Opioid use as a proximal risk factor for suicidal behavior in young adults.

INTRODUCTION: There is a concomitant rise in suicide rates with the prevalence of opioids involved in overdose deaths, especially among adolescents and young adults. However, there are limited studies on whether opioid use prospectively predicts suicidal behavior in youth. METHODS: Our sample included 183 psychiatric patients (18-30 years) admitted for a suicide attempt (SA), have current suicidal ideation (SI), and psychiatric controls without ideation or attempt (PC). Suicidal behavior was assessed using the Columbia Suicide Severity Rating Scale. We also recruited a healthy control group (HC; n = 40). Patients and controls were followed over a year. ANOVA, regression, and cox regression were used. RESULTS: Suicide attempt (ß = 0.87, CI [0.1-1.6], p = 0.02) and SI [(ß = 0.75, CI [0.03-1.5], p = 0.04) were significantly more likely than HCs to have used opioids in the past year at baseline. Opioid use was associated with increased anxiety symptoms (ß = 0.75, CI [0.001-1.5], p = 0.05), PTSD symptoms (ß = 3.90, CI [1.1-6.7], p = 0.01), and aggression (ß = 0.02, CI [0.01-0.04], p = 0.02). Opioid use in the month prior to hospitalization predicted SA at 6 months (OR = 1.87, CI [1.06-3.31], p = 0.032). CONCLUSIONS: Opioid use is a proximal predictor for SA. These findings may help clinicians better identify patients at risk for suicidal behavior, allowing for more personalized treatment approaches.

Outcomes from Indo-United States-Egypt tri-national psychiatric research training programmes.

BACKGROUND: The prevalence of mental health disorders is increasing globally. Countries in South Asia, Southeast Asia and the Middle East regions carry high burdens of mental health need; however, there are relatively few mental health research publications from this region, suggesting inadequate research funds and a paucity of qualified research personnel. To increase and strengthen the pool of mental health researchers in India and Egypt, we conducted three psychiatric research programmes in these countries: the Training Program for Psychiatric Genetics in India (2002-2011), the Tri-National Training Program for Psychiatric Genetics (2009-2014) and the Cross-Fertilized Research Training for New Investigators in Egypt and India (2014-2019). A total of 66 trainees, including psychiatrists, psychiatric social workers, clinical psychologists and research psychologists, were supported in research development, which included didactic training, proposal development, hands-on research and manuscript preparation. METHODS: The aim of this study is to evaluate these three training programmes using the four-level Kirkpatrick Model of Training Evaluation that assesses reaction, learning, behaviour and outcomes. A descriptive analysis was used to explore the data collected throughout the duration of the three training programmes. Online surveys were crafted and sent to the mentors and trainees of the three programmes to supplement objective training data. RESULTS: In addition to positive changes in the areas of reaction, learning and behaviour, significant outcomes were demonstrated. As of the writing of this manuscript, the trainees published a total of 130 papers, 59 as first author. In addition, 26 trainees have co-authored papers with one or more trainees or mentors, which demonstrates successful research networking and collaboration. CONCLUSION: Our findings suggest that our training approach is a successful model for building independent mental health researchers. This is a critical step in the development of effective mental health interventions in low- and middle-income countries.

Age dependent association of inbreeding with risk for schizophrenia in Egypt.

BACKGROUND: Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. METHODS: We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. RESULTS: Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (ß = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. CONCLUSIONS: We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

Randomized controlled trial of adjunctive Valproate for cognitive remediation in early course schizophrenia.

BACKGROUND: Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. METHODS: Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. RESULTS: There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. CONCLUSION: Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.

Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia.

A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.

The Standard for Clinicians' Interview in Psychiatry (SCIP): A Clinician-administered Tool with Categorical, Dimensional, and Numeric Output-Conceptual Development, Design, and Description of the SCIP.

Existing standardized diagnostic interviews (SDIs) were designed for researchers and produce mainly categorical diagnoses. There is an urgent need for a clinician-administered tool that produces dimensional measures, in addition to categorical diagnoses. The Standard for Clinicians' Interview in Psychiatry (SCIP) is a method of assessment of psychopathology for adults. It is designed to be administered by clinicians and includes the SCIP manual and the SCIP interview. Clinicians use the SCIP questions and rate the responses according to the SCIP manual rules. Clinicians use the patient's responses to questions, observe the patient's behaviors and make the final rating of the various signs and symptoms assessed. The SCIP method of psychiatric assessment has three components: 1) the SCIP interview (dimensional) component, 2) the etiological component, and 3) the disorder classification component. The SCIP produces three main categories of clinical data: 1) a diagnostic classification of psychiatric disorders, 2) dimensional scores, and 3) numeric data. The SCIP provides diagnoses consistent with criteria from editions of the Diagnostic and Statistical Manual (DSM) and International Classification of Disease (ICD). The SCIP produces 18 dimensional measures for key psychiatric signs or symptoms: anxiety, posttraumatic stress, obsessions, compulsions, depression, mania, suicidality, suicidal behavior, delusions, hallucinations, agitation, disorganized behavior, negativity, catatonia, alcohol addiction, drug addiction, attention, and hyperactivity. The SCIP produces numeric severity data for use in either clinical care or research. The SCIP was shown to be a valid and reliable assessment tool, and the validity and reliability results were published in 2014 and 2015. The SCIP is compatible with personalized psychiatry research and is in line with the Research Domain Criteria framework.

