Heterogeneity in the longitudinal courses of global functioning in children at familial risk of major psychiatric disorders: Association with trauma and familial characteristics.

OBJECTIVES: The extent to which heterogeneity in childhood risk trajectories may underlie later heterogeneity in schizophrenia (SZ), bipolar disorder (BP), and major depressive disorder (MDD) remains a chief question. Answers may optimally be found by studying the longitudinal trajectories of children born to an affected parent. We aimed to differentiate trajectories of global functioning and their sensitive periods from the age of 6 to 17 years in children at familial risk (FHRs). METHODS: First, a latent class mixed model analysis (LCMM) was applied to yearly ratings of the Children's Global Assessment Scale (CGAS) from the age of 6 to 17 years in 170 FHRs born to a parent affected by DSM-IV SZ (N = 37), BP (N = 82) or MDD (N = 51). Then, we compared the obtained Classes or trajectories of FHRs in terms of sex, parental diagnosis, IQ, child clinical status, childhood trauma, polygenic risk score (PRS), and outcome in transition to illness. RESULTS: The LCMM on yearly CGAS trajectories identified a 4-class solution showing markedly different childhood and adolescence dynamic courses and temporal vulnerability windows marked by a functioning decline and a degree of specificity in parental diagnosis. Moreover, IQ, trauma exposure, PRS level, and timing of later transition to illness differentiated the trajectories. Almost half (46%) of the FHRs exhibited a good and stable global functioning trajectory. CONCLUSIONS: FHRs of major psychiatric disorders show heterogeneous functional decline during development associated with parental diagnosis, polygenic risk loading, and childhood trauma.

Uptrend in distress and psychiatric symptomatology in pregnant women during the coronavirus disease 2019 pandemic.

INTRODUCTION: Prenatal maternal distress has a negative impact on the course of pregnancy, fetal development, offspring development, and later psychopathologies. The study aimed to determine the extent to which the coronavirus disease 2019 (COVID-19) pandemic may aggravate the prenatal distress and psychiatric symptomatology of pregnant women. MATERIAL AND METHODS: Two cohorts of pregnant volunteer women were evaluated, one that was recruited before the COVID-19 pandemic (n = 496) through advertisements in prenatal clinics in Quebec, Canada, from April 2018 to March 2020; the other (n = 1258) was recruited online during the pandemic from 2 April to 13 April 2020. Prenatal distress and psychiatric symptomatology were measured with the Kessler Distress Scale (K10), Post-traumatic Checklist for DSM-5 (PCL-5), Dissociative Experiences Scale (DES-II), and Positive and Negative Affect Schedule (PANAS). RESULTS: The 1754 pregnant women (Mage  = 29.27, SD = 4.23) were between 4 and 41 gestational weeks (M = 24.80, SD = 9.42), were generally educated (91.3% had post-high-school training), and financially well-resourced (85.3% were above the low-income cut-off). A multivariate analysis of covariance controlling for age, gestational age, household income, education, and lifetime psychiatric disorders showed a large effect size (ES) in the difference between the two cohorts on psychiatric symptoms (Wilks' λ = 0.68, F6,1400  = 108.50, P < .001, partial η2  = 0.32). According to post-hoc analyses of covariance, the COVID-19 women reported higher levels of depressive and anxiety symptoms (ES = 0.57), dissociative symptoms (ES = 0.22 and ES = 0.25), symptoms of post-traumatic stress disorder (ES = 0.19), and negative affectivity (ES = 0.96), and less positive affectivity (ES = 0.95) than the pre-COVID-19 cohort. Women from the COVID-19 cohort were more likely than pre-COVID-19 women to present clinically significant levels of depressive and anxiety symptoms (OR = 1.94, χ2 [1] = 10.05, P = .002). Multiple regression analyses indicated that pregnant women in the COVID-19 cohort having a previous psychiatric diagnosis or low income would be more prone to elevated distress and psychiatric symptoms. CONCLUSIONS: Pregnant women assessed during the COVID-19 pandemic reported more distress and psychiatric symptoms than pregnant women assessed before the pandemic, mainly in the form of depression and anxiety symptoms. Given the harmful consequences of prenatal distress on mothers and offspring, the presently observed upsurge of symptoms in pregnant women calls for special means of clinical surveillance.

