Stanley Zammit

Support for RGS4 as a susceptibility gene for schizophrenia

BACKGROUNDnThe gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples.nnnMETHODSnWe have examined a large case (n = 709) control (n = 710) sample for association between schizophrenia using four markers investigated in the earlier study, denoted single nucleotide polymorphisms 1, 4, 7, and 18.nnnRESULTSnWe were able to replicate the associations with single nucleotide polymorphisms 4 and 18 that had previously been reported individually and have also identified significant association with haplotypes constructed from single nucleotide polymorphisms 1 and 4.nnnCONCLUSIONSnOur data give modest support for the hypothesis that the regulator of G-protein signaling 4 is a susceptibility gene for schizophrenia.

A systematic genomewide linkage study in 353 sib pairs with schizophrenia

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk

Epigenetic mechanisms such as methylation of DNA, could lead to abnormal neurodevelopment and may be important in the etiology of schizophrenia. Maternal dietary folate intake may play a role in determining methylation levels. The MTHFR gene C677T polymorphism influences folate metabolism and intracellular availability of folate metabolites for methylation. We carried out a meta‐analysis of MTHFR C677T genotype and schizophrenia risk, and found that TT homozygotes had a significantly increased risk, OR 1.48 (1.18–1.86). This supports the hypothesis that folate status is a determinant of schizophrenia risk. Larger studies of this issue are required, together with studies of maternal genotype which could identify whether maternal folate status during pregnancy is important.

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well‐powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia

People with deletion of the chromosome 22q11 region associated with velo cardio‐facial syndrome (VCFS) have a remarkably high risk of developing schizophrenia. Recently, the gene proline dehydrogenase (PRODH) which maps to 22q11 and is also an excellent functional candidate gene for psychosis, has been reported to show genetic association with schizophrenia. We have screened all the exons and adjacent intronic sequences of PRODH for the presence of sequence variation in 14 DSM IV schizophrenic subjects. Similarly, we also screened all putative exons of a sequence that is similar to proline dehydrogenase (PsPRODH) and which also maps within the deleted region. A total of nine single nucleotide polymorphisms (SNPs) were identified in PRODH, eight of which were exonic, while in PsPRODH, five SNPs were identified, one of which was in a putative exon. All samples were tested for association in a pooled sample of 368 DSM IV diagnosed schizophrenic subjects and 368 matched controls. None of the variants identified in PRODH gave even modest evidence for allelic association (Pu2009<u20090.1). In PsPRODH, two variants (−3864Gu2009>u2009A and 226Gu2009>u2009A) gave P values <u20090.1. These were individually genotyped in the same subjects that had been used to construct the pools. Although a trend for association was confirmed, neither showed evidence for association at the Pu2009≤u20090.05 level. These results do not suggest that PRODH or PsPRODH contribute to the aetiology of schizophrenia, and that the putative schizophrenia susceptibility gene in 22q11 remains unknown.

Mutation screening of the Homer gene family and association analysis in schizophrenia

Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non‐synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4u2009+u200918Au2009>u2009G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (Pu2009=u20090.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (Pu2009=u20090.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

Impairments in Cognition Across the Spectrum of Psychiatric Disorders: Evidence From a Swedish Conscript Cohort

It is well established that cognitive deficits are an almost invariable component of the schizophrenia syndrome. Much less is known about the association of cognitive deficits and the range of psychiatric disorders. The current study made use of a Swedish conscript cohort which included an IQ assessment and full psychiatric evaluation at conscription of all 18- to 19-year-old males. It was found that reduced intellectual functioning was found in association with psychosis and neurotic disorders including depression, personality disorders, alcoholism, and drug dependence. The effect was particularly strong for alcoholism. This presumably represents a combination of premorbid deficits (as demonstrated in those who developed schizophrenia some years later) plus coincident impairments. The direction of causality of this latter association is likely to be both forward and reverse. Different cognitive subtests showed varied strengths of association: mechanical ability/knowledge, which might reflect planning and reasoning more than the other subtests, had the strongest effect. Cognitive deficits are widespread in psychiatric disorders and should be taken into account in clinical interactions.