Hepatitis C virus antibody titers associated with cognitive dysfunction in an asymptomatic community-based sample.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with cognitive dysfunction in clinic-based studies. The risk could be attributed to factors such as antiviral medications, substance abuse, or coincidental infection. AIM: The aim was to evaluate cognitive function in relation to HCV antibody titers in a community-based sample of asymptomatic individuals at low risk for substance abuse. METHOD: Adults were ascertained from a community in Mansoura, Egypt, where HCV is endemic (n = 258). Cognitive performance was evaluated using the Arabic version of the Penn Computerized Neurocognitive Battery. Substance abuse and psychopathology were also assessed. Antibodies to HCV and Toxoplasma gondii (TOX), a common protozoan that can affect cognition, were estimated using serological IgG assays. RESULTS: The prevalence of HCV and TOX infection was 17.6% and 52.9%, respectively. HCV antibody titers were significantly associated with worse function in four cognitive tests for accuracy and three tests for speed, after adjusting for covariates (p < .05, beta coefficients, 2.1-3.2). TOX antibody titers were associated with impaired accuracy in one test. CONCLUSIONS: The association between HCV antibody titers and cognitive impairment is not mediated by antiviral treatment or substance abuse in this sample. Whether HCV has a causal role in the cognitive dysfunction should be investigated.

Regional research priorities in brain and nervous system disorders.

The characteristics of neurological, psychiatric, developmental and substance-use disorders in low- and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low- and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities.

Practice effects distort translational validity estimates for a Neurocognitive Battery.

INTRODUCTION: With the globalization of biomedical research and the advent of "precision medicine," there is increased need for translation of neuropsychological tests, such as computerized batteries that can be incorporated in large-scale genomic studies. Estimates of translational validity are obtained by administering the test in the original and the translated versions to bilingual individuals. We investigated the translation of a neuropsychological battery from English to Arabic and how practice effects influence translational validity estimates. METHODS: The Penn computerized neurocognitive battery (Penn CNB) includes tests that were validated with functional neuroimaging and provides measures of accuracy and speed of performance in several cognitive domains. To develop an Arabic version of the CNB, the English version was translated into Arabic, then back translated and revised. The Arabic and the original English versions were administered in a randomized crossover design to bilingual participants (N = 22). RESULTS: Performance varied by cognitive domain, but generally improved at the second session regardless of the language of the initial test. When performance on the English and Arabic version was compared, significant positive correlations were detected for accuracy in 8/13 cognitive domains and for speed in 4/13 domains (r = .02 to .97). When the practice estimates using linear models were incorporated, the translational validity estimates improved substantially (accuracy, r = .50-.96, speed, r = .63-.92, all correlations, p = .05 or better). CONCLUSION: While crossover designs control for order effects on average performance, practice effects, regardless of language, still need to be removed to obtain estimates of translational validity. When practice effect is controlled for, the Arabic and English versions of the Penn-CNB are well correlated, and the Arabic version is suitable for use in research.

Arabic versions of the sleep timing questionnaire and the composite scale of morningness.

OBJECTIVES: To develop Arabic versions of English language questionnaires to estimate morningness/eveningness and sleep variables. METHODS: We translated the Composite scale of morningness (CSM) and the sleep timing questionnaire (STQ) [with added siesta questions] into Arabic; the Arabic versions were then back translated. The revised Arabic and the original English versions were next administered to bi-lingual Egyptians using a crossover design (n=25). The Arabic versions of both scales were subsequently administered to an independent Egyptian sample (n=79) and the siesta variables examined in relation to the CSM. RESULTS: Satisfactory correlations were present between the English and Arabic versions for total CSM scores (Spearman's ρ=0.90, p<0.001). All but one of the STQ variables were significantly correlated (Spearman's ρ=0.45-0.88, p≤0.05). In the Arabic version, the frequency of siesta naps per week was significantly correlated with the total CSM score, with evening types taking more naps (Spearman's ρ=-0.23, p≤0.05). CONCLUSIONS: Arabic versions of the STQ and CSM have been developed in Egypt, and are freely available. They can be used for behavioral research related to sleep and circadian function and can be adapted for use in other Arab speaking populations.