Polygenic risk scores distinguish patients from non-affected adult relatives and from normal controls in schizophrenia and bipolar disorder multi-affected kindreds.

Recent studies have used results on SNP association with schizophrenia (SZ) and bipolar disorder (BD) to create polygenic risk scores (PRS) discriminating non-familial unrelated patients from controls. Little is known about the role of PRS in densely affected multigenerational families. We tested PRS differences between affected SZ and BD family members from their non-affected adult relatives (NAARs) in Eastern Quebec Kindreds and from controls. We examined 1227 subjects: from 17 SZ and BD kindreds, we studied 153 patients (57 SZ, 13 schizoaffective, and 83 BD) and 180 NAARs, and 894 unrelated controls from the Eastern Quebec population. PRS were derived from published case-control association studies of SZ and BD. We also constructed a combined SZ and BD PRS by using SNPs from both SZ and BD PRS. SZ patients had higher SZ PRS than controls (p = 0.0039, R2 = 0.027) and BD patients had higher BD PRS than controls (p = 0.013, R2 = 0.027). Differences between affected subjects and NAARs and controls were significant with both SZ and BD PRS. Moreover, a combined SZ-BD PRS was also significantly associated with SZ and BD when compared to NAARs (p = 0.0019, R2 = 0.010) and controls (p = 0.0025, R2 = 0.028), revealing a SZ-BD commonality effect in PRS at the diagnosis level. The SZ and the BD PRS, however, showed a degree of specificity regarding thought disorder symptoms. Overall, our report would confirm the usefulness of PRS in capturing the contribution of common genetic variants to the risk of SZ and BD in densely affected families.

A feasibility study of a new computerised cognitive remediation for young adults with schizophrenia.

Cognitive remediation therapy is effective for improving cognition, symptoms and social functioning in individuals with schizophrenia; however, the impact on visual episodic memory remains unclear. The objectives of this feasibility study were: (1) to explore whether or not CIRCuiTS--a new computerised cognitive remediation therapy programme developed in England--improves visual episodic memory and other cognitive domains in young adults with early course schizophrenia; and (2) to evaluate acceptability of the CIRCuiTS programme in French-Canadians. Three participants with visual episodic memory impairments at baseline were recruited from clinical settings in Canada, and consented to participate. Neuropsychological, clinical and social functioning was evaluated at baseline and post-treatment. Intervention involved 40 sessions of cognitive remediation. First, the reliable change index (RCI) revealed that each participant demonstrated significant post-therapy change in episodic memory and in other cognitive domains. The response profile was characterised by the use of organisational strategies. Second, the treatment was considered acceptable to participants in terms of session frequency (number of sessions per week), intensity (hours per week; total hours), and number of missed sessions and total completed sessions. This preliminary study yielded encouraging data demonstrating the feasibility of the CIRCuiTS programme in French-Canadian young adults with schizophrenia.

Childhood abuse and neglect may induce deficits in cognitive precursors of psychosis in high-risk children.

BACKGROUND: Millions of children are born to parents affected by major psychoses. Cognitive dysfunctions seen in patients are already detectable in these children. In parallel, childhood maltreatment increases the risk of adult psychoses through unknown mechanisms. We investigated whether high-risk offspring exposed to abuse/neglect displayed more cognitive precursors of adult psychoses in childhood and adolescence than nonexposed offspring. METHODS: We used a stepwise selection strategy from a 25-year follow-up of 48 densely affected kindreds including 1500 adults (405 patients with schizophrenia or bipolar disorder) to select high-risk offspring aged 6-22 years for inclusion in our study. All offspring were assessed for childhood trauma from direct interviews with the offspring, parents and relatives and from the review of lifetime medical records of parents and children and administered a neuropsychological battery including IQ and 4 of the most impaired neuropsychological domains in psychoses. RESULTS: Our study included 66 high-risk offspring. Those who were exposed to abuse/neglect had significantly lower IQ (effect size [ES] = 0.61) than nonexposed offspring and displayed poorer cognitive performance in visual episodic memory (ES = 0.67) and in executive functions of initiation (ES = 1.01). Moreover, exposed offspring presented more combinations of cognitive deficits that were associated with lower Global Assessment of Functioning scores. LIMITATIONS: Exposure to abuse/neglect was not assessed in the control group, thus the study could not test whether the effect of childhood maltreatment occurred only in a high-risk setting and not in the general population. CONCLUSION: In high-risk youths, maltreatment in childhood/adolescence may negatively impact cognitive domains known to be impaired in adults with psychoses, suggesting an early mediating effect in the association between abuse/neglect and adult psychoses. This finding provides a target for future developmental and preventive research.

