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Background: Cognitive impairment is a core feature of schizophrenia and has been observed in subjects with and without a family history of schizophrenia. Nonetheless, there is a paucity of research directly contrasting cognitive profiles in schizophrenia patients and normal people where family history is present and those where the family history is absent. Aim: This stydy aimed to compare cognitive functions in patients with schizophrenia who had a family history with those that did not and healthy controls. Materials and Methods: Fifty consecutive schizophrenia patients were assessed on admission and follow-up after 6 months of treatment using a specially prepared pro forma, the Positive and Negative Syndrome Scale, and the PGI Battery of brain dysfunction is the name give to the test. An equal number of age- and sex-matched normal control subjects were also assessed. Results: Visual memory scores in this study show improvement between baseline and follow-up in schizophrenia patients with/without a family history. Both verbal learning and memory increase between baseline and follow-up but do not reach control levels. Reasoning and problem-solving deficits follow a similar pattern and are causative in the inability to adapt to a changing world. Speed of processing shows improvement with treatment. Working memory deficits in patients improve with treatment. Conclusions: In this study, all six cognitive domain scores in schizophrenia improved after 6 months of treatment but did not reach the control population level. Individuals with the highest cognitive deficits in the scales were the ones who had a family history of schizophrenia.

We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.

Background: Cognitive impairment is a core feature of schizophrenia and has been observed in subjects with and without a family history of schizophrenia. Nonetheless, there is a paucity of research directly contrasting cognitive profiles in schizophrenia patients and normal people where family history is present and those where the family history is absent. Aim: This stydy aimed to compare cognitive functions in patients with schizophrenia who had a family history with those that did not and healthy controls. Materials and Methods: Fifty consecutive schizophrenia patients were assessed on admission and follow-up after 6 months of treatment using a specially prepared pro forma, the Positive and Negative Syndrome Scale, and the PGI Battery of brain dysfunction is the name give to the test. An equal number of age- and sex-matched normal control subjects were also assessed. Results: Visual memory scores in this study show improvement between baseline and follow-up in schizophrenia patients with/without a family history. Both verbal learning and memory increase between baseline and follow-up but do not reach control levels. Reasoning and problem-solving deficits follow a similar pattern and are causative in the inability to adapt to a changing world. Speed of processing shows improvement with treatment. Working memory deficits in patients improve with treatment. Conclusions: In this study, all six cognitive domain scores in schizophrenia improved after 6 months of treatment but did not reach the control population level. Individuals with the highest cognitive deficits in the scales were the ones who had a family history of schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders.

Highlights • Schizotypy in multiplex but not simplex relatives depends on paternal age at birth. • Paternal age at birth affects cognitive functions mainly in multiplex relatives. • Complex processing speed does not depend on paternal age in both relatives' groups. • The findings have implications in intervention programs for psychosis. Abstract Studies comparing cognitive processes between familial and sporadic schizophrenia have yielded inconsistent findings. In this study we examined differences in neurocognition and schizotypal traits in unaffected relatives of schizophrenia-spectrum patients with either the familial (multiplex) or the sporadic (simplex) subtype of the disorder, taking paternal age at birth into consideration. Simplex (n = 65; SR), multiplex (n = 35; MR) relatives and controls (n = 114) were compared on several cognitive functions and schizotypal traits; between-group differences were evaluated with and without including paternal age in the analyses. SR and MR had higher negative and paranoid traits compared with controls, but paternal age abolished the differences between the SR and control groups. When taking into account schizotypal traits and participants' age, controls outperformed MR in strategy formation and set-shifting and SR in psychomotor speed, set-shifting and executive working memory. After including paternal age in the analyses, controls outperformed MR in strategy formation, working memory and executive working memory and both groups in psychomotor speed and set-shifting. These findings suggest that multiplex relatives present with a "riskier" personality and cognitive profile when considering the effects of paternal age. Nevertheless, simplex relatives are impaired in fundamental cognitive processes, thus highlighting the detrimental effects of paternal age on neurocognition. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the executive functions in patients with sporadic schizophrenia (SS) and familial schizophrenia (FS), and the executive func- tions in their parents. Methods: The study included 30 patients with FS and their 37 parents with a positive family history of schizophrenia; 30 patients with SS and their 44 parents; 30 controls matched with the patients for gender, age and education, and 40 controls matched with the parents for gender, age and education (211 subjects in total). All the subjects were interviewed with the Structured Clinical Interview for DSM-lV-Axis I (SCID-l). The executive functions were as- sessed using the Verbal Fluency Test (VFT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test. Results: Patients with FS and their parents, and patients with SS performed significantly worse than their controls on the VFT, TMT, WCST and the Stroop test. There were no statistically significant differences between parents of patients with SS and their controls on any of the tests except for the Stroop color score. FS parents performed significaritly worse than 55 parents on all tests. FS patients performed significantly worse than 55 patients on the VFT, TMT, Stroop test. Conclusion: Previous studies that investigated the cognitive functions of relatives of patients with schizo- phrenia brought out inconsistent results. The present study investigated relatives with and without a family history of schizophrenia separately and found that executive functions were impaired only in parents with a positive family history of schizophrenia. These findings suggest that impairment in executive functions may represent a genetic endophenotype for schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Few brain imaging studies of schizophrenia involve samples with enhanced genetic homogeneity. We compared MRI volumetric data between individuals with 1q21–q23 linked familial schizophrenia associated with NOS1AP and their first and second degree unaffected relatives. We found significant gray matter reductions in the anterior cingulate gyrus in both affected individuals and their unaffected first degree relatives when compared with their unaffected second degree relatives. These results suggest that the changes are primarily due to genetic risk and not illness effects, and may represent an intermediate phenotype. [ABSTRACT FROM AUTHOR]

Abstract: There is some evidence that childhood adversity may be associated with the expression of schizophrenia but whether genetic risk affects this finding is unknown. We investigated the history of early trauma in 194 subjects from 24 multiply affected families where schizophrenia was previously shown to be associated with a functional allele in the NOS1AP gene. In subjects with schizophrenia (n=79), only events prior to the onset of psychosis were considered. Generalized estimating equation models that adjusted for familial clustering were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Subjects with narrowly defined schizophrenia were more likely than their unaffected family members to have a history of early trauma (adjusted OR=4.17, 95% CI=1.52, 11.44). The results were similar after adjusting for the NOS1AP risk genotype (adjusted OR=3.57, 95% CI=1.32, 9.65) and for maternal or paternal history of schizophrenia (adjusted ORs=3.27, 95% CI=1.45, 7.38; 4.38, 95% CI=1.61, 11.91, respectively). The results suggest that childhood trauma is associated with expression of schizophrenia independent of measured genetic susceptibility and may be a candidate for gene-environment research using genetic variants. [Copyright &y& Elsevier]

Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders. [ABSTRACT FROM AUTHOR]

Abstract: There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.55 (1.01, 2.38)). The results provide further support that early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition. [Copyright &y& Elsevier]