J. Valente

Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population (‘HapICE’), and two haplotypes located in the 3′ end of NRG1 (all P<0.05). However, association was not detected with HapICE itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.

Genomewide Linkage Analysis of Bipolar Disorder by Use of a High-Density Single-Nucleotide–Polymorphism (SNP) Genotyping Assay: A Comparison with Microsatellite Marker Assays and Finding of Significant Linkage to Chromosome 6q22

We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.

Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3η gene

Although the genetic contribution to schizophrenia is substantial, positive findings in whole-genome linkage scans have not been consistently replicated. We analyzed gene expression in various rat conditions to identify novel candidate genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA mRNA from temporal and frontal cortex of rats, was used to identify differentially expressed genes. Expression of mRNA was compared between adult Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult F344 treated with haloperidol or control vehicle. These groups were chosen because each highlights a particular aspect of schizophrenia: differences in strain vulnerability to behavioral analogs of psychosis; factors that may relate to disease onset in relation to CNS development; and improvement of symptoms by haloperidol. The 14-3-3 gene family, as represented by 14-3-3γ and 14-3-3ζ isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic association between schizophrenia and the 14-3-3η gene, positioned close to a genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168 schizophrenia probands and their families. These findings address three different genes in the 14-3-3 family. We find a significant association with schizophrenia for two polymorphisms in the 14-3-3η gene: a 7 bp variable number of tandem repeats in the 5′ noncoding region (P=0.036, 1 df), and a 3′ untranslated region SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no significant genetic association with SNAP-25. The candidate genes identified may be of functional importance in the etiology, pathophysiology or treatment response of schizophrenia or psychotic symptoms. This is to our knowledge the first report of a significant association between the 14-3-3η-chain gene and schizophrenia in a family-based sample, strengthening prior association reports in case–control studies and microarray gene expression studies.

Genome‐wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: Fine mapping adds support on chromosomes 6 and 11

As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome‐wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome‐wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107–114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher‐density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher‐density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome‐wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley‐Liss, Inc.

Human p53 tumor suppressor gene (TP53) and schizophrenia: Case–control and family studies

The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.

Is insomnia in late pregnancy a risk factor for postpartum depression/depressive symptomatology?

The aim of the present work was to investigate if insomnia in late pregnancy is a risk factor for postpartum depressive symptomatology/postpartum depression (PPD). 581 women in their last trimester of pregnancy answered questions/questionnaires about lifetime history of insomnia, current sleep perception, current mood and depressive symptomatology. They were interviewed with the Portuguese version of the Diagnostic Interview for Genetic Studies. After delivery 382 (65.7%) mothers participated again in the study. Insomnia in pregnancy was not a risk factor for PPD (DSM-IV or ICD-10) but was a significant predictor of postpartum depressive symptomatology. Negative Affect (NA) was a significant predictor of postpartum depressive symptomatology. Women with higher NA were 4.6 (CI95%=1.69-12.74) and 5.3 times (CI95%=2.26-12.58) more likely of experiencing PPD (DSM-IV/ICD-10, respectively) than women with lower NA. Lifetime Depression was a significant predictor of postpartum depressive symptomatology and ICD-10/PPD (OR=2.6; CI95%=1.16-4.38). Positive Affect (PA) showed to be a protective factor for postpartum depressive symptomatology and DSM-IV/PPD (OR=1.5; CI95%=1.20-2.33). Controlling NA, PA and Lifetime Depression, insomnia lost its predictive role, suggesting these variables might work as mediators. Associations between insomnia, NA, PA and Lifetime Depression should be assessed in pregnancy. This might help to preventively target NA, enhance PA and reduce the likelihood of experiencing postpartum depressive symptomatology.

Perfectionism and eating behaviour in Portuguese adolescents.

