Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm.

BACKGROUND: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. METHODS: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N = 1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. RESULTS: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. CONCLUSIONS: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The role of perfectionism in postpartum depression and symptomatology.

The role of perfectionism as a correlate and as a predictor of perinatal depressive symptomatology and disorder was examined. Three-hundred and eighty-six pregnant women (mean age = 30.08 years; SD = 4.205; range = 19-44) completed the Portuguese versions of the Multidimensional Perfectionism Scale, Beck Depression Inventory-II/BDI-II and three questions evaluating anxiety trait, life stress and social support perception. Diagnoses of depression were obtained using the Portuguese version of the Diagnostic Interview for Genetic Studies/OPCRIT system. Women who were depressed in pregnancy (ICD-10/DSM-IV) were excluded from the analyses. Self-Oriented Perfectionism and Socially Prescribed Perfectionism subcomponents (Conditional Acceptance and Others' High Standards) were significant correlates of depressive symptomatology/BDI-II in pregnancy. Others' High Standards was a significant predictor of postpartum depressive symptomatology/BDI-II, after controlling the other independent variables (depressive symptomatology and trait anxiety in pregnancy, life stress and social support perception in postpartum). None of the perfectionism subscales predicted postpartum depressive disorder (ICD-10/DSM-IV). Self-Oriented Perfectionism was an important correlate of depressive symptomatology in pregnancy and Others' High Standards and Conditional Acceptance were significant correlates of perinatal depressive symptomatology. Others' High Standards accounted for 0.8 % of the depressive symptomatology variance in postpartum after controlling the effect for other depressive symptomatology correlates. Perfectionism was not a risk factor for postpartum depressive disorder. Our findings improve the knowledge regarding the risk factors implicated in the development of postpartum depressive symptomatology/disorder, which is of utmost importance to develop adequate prevention and intervention strategies.

Genetic overlap of schizophrenia and bipolar disorder in a high-density linkage survey in the Portuguese Island population.

Recent family and genome-wide association studies strongly suggest shared genetic risk factors for schizophrenia (SZ) and bipolar disorder (BP). However, linkage studies have not been used to test for statistically significant genome-wide overlap between them. Forty-seven Portuguese families with sibpairs concordant for SZ, BP, or psychosis (PSY, which includes either SZ or psychotic BP) were genotyped for over 57,000 markers using the Affymetrix 50K Xba SNP array. NPL and Kong and Cox LOD scores were calculated in Merlin for all three phenotypes. Empirical significance was determined using 1,000 gene-dropping simulations. Significance of genome-wide genetic overlap between SZ and BP was determined by the number of simulated BP scans having the same number of loci jointly linked with the real SZ scan, and vice versa. For all three phenotypes, a number of regions previously linked in this sample remained so. For BP, chromosome 1p36 achieved significance (11.54-15.71 MB, LOD = 3.51), whereas it was not even suggestively linked at lower marker densities, as did chromosome 11q14.1 (89.32-90.15 MB, NPL = 4.15). Four chromosomes had loci at which both SZ and BP had NPL ≥ 1.98, which was more than would be expected by chance (empirical P = 0.01 using simulated SZ scans; 0.07 using simulated BP scans), although they did not necessarily meet criteria for suggestive linkage individually. These results suggest that high-density marker maps may provide greater power and precision in linkage studies than lower density maps. They also further support the hypothesis that SZ and BP share at least some risk alleles.

Sleep-wake patterns and disturbances in Portuguese primary school children: a comparison between 1995 and 2016.

Purpose: It is often assumed sleep duration has decreased and sleep schedules have delayed over the last decades, as society modernized. We aimed to investigate changes in the sleep patterns of school-age children over time. Methods: We compared the sleep timings, durations, and disturbances of primary school-age children in 1995 and roughly two decades later, in 2016. Data from 666 children attending the 3rd and 4th grades of basic education were combined from two different cross-sectional school-based studies conducted within the same educational region of mainland Portugal using the same parent-report questionnaire (Children's Sleep-wake Patterns Questionnaire). Results: Mean sleep duration did not differ significantly between the two time points (schooldays: t = .118, p = .906; free days: t = 1.310, p = .191), albeit the percentage of children sleeping the recommended number of hours decreased significantly in 2016 when compared to 1995 (schooldays: χ2 = 4.406, p = .036; free days: χ2 = 16.859, p < .001). Wake-times advanced on free days in 2016. Difficulties on settling to sleep alone and returning to sleep were more prevalent in 2016, as well as fearing the dark and needing lights on or parent's presence to fall asleep. Conclusions: Sleep onset-related disturbances appear to have increased from 1995 to 2016. One possible explanation for this increase might be the change in parental practices preventing children from learning to fall asleep autonomously.

