Genetic variation in the 22q11 locus and susceptibility to schizophrenia

Liu, Hui; Abecasis, Gonçalo R.; Heath, Simon; Knowles, Alyson; Demars, Sandra; Chen, Ying Jiun; Roos, J.L.; Rapoport, Judith L.; Gogos, Joseph A.; Karayiorgou, Maria

doi:10.1073/pnas.232186099

Cited by 189 publications

(163 citation statements)

References 37 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…12,13,19,20,[60][61][62] They are especially interesting as the same regions may encompass susceptibility genes for schizophrenia. [63][64][65][66][67][68][69][70] Park et al 71 made similar conclusions in a study of psychotic BD in which most areas of linkage overlapped with those reported in previous investigations of schizophrenia.…”

Section: Psychotic Symptoms In Bdsupporting

confidence: 71%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

View full text Add to dashboard Cite

The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

show abstract

Section: Psychotic Symptoms In Bdsupporting

confidence: 71%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

View full text Add to dashboard Cite

show abstract

“…To identify potential functional polymorphisms in these four genes that could contribute to schizophrenia susceptibility, as well as polymorphisms that could be used for association studies, we determined the sequence of coding and noncoding exons, splice donor and acceptor sites, and some intronic and promoter regions of these genes in genomic DNA isolated from 12 independent schizophrenia patients (U.S. schizophrenia sample) (18,19). The obtained sequences were compared with the human draft sequence to identify polymorphisms.…”

Section: Resultsmentioning

confidence: 99%

“…Insertion͞deletion polymorphisms were typed by PCR of genomic DNA from individual subjects and identified by altered fragment size as assessed by agarose gel electrophoresis. SNPs were typed either by PCR-restriction fragment length polymorphism genotyping or by fluorescence polarization templatedirected dye-terminator incorporation genotyping as described (18,19). See supporting information for genotyping primer sequences.…”

mentioning

confidence: 99%

Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC , encoding the calcineurin gamma subunit

Gerber

Hall

Miyakawa

et al. 2003

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

Self Cite

229

143

View full text Add to dashboard Cite

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurinrelated genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin ␥ catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis. S chizophrenia is a severe psychiatric condition that affects Ϸ1% of the population worldwide (1). Studies of the inheritance of schizophrenia have revealed that it is a multifactorial disease characterized by multiple genetic susceptibility elements, each contributing a modest increase in risk (2). Family linkage studies and studies of chromosomal abnormalities associated with schizophrenia have identified a number of schizophrenia susceptibility loci (2, 3). Such loci provide a basis for higher resolution genetic studies and a criterion for assessment of potential candidate genes. In addition to direct genetic analysis, a longstanding body of pharmacological studies has led to the prevailing hypotheses that dysfunction of dopaminergic or Nmethyl-D-aspartate (NMDA) receptor-mediated signaling are major contributing factors in schizophrenia pathogenesis (4-6).Calcineurin is a calcium-dependent serine͞threonine protein phosphatase that is highly expressed in the CNS (7,8). Calcineurin consists of a heterodimer composed of a regulatory subunit, CNB, and a catalytic subunit, CNA (7, 8). There are three different CNA isoforms encoded by distinct genes. Calcineurin activity plays a key role in the downstream regulation of dopaminergic signal transduction (9) and in the induction of certain forms of N-methyl-D-aspartate receptor-dependent synaptic plasticity (10, 11). Thus, calcineurin function could comprise a critical link between dopaminergic and glutamatergic signaling.In an accompanying study, we report that forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities that is strikingly reminiscent of altered behaviors observed in schizophrenia patients (12). Based on these findings, we decided to further investigate the potential involvement of calcineurin dysfunction in schizophrenia etiology by directly testing for genetic association of calcineurin-related candidate genes with schizophrenia. We prioritized examination of genes encoding calcineurin subunits or calcineurin-related molecules that map to schizophrenia susceptibility loci. We present direct genetic evidence for association of the PPP3CC gene with schizophrenia. PP...

show abstract

“…Our data suggests additional candidates (particularly Ranbp1 and Cdc45l) as potential contributors to altered cortical development in 22q11DS. RANBP1 polymorphisms have been associated with schizophrenia vulnerability in non-22q11 deleted individuals (45) and restricted CDC45L, as well as UFD1L, deletion has been associated with 22q11DS clinical features including heart, craniofacial, and thymic anomalies (42). The cell-cycle functions of both Ranbp1 and Cdc45l, their diminished expression in LgDel VZ/SVZ, and parallel diminished expression of CyclinD1 and E2f2, major regulators of the G1/S check point, indicate that local activity of 22q11 genes may inf luence cortical cell-cycle dynamics.…”

Section: Discussionmentioning

confidence: 99%

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Meechan¹,

Tucker²,

Maynard³

et al. 2009

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

155

173

View full text Add to dashboard Cite

The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5-to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for ''diseases of cortical connectivity'' thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbuminlabeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. psychiatric disease T he neurodevelopmental hypothesis for diseases of cortical connectivity, initially proposed for schizophrenia (1), and later extended to autism spectrum disorders (2), suggests that anomalous cortical development underlies behavioral pathology. Despite inferred relationships between suspect developmental mechanisms, neuroanatomical or functional changes in patients, and postmortem cortical pathology, to our knowledge, there are no known direct links between specific cortical developmental mechanisms and pathogenesis. The near impossibility of prospective analyses in at-risk human fetuses further complicates rigorous evaluation of the hypothesis. Thus, the hypothesis may be more effectively evaluated in animal models of genetic or environmental risk for relevant diseases. In humans, 22q11 deletion/DiGeorge syndrome (22q11DS) confers the highest known genetic risk for schizophrenia (Ϸ30%) (3, 4), increased susceptibility for autism spectrum disorders (Ϸ25%) (5), and vulnerability for additional behavioral and learning disabilities (Ͼ60%) (5). Brain imaging in 22q11DS patients shows consistent anatomical defects, including reduced cortical gray matter and polymicrogyria (6-8), and postmortem analysis indicates cellular pathology associated with developmental defects including periventricular heteropias (9). We found that diminished 22q11 gene dosage in a 22q11DS mouse model compromises specific cortical neural stem cells, basal progenitors, and alters frequency and distribution of cortical projection neurons and GABAergic interneurons. These phenotypes suggest a link between a genomic lesion, altered cortical development, and subsequent changes in cortical circuitry that likely intensify risk for behavioral diso...

show abstract

Genetic variation in the 22q11 locus and susceptibility to schizophrenia

Cited by 189 publications

References 37 publications

The phenotypes of bipolar disorder: relevance for genetic investigations

The phenotypes of bipolar disorder: relevance for genetic investigations

Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC , encoding the calcineurin gamma subunit

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Contact Info

Product

Resources

About