Gene/Protein Disease Symptom Drug Enzyme Compound
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Pitt-Hopkins syndrome (PHS) is a rare syndromic mental disorder, which is mainly characterized by severe motor and mental retardation including absent language development, a characteristic facial gestalt and episodes of hyperventilation. We report on a female patient with PHS showing severe mental retardation with absent speech, pronounced muscular hypotonia, ataxia, distinctive facial features, such as a coarse face, a broad nasal bridge and a wide mouth, and hyperventilation attacks. In this patient, genomic profiling by array-based comparative genomic hybridization and fluorescence in situ hybridization studies detected and confirmed a de novo 0.5 Mb deletion in 18q21.2 containing a single gene, the basic helix-loop-helix transcription factor TCF4. cDNA and genomic analyses in the patient and her parents demonstrated TCF4 haploinsufficiency as the underlying cause of the disease. Analysis of the embryonal expression pattern of the Danio rerio ortholog, tcf4, by whole-mount in situ hybridization showed a highly specific expression domain in the pallium of the telencephalon during late somitogenesis, when the patterning of the zebrafish brain is advanced and neural differentiation commences. Later expression domains were restricted to several regions in the central nervous system, including continued expression in the pallium of the telencephalon, and starting expression in the diencephalon (thalamus, ventral thalamus and posterior tuberculum), the midbrain tegmentum, the hindbrain and the branchial arches. This expression pattern correlates with the clinical phenotype. Our results show that haploinsufficiency of TCF4 causes PHS and suggest that D. rerio is a valuable model to study the molecular pathogenesis of PHS and the role of TCF4 in brain development.
Hum Mol Genet 2007 Jun 15
PMID:Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. 1747 76

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.
Mol Psychiatry 2008 Jul
PMID:Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. 1768

It has long been established that the development of psychiatric illness results from a complex interplay between genetic and environmental factors. Postmortem and genetic linkage studies have identified a number of promising candidate genes which have been reinforced by replication and functional studies. However, the fact that concordance rates for monozygotic twins rarely approach 100% highlights the involvement of environmental factors. Whilst epidemiological studies of psychiatric cohorts have demonstrated potential risk factors, such studies are clearly limited and in many cases the potential mechanism linking a given risk factor with pathogenesis remains unclear. A very powerful method of elucidating the mechanisms underlying gene-environment interactions is the use of appropriate animal models of psychiatric pathology. Whilst animals cannot be used to map the entire complexity of diseases such as schizophrenia, dissecting the symptom profile into more simply encapsulated traits or endophenotypes has proved to be a successful approach. Such endophenotypes provide a measurable link between aetiological factors and phenotypic outcome. Given the potential for the careful control and modification of an experimental animal's environment, the combination of studies of candidate genes with investigations of environmental factors is an effective heuristic tool, allowing examination of behavioural endophenotypes in conjunction with cellular and molecular outcomes. This review will consider the extant genetic, molecular, pharmacological and lesion-based models of psychiatric disorders, and the relevant methods of environmental manipulation appearing in the literature. We will discuss studies where such models have been combined, and the potential for future experimentation in this area.
Curr Mol Med 2007 Aug
PMID:Dissecting cause and effect in the pathogenesis of psychiatric disorders: genes, environment and behaviour. 1769 62

The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention.
Mol Psychiatry 2008 Jan
PMID:The DISC locus in psychiatric illness. 1791 48

Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.
Mol Psychiatry 2008 Mar
PMID:The myelin-pathogenesis puzzle in schizophrenia: a literature review. 1792 96

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.
Mol Psychiatry 2009 Jan
PMID:Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. 1793 36

Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop after the experiencing or witnessing of a life-threatening event. PTSD is defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyperarousal, which persist for at least 1 month in survivors of the event (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Using an established model of PTSD, we addressed the well-accepted clinical finding that only a minority (about 20%) of the individuals exposed to a traumatic event develop PTSD. Moreover, we followed individual rat behavior for up to a month, and then treated the PTSD-like animals with citalopram. Our data demonstrate high face (20% of rats exposed to a reminder of the stressor develop symptoms characteristic of PTSD) and predictive (response to citalopram) validities. Based on these validities we identified alterations in the Wolframin gene in the CA1 and amygdala regions, specifically in exposed PTSD-like rats, which were normalized after treatment with citalopram. We suggest the Wolframin gene as a putative biomarker for PTSD. Since Wolframin gene undergoes alternative splicing and has polymorphism in the population, it may serve a future marker for identification of the vulnerable population exposed to a traumatic event.
Mol Psychiatry 2009 Jan
PMID:WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model. 1796 52

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.
Mol Psychiatry 2008 May
PMID:A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. 1818 Jul 56

A representative sample of 815 pre-hurricane residents of the areas affected by Hurricane Katrina was interviewed 5-8 months after the hurricane and again 1 year later as the Hurricane Katrina Community Advisory Group (CAG). The follow-up survey was carried out to study patterns-correlates of recovery from hurricane-related post-traumatic stress disorder (PTSD), broader anxiety-mood disorders and suicidality. The Trauma Screening Questionnaire screening scale of PTSD and the K6 screening scale of anxiety-mood disorders were used to generate DSM-IV prevalence estimates. Contrary to results in other disaster studies, where post-disaster mental disorder typically decreases with time, prevalence increased significantly in the CAG for PTSD (20.9 vs 14.9% at baseline), serious mental illness (SMI; 14.0 vs 10.9%), suicidal ideation (6.4 vs 2.8%) and suicide plans (2.5 vs 1.0%). The increases in PTSD-SMI were confined to respondents not from the New Orleans Metropolitan Area, while the increases in suicidal ideation-plans occurred both in the New Orleans sub-sample and in the remainder of the sample. Unresolved hurricane-related stresses accounted for large proportions of the inter-temporal increases in SMI (89.2%), PTSD (31.9%) and suicidality (61.6%). Differential hurricane-related stress did not explain the significantly higher increases among respondents from areas other than New Orleans, though, as this stress was both higher initially and decreased less among respondents from the New Orleans Metropolitan Area than from other areas affected by the hurricane. Outcomes were only weakly related to socio-demographic variables, meaning that high prevalence of hurricane-related mental illness remains widely distributed in the population nearly 2 years after the hurricane.
Mol Psychiatry 2008 Apr
PMID:Trends in mental illness and suicidality after Hurricane Katrina. 1818 Jul 68

The neuronal PAS domain 3 (NPAS3) gene encodes a neuronal transcription factor that is implicated in psychiatric disorders by the identification of a human chromosomal translocation associated with schizophrenia and a mouse knockout model with behavioural and hippocampal neurogenesis defects. To determine its contribution to the risk of psychiatric illness in the general population, we genotyped 70 single-nucleotide polymorphisms across the NPAS3 gene in 368 individuals with bipolar disorder, 386 individuals with schizophrenia and 455 controls. Modestly significant single-marker and global and individual haplotypes were identified in four discrete regions of the gene. The presence of both risk and protective haplotypes at each of these four regions indicated locus and allelic heterogeneity within NPAS3 and suggested a model whereby interactions between variants across the gene might contribute to susceptibility to illness. This was supported by predicting the most likely haplotype for each individual at each associated region and then calculating an NPAS3-mediated 'net genetic load' value. This value differed significantly from controls for both bipolar disorder (P=0.0000010) and schizophrenia (P=0.0000012). Logistic regression analysis also confirmed the combinatorial action of the four associated regions on disease risk. In addition, sensitivity/specificity plots showed that the extremes of the genetic loading distribution possess the greatest predictive power-a feature suggesting multiplicative allele interaction. These data add to recent evidence that the combinatorial analysis of a number of relatively small effect size haplotypes may have significant power to predict an individual's risk of a complex genetic disorder such as psychiatric illness.
Mol Psychiatry 2009 Sep
PMID:Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. 1831 62


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