Sleep disturbances, body mass index and eating behaviour in undergraduate students.

This study investigates the association between sleep disturbances, body mass index (BMI) and eating behaviour in a sample of undergraduate students. The sample comprises 870 medicine and dentistry students from Coimbra University (62.5% females), aged between 17 and 25 years. The Eating Attitudes Test-40 was used to measure eating behaviour, and two questions were applied addressing difficulties of initiating sleep (DIS) and difficulties of maintaining sleep (DMS). A sleep disturbance index (SDI) was calculated from the sum of DIS and DMS scores. Body mass index (BMI) was determined from self-reported weight and height. The correlation analyses generally indicated that global eating disturbance, bulimic behaviour dimension and social pressure to eat were associated particularly with sleep difficulties. An association between diet concerns and sleep difficulties was less consistent. Regression analyses showed that bulimic behaviour (BB) and social pressure to eat (SPE) dimensions were associated significantly with sleep difficulties (DIS, DMS, SDI) in the total sample (BB: from P<0.01 to P<0.001; SPE: P<0.05) and in males (BB: from P<0.05 to P<0.001; SPE: P<0.05) and with insomnia symptoms (P<0.01). In females, bulimic behaviour was the only factor associated significantly with sleep difficulties (SDI, DIS; P<0.01) and with insomnia symptoms (P<0.05). Although BMI was correlated negatively with sleep difficulties (P<0.05), regression analyses indicated that it was not associated significantly with them. Our findings support an association between eating behaviour and sleep disturbances in both genders, which may have treatment implications.

Association of the gene encoding neurogranin with schizophrenia in males.

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.

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 (chi(2) = 29.55, p<0.01). The A-C haplotype had a higher frequency in patients (chi(2) = 7.153, p<0.01). Family studies also showed that the A-C haplotype was transmitted more often to patients with schizophrenia (chi(2) = 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.

Transthyretin: no association between serum levels or gene variants and schizophrenia.

It has been proposed that schizophrenia results from an environmental insult in genetically predisposed individuals. Environmental factors capable of modulating transcriptional activity and their carriers could link the genetic and environmental components of schizophrenia. Among these is transthyretin (TTR), a major carrier of thyroid hormones and retinol-binding protein (RBP). Retinoids and thyroid hormones regulate the expression of several genes, both during development and in the adult brain. Decreased TTR levels have been reported in the cerebrospinal fluid of patients with depression and Alzheimer's disease, and the absence of TTR influences behavior in mice. DNA variants capable of altering TTR ability to carry its ligands, either due to reduced transcription of the gene or to structural modifications of the protein, may influence development of the central nervous system and behavior. In the present study we searched for variants in the regulatory and coding regions of the TTR gene, and measured circulating levels of TTR and RBP. We found a novel single nucleotide polymorphism (SNP), ss46566417, 18 bp upstream of exon 4. Neither this SNP nor the previously described rs1800458 were found associated with schizophrenia. In addition, serum TTR and RBP levels did not differ between mentally healthy and schizophrenic individuals. In conclusion, our data does not support an involvement of the TTR gene in the pathophysiology of schizophrenia.

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.

A linkage study between the GABAA beta2 and GABAA gamma2 subunit genes and major psychoses.

BACKGROUND: Alterations of the gamma-aminobutyric acid (GABA) system have been implicated in the pathophysiology of major psychoses. OBJECTIVE: Restriction fragment length polymorphisms associated with the human gamma-aminobutyric acid type A (GABAA) beta2 and GABAA gamma2 subunit genes on chromosome 5q32-q35 were tested to determine whether they confer susceptibility to major psychoses. METHODS: Thirty-two schizophrenic families and 25 bipolar families were tested for linkage. RESULTS: Nonparametric linkage (NPL) analysis performed by GENEHUNTER showed no significant NPL scores for both genes in schizophrenia (GABAA beta2: NPL narrow= -0.450; NPL broad= -0.808; GABAA gamma2: NPL narrow=0.177; NPL broad= -0.051) or bipolar disorder (GABAA beta2: NPL narrow=0.834; NPL broad=0.783; GABAA gamma2: NPL narrow= -0.159; NPL broad=0.070). CONCLUSION: Linkage analysis does not support the hypothesis that variants within the GABAA beta2 and GABAA gamma2 genes are significantly linked to major psychoses in a Portuguese population.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Affective state dependence and relative trait stability of perfectionism in sleep disturbances.

