based on studies of a chromosomal translocation found in a large Scottish family that had a high frequency of schizophrenia and other psychiatric disorders, including bipolar disorder and major depression (5-7). Although the translocation identified in the Scottish family has not been observed in any other families, independent support for involvement of DISC1 in the etiology of mental illness has come from a number of genetic linkage and association studies in diverse populations (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the specific SNPs, alleles, and haplotypes have varied across these studies, raising issues of allelic and populations heterogeneity, the overall evidence implicates DISC1 as a promising candidate susceptibility gene for schizophrenia. However, the mechanism by which DISC1 contributes to the pathophysiology of schizophrenia remains unknown. Although reduced expression of DISC1 mRNA was found in lymphoblastoid cell lines of family members with the translocation (26) and in bipolar disorder patients with a putative risk-associated haplotype (27), no changes were detected in the brain tissue of unre...

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“…These candidate genes, given the evidence for abnormal brain development in most (severe) psychiatric disorders, are likely to be involved in the brain pathology of neuropsychiatric disorders with an onset during puberty. A number of studies have been published in which particular genetic polymorphisms, i.e., BDNF [Bueller et al, 2006;Nemoto et al, 2006;Pezawas et al, 2004], DISC1 [Szeszko et al, 2008], COMT [Cerasa et al, 2008], and AKT1 [Tan et al, 2008] are associated with variation in brain structure in the healthy population. It can be argued that certain genes are typically expressed or exert an effect in puberty [Barnett et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

Heritability of regional and global brain structure at the onset of puberty: A magnetic resonance imaging study in 9‐year‐old twin pairs

Peper

Schnack

Brouwer

et al. 2009

Human Brain Mapping

163

139

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Puberty represents the phase of sexual maturity, signaling the change from childhood into adulthood. During childhood and adolescence, prominent changes take place in the brain. Recently, variation in frontal, temporal, and parietal areas was found to be under varying genetic control between 5 and 19 years of age. However, at the onset of puberty, the extent to which variation in brain structures is influenced by genetic factors (heritability) is not known. Moreover, whether a direct link between human pubertal development and brain structure exists has not been studied. Here, we studied the heritability of brain structures at 9 years of age in 107 monozygotic and dizygotic twin pairs (N 5 210 individuals) using volumetric MRI and voxel-based morphometry. Children showing the first signs of secondary sexual characteristics (N 5 47 individuals) were compared with children without these signs, based on Tanner-stages. High heritabilities of intracranial, total brain, cerebellum, and gray and white matter volumes (up to 91%) were found. Regionally, the posterior fronto-occipital, corpus callosum, and superior longitudinal fascicles (up to 93%), and the amygdala, superior frontal and middle temporal cortices (up to 83%) were significantly heritable. The onset of secondary sexual characteristics of puberty was associated with decreased frontal and parietal gray matter densities. Thus, in 9-year-old children, global brain volumes, white matter density in fronto-occipital and superior longitudinal fascicles, and gray matter density of (pre-)frontal and temporal areas are highly heritable. Pubertal development may be directly involved in the decreases in gray matter areas that accompany the transition of our brains from childhood into adulthood.

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DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia

Cited by 87 publications

References 52 publications

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Heritability of regional and global brain structure at the onset of puberty: A magnetic resonance imaging study in 9‐year‐old twin pairs

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