OBJECTIVES The main objective was to investigate the association between perfectionism and eating behaviour in a non-clinical sample of adolescents of both genders. METHOD 997 middle and high school students completed the Portuguese versions of the child-adolescent perfectionism scale (CAPS) and of the eating attitudes test -25 (EAT-25). RESULTS In both genders, the perfectionism total score and the sociallyprescribed perfectionism (SPP) score were positive and significantly correlated with the EAT total score and with all EAT dimensions: Drive for Thinness (DT), Bulimic Related Behaviour (BRB), Social Pressure to Eat (SPE). In girls, self-oriented perfectionism (SOP) was also associated with the EAT total score and its dimensions, whereas in boys it was only associated with EAT total score and DT. In both genders SPP was a useful predictor of the EAT-25 total score and of all its dimensions. In which respects SOP, there were some gender differences showing that in boys this dimension should not be considered a predictor of eating behaviours. CONCLUSION These results confirm that high levels of perfectionism (SOP and SPP) are associated with abnormal eating behaviour in both genders.

Selection of homogeneous populations for genetic study: The Portugal genetics of psychosis project

Molecular genetic studies of psychiatric disorders must face the possibility that despite the significant contribution of genetic factors to the expression of syndromes like schizophrenia, these syndromes may be a heterogeneous collection of genetic and non-genetic illnesses. These illnesses may be etiologically distinct from each other and still share many clinical features in common. Linkage studies of families with multiple affected members tend to favor the selection of genetic forms of a syndrome but can still represent a heterogeneous set of different genetic illnesses. To limit the potential genetic heterogeneity of a study sample, we selected a population that was geographically isolated and was historically relatively genetically homogeneous. We then assessed the relative level of homogeneity utilizing a surname analysis of the population of the Azores, mainland Portugal, rural USA, and urban USA. The average number of families with the same last name corrected for population size in the Azores is 30.88, in Coimbra it is 21.42, compared to 1.13 in a rural American population and 0.38 in an urban American population. The results of this analysis indicate that the Azores have the highest degree of homogeneity, and mainland Portugal has a high degree of homogeneity.

Connexin 50 gene on human chromosome 1q21 is associated with schizophrenia in matched case–control and family-based studies

Background: The gap junction subunit connexin permits direct intercellular exchange of ions and molecules including glutamate, and plays an important role in the central nervous system. The connexin 40 (Cx40) and connexin 50 (Cx50) genes are located on chromosome 1q21.1, a region strongly linked with schizophrenia. These lines of evidence suggest that Cx40 and Cx50 may play a role in schizophrenia. Methods: Using an allele-specific PCR assay, four polymorphisms each were genotyped for Cx40 and Cx50 in 190 Caucasian patients with schizophrenia and 190 controls matched for sex, age and ethnicity. Following up, Cx50 rs989192 and rs4950495 were investigated in 99 Canadian and 163 Portuguese trios and nuclear families with schizophrenia probands. Hardy–Weinberg equilibrium and linkage disequilibrium (LD) block identification was carried out with HaploView, and association analysis for alleles and haplotypes with a permutation test of 10 000 simulations was carried out using the UNPHASED software program. Results: Distributions of genotype frequencies of all markers were in Hardy–Weinberg equilibrium in Caucasian patients, controls and families. One rs989192-rs4950495 LD block was found in patients but not in controls. We found a significant association between the Cx50 rs989192-rs4950495 haplotype and schizophreniay (χ2 = 29.55, p<0.01). The A-C haplotype had a higher frequency in patients (χ2 = 7.153, p<0.01). Family studies also showed that the A-C haplotype was transmitted more often to patients with schizophrenia (χ2 = 8.43, p<0.01). No association of Cx40 with schizophrenia was found for allele, genotype or haplotype analyses. Conclusions: Our matched case–control and family study indicate that Cx50, but not Cx40, may play a role in the genetic susceptibility to schizophrenia.

Revisiting Thyroid Hormones in Schizophrenia

Thyroid hormones are crucial during development and in the adult brain. Of interest, fluctuations in the levels of thyroid hormones at various times during development and throughout life can impact on psychiatric disease manifestation and response to treatment. Here we review research on thyroid function assessment in schizophrenia, relating interrelations between the pituitary-thyroid axis and major neurosignaling systems involved in schizophrenias pathophysiology. These include the serotonergic, dopaminergic, glutamatergic, and GABAergic networks, as well as myelination and inflammatory processes. The available evidence supports that thyroid hormones deregulation is a common feature in schizophrenia and that the implications of thyroid hormones homeostasis in the fine-tuning of crucial brain networks warrants further research.