Suggested avenues to reduce the stigma of mental illness in the Middle East.

BACKGROUND: Stigma toward mentally ill individuals acts as a barrier to accessing care and receiving treatment. AIM: To review current evidence pertaining to stigma toward mental illness in the Middle East in order to inform effective and sustainable interventions in this region. METHODS: We conducted a systematic literature search using the PubMed database and evaluated all identified studies according to specific inclusion criteria. RESULTS: Stigma toward individuals with mental illness does exist in the Middle East. Stigmatizing attitudes are particularly high toward culturally proscribed mental illnesses like alcohol abuse and lower for other disorders such as depression and psychosis. CONCLUSIONS: We propose the following initiatives to reduce stigma toward mental illness in the Middle East: (a) educate families to enable them to support their affected relatives, (b) increase cooperation between psychiatrists and faith healers and (c) educate young people in schools to increase their awareness and understanding of mental illnesses and to combat negative stereotypes.

The reliability of the standard for clinicians' interview in psychiatry (SCIP): a clinician-administered tool with categorical, dimensional and numeric output.

BACKGROUND: Existing standardized diagnostic interviews are not used by psychiatrists in clinical settings. There is an urgent need for a clinician-administered tool for assessment of adult psychopathology that produces dimensional measures, in addition to categorical diagnoses. METHODS: The Standard for Clinicians' Interview in Psychiatry (SCIP) was designed to be used in clinical settings and generates dimensional measures. The reliability of the SCIP was tested at six sites: one hospital and two clinics in USA, two hospitals in Egypt and one clinic in Canada. Participants were adult patients who were admitted for inpatient psychiatric treatment or came for regular office visits in the outpatient clinic. Refusal rate was <1%. Missing data were <1.1%. Patients with dementia, mental retardation or serious medical conditions were excluded. A total of 1,004 subjects were interviewed between 2000 and 2012. RESULTS: Inter-rater reliability (Kappa) was measured for 150 SCIP items: 116 items (77.3%) had good reliability (Kappa>0.7), 28 items (18.7%) had fair reliability (Kappa ranges from 0.5 to 0.7) and six items (4%) had poor reliability (Kappa<0.5). Cronbach's alpha for internal consistency was measured for the SCIP dimensions: anxiety, posttraumatic stress, depression, mania, hallucinations, Schneider first-rank symptoms, delusions, disorganized thoughts, disorganized behavior, negative symptoms, alcohol addiction, drug addiction, attention and hyperactivity. All of the SCIP dimensions had substantial Cronbach's alpha values (>0.7) with the exception of disorganized thoughts (Cronbach's alpha=0.375). CONCLUSIONS: The SCIP is a reliable tool for assessing psychological symptoms, signs and dimensions of the main psychiatric diagnoses.

HLA associations in schizophrenia: are we re-discovering the wheel?

Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n = 100-400). The risk conferred by individual alleles was modest (odds ratios < 2.0). The basis for the associations could not be determined, though connections with known immune and auto-immune abnormalities in SZ were postulated. Interest in the HLA associations has re-emerged following several recent genome-wide association studies (GWAS); which utilized 10- to 100-fold larger samples and also identified associations on the short arm of chromosome 6. Unlike the earlier candidate gene studies, the associations are statistically significant following correction for multiple comparisons. Like the earlier studies; they have modest effect sizes, raising questions about their utility in risk prediction or pathogenesis research. In this review, we summarize the GWAS and reflect on possible bases for the associations. Suggestions for future research are discussed. We favor, in particular; efforts to evaluate local population sub-structure as well as further evaluation of immune-related variables in future studies.

Application of an ex vivo cellular model of circadian variation for bipolar disorder research: a proof of concept study.

OBJECTIVES: Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. METHODS: Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. RESULTS: Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. CONCLUSIONS: An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research.

Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure.

BACKGROUND: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. METHOD: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. RESULTS: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. CONCLUSIONS: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.

PER2 rs2304672 polymorphism moderates circadian-relevant reward circuitry activity in adolescents.

BACKGROUND: Reward behavior in animals is influenced by circadian genes, including clock-pathway genes such as Period2 (PER2). Several forms of psychiatric illness are associated with both altered reward function and disturbances in circadian function. The PER2 single nucleotide polymorphism (SNP) rs2304672 has been associated with psychiatric illnesses involving reward dysfunction. Associations among circadian genes, function in neural reward circuits, and circadian-influenced behavior have not yet been studied in humans, however. METHODS: 90 healthy adolescents underwent functional magnetic resonance imaging during a guessing task with monetary reward, genotyping for two PER2 SNPs (rs2304672, rs2304674), and actigraphy to measure sleep in their home environments. Weekend sleep midpoint, a behavioral index of circadian function, was derived from actigraphy. Puberty was measured by physical exam. RESULTS: The rs2304672 SNP predicted blood oxygenation level-dependent response to monetary reward as constrained by sleep midpoint. Later sleep midpoint was associated with reduced activity in a key component of reward circuitry, medial prefrontal cortex (mPFC; Brodmann area 9/10/32), to reward outcome (p(corrected) < .05). G allele carriers showed reduced activity in mPFC relative to CC homozygotes. CONCLUSIONS: Our findings are the first to indicate that circadian genes have a significant impact upon circadian-relevant reward circuitry in humans. These findings have the potential to elucidate gene-brain-behavior relationships underlying reward processing and psychopathology.