GRIN2B predicts attention problems among disadvantaged children.

It is well established that adversities and GRIN2B (coding an N-methyl-D-aspartate receptor subunit) are independently associated with behavioral and cognitive impairments in childhood. However, a high proportion of children exposed to adversities have good, long-term outcomes. We hypothesized that among children exposed to adversities, GRIN2B variants would predict the worst cognitive and behavioral outcomes. 6 single nucleotide polymorphisms of GRIN2B were genotyped in 625 children aged 6-11 years from an Italian community-based sample. The interacting effect of GRIN2B variants with 4 measures of adversities [low socioeconomic status (SES), preterm delivery, maternal smoking during pregnancy, and absence of breastfeeding] was investigated upon blindly assessed cognitive abilities (vocabulary, block design, digit spans of Wechsler's Intelligence Scale, and Rey complex figure) and parents-rated behavioral problems (Child Behavior Checklist/6-18). Rs2268119 × SES interaction (Hotelling's Trace = 0.07; F(12,1154) = 3.53; p = 0.00004) influenced behavior, with more attention problems among children in the 'either A/T or T/T genotype and low SES' group, compared to all other groups. This interaction effect was not significant in an independent, replication sample of 475 subjects from an Italian community-based sample. GRIN2B variants predict children with the worst outcome in attention functioning among children exposed to low SES. Our findings, if replicated, could help in the identification of children with the highest risk and may prompt cost-effective preventive/treatment strategies.

Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment.

Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response.

Principal components of heritability for high dimension quantitative traits and general pedigrees.

For many complex disorders, genetically relevant disease definition is still unclear. For this reason, researchers tend to collect large numbers of items related directly or indirectly to the disease diagnostic. Since the measured traits may not be all influenced by genetic factors, researchers are faced with the problem of choosing which traits or combinations of traits to consider in linkage analysis. To combine items, one can subject the data to a principal component analysis. However, when family date are collected, principal component analysis does not take family structure into account. In order to deal with these issues, Ott & Rabinowitz (1999) introduced the principal components of heritability (PCH), which capture the familial information across traits by calculating linear combinations of traits that maximize heritability. The calculation of the PCHs is based on the estimation of the genetic and the environmental components of variance. In the genetic context, the standard estimators of the variance components are Lange's maximum likelihood estimators, which require complex numerical calculations. The objectives of this paper are the following: i) to review some standard strategies available in the literature to estimate variance components for unbalanced data in mixed models; ii) to propose an ANOVA method for a genetic random effect model to estimate the variance components, which can be applied to general pedigrees and high dimensional family data within the PCH framework; iii) to elucidate the connection between PCH analysis and Linear Discriminant Analysis. We use computer simulations to show that the proposed method has similar asymptotic properties as Lange's method when the number of traits is small, and we study the efficiency of our method when the number of traits is large. A data analysis involving schizophrenia and bipolar quantitative traits is finally presented to illustrate the PCH methodology.

Detection of phenotype modifier genes using two-locus linkage analysis in complex disorders such as major psychosis.

OBJECTIVE: To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach. METHODS: We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype. RESULTS: Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21-q23 (D3S2418, cMOD = 4.09, p = 0.0005). CONCLUSION: The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.

Multivariate extension of penalized regression on summary statistics to construct polygenic risk scores for correlated traits.