Screening the human protocadherin 8 (PCDH8) gene in schizophrenia

Abnormalities in synaptic connectivity and plasticity have been implicated in the pathophysiology of schizophrenia. Molecules involved in the development and maintenance of neural circuitry include the recently cloned protocadherins. Human protocadherin 8 (PCDH8) is homologous to ‘arcadlin’, a molecule shown to play a role in hippocampal synaptic function in the rat. The gene encoding PCDH8 maps to a region on chromosome 13 where linkage to schizophrenia has been reported. In this study, the entire expressed sequence of the PCDH8 gene and over 800u2003bp of the 5′ flanking region were screened for polymorphisms in 30 DSM‐IV schizophrenia individuals using Denaturing High Performance Liquid Chromatography (DHPLC). A total of nine single nucleotide polymorphisms were identified, including three in the first exon that are predicted to change the amino acid sequence. One polymorphism, causing the Trp7Arg change in the putative signal peptide, showed a trend towards excess of the arginine encoding allele in a case‐control sample consisting of 520 DSM‐IV schizophrenia patients and 535 matched controls from the UK (χ2u2003=u20033.72, P[1df]u2003=u20030.054). However, this polymorphism did not show preferential transmission to schizophrenic individuals in a separate sample of 203 proband–parent trios from Bulgaria. A second, rare single nucleotide variation, predicting the non‐conservative amino acid change Glu39Ala, was found in one schizophrenic individual and their affected sibling but not in a further 352 affected individuals, nor 357 controls. These results suggest that any contribution of PCDH8 polymorphisms to schizophrenia susceptibility is likely to be weak, although the existence of rare variations of stronger effect cannot be excluded.

A Population-based Longitudinal Study of Childhood Neurodevelopmental Disorders, IQ and Subsequent Risk of Psychotic Experiences in Adolescence

BACKGROUNDnSchizophrenia has a neurodevelopmental component to its origin, and may share overlapping pathogenic mechanisms with childhood neurodevelopmental disorders (NDs). Nevertheless, longitudinal studies of psychotic outcomes among individuals with NDs are limited. We report a population-based prospective study of six common childhood NDs, subsequent neurocognitive performance and the risk of psychotic experiences (PEs) in early adolescence.nnnMETHODnPEs were assessed by semi-structured interviews at age 13 years. IQ and working memory were measured between ages 9 and 11 years. The presence of six NDs (autism spectrum, dyslexia, dyspraxia, dysgraphia, dysorthographia, dyscalculia) was determined from parent-completed questionnaires at age 9 years. Linear regression calculated the mean difference in cognitive scores between children with and without NDs. Associations between NDs and PEs were expressed as odds ratios (ORs) with 95% confidence intervals (CIs); effects of cognitive deficits were examined. Potential confounders included age, gender, fathers social class, ethnicity and maternal education.nnnRESULTSnOut of 8220 children, 487 (5.9%) were reported to have NDs at age 9 years. Children with, compared with those without, NDs performed worse on all cognitive measures; the adjusted mean difference in total IQ was 6.84 (95% CI 5.00-8.69). The association between total IQ and NDs was linear (p < 0.0001). The risk of PEs was higher in those with, compared with those without, NDs; the adjusted OR for definite PEs was 1.76 (95% CI 1.11-2.79). IQ (but not working memory) deficit partly explained this association.nnnCONCLUSIONSnHigher risk of PEs in early adolescence among individuals with childhood ND is consistent with the neurodevelopmental hypothesis of schizophrenia.

Prenatal vitamin D status and risk of psychotic experiences at age 18years - a longitudinal birth cohort

BACKGROUNDnLow early life vitamin D status is associated with an increased risk of schizophrenia and psychotic experiences. Here we examine if maternal pregnancy vitamin D concentrations are associated with offspring psychotic experiences as young adults.nnnMETHODSnA community sample of 2047 participants was investigated. Maternal prenatal 25 hydroxyvitamin D (25(OH)D) concentrations were assessed with tandem mass spectroscopy. Psychotic experiences were assessed at age 18years using a semi-structured clinical interview.nnnRESULTSn177 cohort members reported suspected or definite psychotic experiences, There was no evidence of an association between maternal 25(OH)D concentrations as quartiles (p=0.85 hypothesis test of general association versus no association across the quartiles) or as a continuous variable (p=0.89) versus experience of suspected and definite psychotic experiences at 18years. Within the cohort, only 29 subjects met criteria for a psychotic disorder at age 18. Based on this sample, there was no significant association between maternal 25(OH)D and psychotic disorder at 18years.nnnDISCUSSIONnMaternal vitamin D levels were not associated with risk of psychotic experiences nor psychotic disorders in this birth cohort.