Reduced Fertility and Fecundity among Patients with Bipolar I Disorder and Schizophrenia in Egypt.

OBJECTIVE: To evaluate reproduction among patients with bipolar I disorder (BP1) or schizophrenia (SZ) in Egypt. METHODS: BP1 patients (n=113) were compared with community based, demographically balanced controls (n=124) and SZ patients (n=79, DSM-IV). All participants were evaluated using structured interviews and corroborative data were obtained from relatives. Standard indices of procreation were included in multivariate analyses that incorporated key demographic variables. RESULTS: Control individuals were significantly more likely to have children than BP1 or SZ patients (controls 46.8%, BP1 15.9%, SZ 17.7%), but the BP1-SZ differences were non-significant. The average number of children for BP1 patients (0.37±0.9) and SZ patients (0.38±0.9) was significantly lower than for controls (1.04±1.48) (BP1 vs controls, p<0.001; SZ vs controls, p<0.001). The frequency of marriages among BP1 patients was nominally higher than the SZ group, but was significantly lower than controls (BP1: 31.9% SZ: 27.8% control: 57.3%). Even among married individuals, BP1 (but not SZ) patients were childless more often than controls (p=0.001). The marital fertility, i.e., the average number of children among patients with conjugal relationships for controls (1.8±1.57) was significantly higher than BP1 patients (1.14±1.31, p=0.02), but not significantly different from SZ patients (1.36±1.32, p=0.2). CONCLUSION: Selected reproductive measures are significantly and substantially reduced among Egyptian BP1 patients. The reproductive indices are similar among BP1 and SZ patients, suggesting a role for general illness related variables. Regardless of the cause/s, the impairment constitutes important, under-investigated disability.

Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?

We have recently found that consanguinity is a risk factor for bipolar I disorder (BP1) and schizophrenia (SZ) in Egypt. Inbreeding has been associated with increased cellular stress and impaired physiological function in plants and animals. Previous studies have reported that telomere length (TL), an index of oxidative stress and cellular senescence is significantly reduced among patients with SZ or mood disorders compared with control individuals. Hence we evaluated TL as a possible mediator of the observed association between consanguinity and BP1/SZ risk. Patients with BP1 (n=108), or SZ (n=60) were compared with screened adult controls in separate experiments. TL was estimated using a quantitative PCR (qPCR) based assay. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ('DNA-based' rate); and from family history data ('self report'). Significant correlation between TL and DNA based inbreeding was not observed overall, though suggestive trends were present among the SZ cases. No significant case-control differences in TL were found after controlling for demographic variables. In conclusion, reduced TL may not explain a significant proportion of observed associations between consanguinity and risk for BP1/SZ.

Fine-mapping reveals novel alternative splicing of the dopamine transporter.

The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc.

Consanguinity and increased risk for schizophrenia in Egypt.

BACKGROUND: Consanguinity has been suggested as a risk factor for psychoses in some Middle Eastern countries, but adequate control data are unavailable. Our recent studies in Egypt have shown elevated parental consanguinity rates among patients with bipolar I disorder (BP1), compared with controls. We have now extended our analyses to schizophrenia (SZ) in the same population. METHODS: A case-control study was conducted at Mansoura University Hospital, Mansoura, Egypt (SZ, n=75; controls, n=126, and their available parents). The prevalence of consanguinity was estimated from family history data ('self report'), followed by DNA analysis using short tandem repeat polymorphisms (STRPs, n=63) ('DNA-based' rates). RESULTS: Self-reported consanguinity was significantly elevated among the patients (SZ: 46.6%, controls: 19.8%, OR 3.53, 95% CI 1.88, 6.64; p=0.000058, 1 d.f.). These differences were confirmed using DNA-based estimates for coefficients of inbreeding (inbreeding coefficients as means+/-standard error, cases: 0.058+/-0.007, controls: 0.022+/-0.003). CONCLUSIONS: Consanguinity rates are significantly elevated among Egyptian SZ patients in the Nile delta region. The associations are similar to those observed with BP1 in our earlier study. If replicated, the substantial risk associated with consanguinity raises public health concerns. They may also pave the way for gene mapping studies.