Genetic correlations between human traits and disorders such as schizophrenia (SZ) and bipolar disorder (BD) diagnoses are well established. Improved prediction of individual traits has been obtained by combining predictors of multiple genetically correlated traits derived from summary statistics produced by genome-wide association studies, compared with single trait predictors. We extend this idea to penalized regression on summary statistics in Multivariate Lassosum, expressing regression coefficients for the multiple traits on single nucleotide polymorphisms (SNPs) as correlated random effects, similarly to multi-trait summary statistic best linear unbiased predictors (MT-SBLUPs). We also allow the SNP contributions to genetic covariance and heritability to depend on genomic annotations. We conducted simulations with two dichotomous traits having polygenic architecture similar to SZ and BD, using genotypes from 29,330 subjects from the CARTaGENE cohort. Multivariate Lassosum produced polygenic risk scores (PRSs) more strongly correlated with the true genetic risk predictor and had better discrimination power between affected and non-affected subjects than previously published sparse multi-trait (PANPRS) and univariate (Lassosum, sparse LDpred2, and the standard clumping and thresholding) methods in most simulation settings. Application of Multivariate Lassosum to predict SZ, BD, and related psychiatric traits in the Eastern Quebec SZ and BD kindred study revealed associations with every trait stronger than those obtained with univariate sparse PRSs, particularly when heritability and genetic covariance depended on genomic annotations. Multivariate Lassosum thus appears promising to improve prediction of genetically correlated traits with summary statistics for a selected subset of SNPs.

A novel rare variants association test for binary traits in family-based designs via copulas.

With the cost-effectiveness technology in whole-genome sequencing, more sophisticated statistical methods for testing genetic association with both rare and common variants are being investigated to identify the genetic variation between individuals. Several methods which group variants, also called gene-based approaches, are developed. For instance, advanced extensions of the sequence kernel association test, which is a widely used variant-set test, have been proposed for unrelated samples and extended for family data. Family data have been shown to be powerful when analyzing rare variants. However, most of such methods capture familial relatedness using a random effect component within the generalized linear mixed model framework. Therefore, there is a need to develop unified and flexible methods to study the association between a set of genetic variants and a trait, especially for a binary outcome. Copulas are multivariate distribution functions with uniform margins on the [0,1] interval and they provide suitable models to capture familial dependence structure. In this work, we propose a flexible family-based association test for both rare and common variants in the presence of binary traits. The method, termed novel rare variant association test (NRVAT), uses a marginal logistic model and a Gaussian Copula. The latter is employed to model the dependence between relatives. An analytic score-type test is derived. Through simulations, we show that our method can achieve greater power than existing approaches. The proposed model is applied to investigate the association between schizophrenia and bipolar disorder in a family-based cohort consisting of 17 extended families from Eastern Quebec.

Animal models of human anxiety disorders: reappraisal from a developmental psychopathology vantage point.

We are witnessing a tremendous expansion of strategies and techniques that derive from basic and preclinical science to study the fine genetic, epigenetic, and proteomic regulation of behavior in the laboratory animal. In this endeavor, animal models of psychiatric illness are becoming the almost exclusive domain of basic researchers, with lesser involvement of clinician researchers in their conceptual design, and transfer into practice of new paradigms. From the side of human behavioral research, the growing interest in gene-environment interplay and the fostering of valid endophenotypes are among the few substantial innovations in the effort of linking common mental disorders to cutting-edge clinical research questions. We argue that it is time for cross-fertilization between these camps. In this article, we a) observe that the "translational divide" can-and should-be crossed by having investigators from both the basic and the clinical sides cowork on simpler, valid "endophenotypes" of neurodevelopmental relevance; b) emphasize the importance of unambiguous physiological readouts, more than behavioral equivalents of human symptoms/syndromes, for animal research; c) indicate and discuss how this could be fostered and implemented in a developmental framework of reference for some common anxiety disorders and ultimately lead to better animal models of human mental disorders.

Characterising phospholipids and free fatty acids in patients with schizophrenia: A case-control study.