OBJECTIVE: To evaluate the degree of absolute change, relative stability and state dependence of trait perfectionism in sleep disturbances in a sample of university students. METHOD: Participants completed the Multidimensional Perfectionism Scale and two items concerning sleep difficulties. The mean age at T0 (baseline) was 19.59 years (SD = 1.61, range = 17-25) and 62.5% of the sample were female. RESULTS: Absolute changes in self-oriented and socially-prescribed perfectionism were found. Relative stability was found for all perfectionism dimensions. Prior and concurrent sleep disturbances explained a significant amount of variance in perfectionism. Controlling for the effects of sleep measures, prior self-oriented perfectionism and other-oriented perfectionism were the only significant predictors of subsequent self-oriented perfectionism and other-oriented perfectionism, at T1 and T2. Difficulties falling asleep at T1 and socially-prescribed perfectionism at T0 were significant predictors of socially-prescribed perfectionism at T1. CONCLUSION: Despite significant changes in perfectionism mean scores over the follow-up, the correlation analyses demonstrated that participants remained quite stable in regard to their relative levels of perfectionism. As concurrent difficulties initiating sleep also predicted concurrent socially-prescribed perfectionism, this seems to be one dimension of perfectionism with trait-state characteristics.

Affective state dependence and relative trait stability of perfectionism in sleep disturbances / Dependência do estado afetivo e estabilidade relativa do traço do perfeccionismo nas perturbações de sono

OBJECTIVE: To evaluate the degree of absolute change, relative stability and state dependence of trait perfectionism in sleep disturbances in a sample of university students. METHOD: Participants completed the Multidimensional Perfectionism Scale and two items concerning sleep difficulties. The mean age at T0 (baseline) was 19.59 years (SD = 1.61, range = 17-25) and 62.5 percent of the sample were female. RESULTS: Absolute changes in self-oriented and socially-prescribed perfectionism were found. Relative stability was found for all perfectionism dimensions. Prior and concurrent sleep disturbances explained a significant amount of variance in perfectionism. Controlling for the effects of sleep measures, prior self-oriented perfectionism and other-oriented perfectionism were the only significant predictors of subsequent self-oriented perfectionism and other-oriented perfectionism, at T1 and T2. Difficulties falling asleep at T1 and socially-prescribed perfectionism at T0 were significant predictors of socially-prescribed perfectionism at T1. CONCLUSION: Despite significant changes in perfectionism mean scores over the follow-up, the correlation analyses demonstrated that participants remained quite stable in regard to their relative levels of perfectionism. As concurrent difficulties initiating sleep also predicted concurrent socially-prescribed perfectionism, this seems to be one dimension of perfectionism with trait-state characteristics.

OBJETIVOS: Avaliar o grau de mudança absoluta, de estabilidade relativa e dependência do estado do perfeccionismo nas perturbações de sono numa amostra de estudantes universitários. MÉTODO: Os sujeitos completaram a Escala Multidimensional do Perfeccionismo e dois itens sobre dificuldades em dormir. Os dados foram recolhidos em três momentos de avaliação, separados por um intervalo de um ano acadêmico. A idade média dos sujeitos no T0 era de 19,59 anos (DP = 1,61, variação = 17-25); 62,5 por cento eram mulheres. RESULTADOS: Foram encontradas ao longo do follow-up mudanças absolutas para o perfeccionismo auto-orientado e para o perfeccionismo socialmente prescrito. Foi encontrada estabilidade relativa para todas as dimensões do perfeccionismo. As dificuldades de sono prévias e concorrentes explicaram significativamente a variância do perfeccionismo. Controlando o efeito das dificuldades em dormir, o perfeccionismo auto-orientado e o perfeccionismo orientado para o outro prévios foram os únicos preditores significativos de perfeccionismo auto-orientado e perfeccionismo orientado para o outro (T1 e T2). As dificuldades em iniciar o sono no T1 e o perfeccionismo socialmente prescrito prévio (T0) revelaram-se preditores significativos de perfeccionismo socialmente prescrito no T1. CONCLUSÃO: Apesar das mudanças significativas nas pontuações médias de perfeccionismo ao longo do follow-up, as análises de correlação demonstraram que os participantes permaneceram relativamente estáveis nos seus níveis de perfeccionismo. Uma vez que as dificuldades em iniciar o sono concorrentes se revelaram um preditor significativo de perfeccionismo socialmente prescrito, esta é a dimensão do perfeccionismo que possui características traço-estado.