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.

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.

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.

Depression in obese patients with primary fibromyalgia: the mediating role of poor sleep and eating disorder features.

Depression is a prominent feature in fibromyalgia syndrome. Patients with fibromyalgia syndrome who are obese, with poor sleep quality, and those who have recurrent episodes of binge eating are at greater risk to develop depression. The aim of this cross-sectional study was to examine the hypothesis that the relationship between obesity and depression in patients with primary fibromyalgia syndrome is mediated by poor sleep, binge eating disorder (BED), and weight and shape concern. This study included 131 patients with primary fibromyalgia syndrome. Participants completed the following questionnaires: Pittsburgh Sleep Quality Index, Beck Depression Inventory-II, Eating Disorder questionnaire, and Fibromyalgia Impact Questionnaire. Body mass index (BMI) provided the primary indicator of obesity. Sobel test showed that the conditions for complete mediation were satisfied on the weight and shape concern as mediator between BMI and depression because the association between BMI and depression score became insignificant after controlling of weight and shape concern. However, since the association between BMI and depression remained significant after BED and poor sleep score were controlled, thus for both mediators, the conditions for partial mediation on the depression were satisfied. The findings suggest that in patients with primary fibromyalgia syndrome, weight and shape concern, BED, and poor sleep quality are important mediators of the relationship between obesity and depression. We suggest that a greater focus on these mediators in depression treatment may be indicated.

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.

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.

Consanguinity associated with increased risk for bipolar I disorder in Egypt.

We aimed to contrast rates of consanguinity among patients with bipolar I disorder (BP1) and controls in a population with customary consanguineous marriages (i.e., marriage between related individuals). Consanguinity increases risk for numerous monogenic and polygenic diseases. Whether the risk for BP1 increases with consanguinity has not been investigated systematically. Two independent studies were conducted in Egypt: (1) Case-control study 93 patients with BP1, 90 screened adult control individuals, and available parents. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ("DNA-based" rate); and from family history data ("self report"); (2) Epidemiological survey: total of 1,584 individuals were screened, from whom self-reported consanguinity data were obtained for identified BP1 cases (n = 35) and 150 randomly selected, unaffected control individuals. DNA-based consanguinity rates showed significant case-control differences (P = 0.0039). Self-reported consanguinity rates were also elevated among BP1 patients in both samples (Study #1 OR = 2.66, 95% confidence intervals, CI: 1.34, 5.29; Study #2: OR = 4.64, 95% CI: 2.01, 10.34). In conclusion, two independent, systematic studies indicate increased consanguinity among Egyptian BP1 patients in the Nile delta region. Self-reported estimates of consanguinity are bolstered by DNA-based estimates, and both show significant case-control differences for BP1.