OBJECTIVES: Previous studies have indicated that schizophrenia (SCZ) is linked to abnormal phospholipid and fatty acid metabolism. However, comprehensive analysis of phospholipids and free fatty acids (FFAs) for SCZ is very limited. Herein, we sought to compare serum levels of phospholipids and FFAs between patients with SCZ and healthy controls (HCs). METHODS: One hundred and nineteen SCZ patients and 109 HCs were enrolled in the study. The levels of 177 phospholipids and FFAs were measured in serum samples using a targeted liquid chromatography-mass spectrometry (LC-MS)-based platform. RESULTS: One hundred and ten metabolites, including 16 FFAs, 25 phosphatidylcholines, 23 lysophosphatidylcholines, 11 phosphatidylcholine plasmalogens, 7 phosphatidylethanolamines, 9 lysophosphatidylethanolamines, 6 phosphatidylethanolamine plasmalogens, and 13 sphingomyelins, were observed to be significantly altered in SCZ patients compared to HCs. These disturbances may represent underlying pathophysiology, including but not limited to altered activity of phospholipases and acyltransferases, increased oxidative stress, dysfunctional oligodendrocyte glycosynapses, and elevated lipid mobilisation and ß-oxidation. CONCLUSIONS: Our findings suggest that complex lipid profile abnormalities are associated with SCZ. This study may contribute to investigating the role of phospholipid and FFA alterations in the pathoetiology of SCZ.

Familiarity and recollection processes in patients with recent-onset schizophrenia and their unaffected parents.

Episodic memory deficits are present in patients with schizophrenia (SZ) and their unaffected relatives and could be considered as a cognitive indicator of genetic vulnerability to SZ. The present study, involving patients with SZ as well as their parents, used experimental tasks specifically designed to disentangle the contribution of familiarity and recollection processes to episodic memory. The performance of patients with SZ (n=26) and their unaffected parents (n=35) was compared with that of healthy control groups matched on socio-demographic variables (controls of patients, n=26; controls of parents, n=35) on two memory tasks assessing recollection and familiarity. The first task was designed to investigate item recognition and memory for item-spatial context associations whereas the second targeted item-item associations. The results revealed an overall episodic memory deficit in patients with SZ, encompassing both familiarity and recollection, while unaffected parents showed a dysfunction restricted to the recollection process. Our study highlights differences and similarities in the source of the episodic memory deficit found in patients with SZ and their unaffected parents, and it suggests that recollection could act as a cognitive endophenotype of SZ. The results also suggest that use of experimental tasks represents a promising method in the search of cognitive endophenotypes in SZ.

A new strategy for linkage analysis under epistasis taking into account genetic heterogeneity.

BACKGROUND/AIMS: Epistasis, the biological interaction of multiple genes modulating their individual effects, is likely omnipresent in complex diseases, and modelling epistasis in linkage studies can help detect loci with little marginal effect and detect epistatic effects themselves. We propose a complete three-step strategy for parametric linkage analysis under epistasis and heterogeneity in extended pedigrees. METHODS: (1) Loci most likely involved in epistatic interactions are pre-screened using two-locus one-marker analyses. (2) Among selected loci, linkage to each locus is evaluated conditionally on linkage information at another locus under two-locus epistatic models. Linkage statistics are maximized over a space of epistatic models to avoid misspecification of model parameters. (3) Families linked to the conditioning locus are selected to deal with heterogeneity between pairs of epistatically interacting loci and other unlinked loci. Properties of conditional linkage statistics prevent the introduction of bias. RESULTS: Simulations reveal important gains in power to detect a locus with weak marginal effect involved in epistatic interaction. Application of our methods to schizophrenia and bipolar disorder in Eastern Quebec kindreds suggests epistasis between three locus pairs for bipolar disorder: 8p11-16p13, 15q11-16p13 and 18q12-15q11. CONCLUSION: These results suggest that the proposed strategy is powerful for tackling complex phenotypes involving epistasis and heterogeneity.

Electroretinography may reveal cognitive impairment among a cohort of subjects at risk of a major psychiatric disorder.

INTRODUCTION: Almost a third of the offspring of parents diagnosed with schizophrenia or bipolar disorder could develop a mental disorder or related symptoms. The objectives of this study were to test the existence of two distinct subgroups of youth at-risk, according to their retinal response to luminance measured with electroretinography (ERG), and to relate the resulting cluster memberships with the cognitive clusters previously reported. METHODOLOGY: A clustering analysis was performed with ERG measurements in 107 at-risk offspring. Each subgroup was compared to a healthy control group of 203 individuals. The ERG subgroup memberships were then associated with the cognitive clusters. RESULTS: A two-cluster solution was obtained: HR-Cluster1 (n=53) showed a control-like ERG profile and HR-Cluster2 (n=54) showed reduced rod amplitudes and prolonged cone latencies of the b-wave. Subjects in the HR-Cluster2 were 2.7 times more likely to belong to the most detrimental cognitive subgroup than subjects in the HR-Cluster1 (49% Vs 18%). CONCLUSION: At-risk offspring showed two distinct ERG profiles: a control-like and an altered profile. A higher risk of impaired cognitive function was observed in subjects with the altered ERG profile, suggesting the ERG as a potential biomarker of susceptibility to mental illness among youth at risk.

Retinal function anomalies in young offspring at genetic risk of schizophrenia and mood disorder: The meaning for the illness pathophysiology.

BACKGROUND: Visual defects are documented in psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. One of the most consistent alterations in patients is a change in cone and rod electroretinographic (ERG) responses. We previously showed a reduced rod b-wave amplitude in a small sample of young offspring born to an affected parent. A confirmation of the patients ERG anomalies in young offspring at high genetic risk would offer a new approach to the neurodevelopmental investigation of the illness. We thus investigated cone and rod responses in a larger sample of young healthy high-risk offspring. METHODS: The ERG was recorded in 99 offspring of patients having DMS-IV schizophrenia, bipolar or major depressive disorder (mean age 16.03; SD 6.14) and in 223 healthy controls balanced for sex and age. The a- and b-wave latency and amplitude of cones and rods were recorded. RESULTS: Cone b-wave latency was increased in offspring (ES = 0.31; P = 0.006) whereas rod b-wave amplitude was decreased (ES = -0.37; P = 0.001) and rod latency was increased (ES = 0.35; P = 0.002). CONCLUSIONS: The ERG rod and cone abnormal response previously reported in adult patients having schizophrenia, bipolar disorder or major depressive disorder are detectable in genetically high-risk offspring as early as in childhood and adolescence. Moreover, a gradient of effect sizes among offspring and the three adult diagnoses was found in the cone response. This suggests that ERG waveform as a risk endophenotype might become part of the definition of a "childhood risk syndrome".

The Electroretinogram May Differentiate Schizophrenia From Bipolar Disorder.

BACKGROUND: The retina is recognized as an approachable part of the brain owing to their common embryonic origin. The electroretinogram (ERG) has proved to be a valuable tool to investigate psychiatric disorders. We therefore investigated its accuracy as a tool to differentiate schizophrenia (SZ) from bipolar disorder (BP) even after balancing patients for their main antipsychotic medication. METHODS: ERG cone and rod luminance response functions were recorded in 150 patients with SZ and 151 patients with BP and compared with 200 control subjects. We created a subgroup of subjects-45 with SZ and 45 with BP-balanced for their main antipsychotic medication. RESULTS: A reduced cone a-wave amplitude and a prolonged b-wave latency were observed in both disorders, whereas a reduced cone b-wave amplitude was present in SZ only. Reduced mixed rod-cone a- and b-wave amplitudes were observed in both disorders. Patients with SZ were distinguishable from control subjects with 0.91 accuracy, 77% sensitivity, and 91% specificity with similar numbers for patients with BP (0.89, 76%, and 88%, respectively). Patients with SZ and patients with BP could be differentiated with an accuracy of 0.86 (whole sample) and 0.83 (subsamples of 45 patients with 80% sensitivity and 82% specificity). Antipsychotic dosages were not correlated with ERG parameters. CONCLUSIONS: The ERG waveform parameters used in this study provided a very accurate distinction between the two disorders when using a logistic regression model. This supports the ERG as a tool that could aid the clinician in the differential diagnosis of SZ and BP in stabilized medicated patients.

A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds.

The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.