Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.

A current focus in psychiatric genetics is detection of multiple common risk alleles through very large genome-wide association study analyses. Yet families do exist, albeit rare, that have multiple affected members who are presumed to have a similar inherited cause to their illnesses. We hypothesized that within some of these families there may be rare highly penetrant mutations that segregate with illness. In this exploratory study, the genomes of 90 individuals across nine families were sequenced. Each family included a minimum of three available relatives affected with a psychotic illness and three available unaffected relatives. Twenty-six variants were identified that are private to a family, alter protein sequence, and are transmitted to all sequenced affected individuals within the family. In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. This variant lies within the consensus SH3 protein-binding motif by which SHANK2 may interact with post-synaptic glutamate receptors. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome. Both variants represent candidates that may be causal for psychotic disorders when considered in the context of their transmission pattern and known gene and disease biology.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder.

This study investigated adolescent cannabis use as a risk factor for schizophrenia spectrum disorder (SSD). Motives for early cannabis use and resulting usage patterns were examined alongside clinical measures of SSD onset and symptomatology. Participants (N = 178) were recruited for two samples, 1: healthy controls (HC) with cannabis use, 2: schizophrenia patients (SSD) with cannabis use. Structured interviews of participants and family informants were used to obtain diagnostic and biographical information. Factor-analysis of reported motives for initiating cannabis use produced four groups; sedation, stimulation, social pressure, and recreation. Regression analyses revealed significant relationships between these groups and SSD. Most notably, reason group factor scores predict SSD risk as well as schizotypal symptom severity. Findings also indicate that these factors follow a hierarchical structure, which explains their relative involvement in increased SSD risk. We suggest that adolescent cannabis use both hastens the onset and amplifies the severity of SSD. In response we propose a model for identifying at risk individuals, predicting the onset and severity of SSD, and potentially mitigating the associated psychiatric impairments.

The third biannual winter workshop on schizophrenia. Schladming, Austria, Jan 26-31, 1986.

The following general principles seem to summarize the emphasis that was evident from the several days of multiple presentations and discussions. The need exists to continue to develop improvements in the tools applicable to research in psychiatry, both clinical and biological "instruments" that are both sensitive and specific to the questions asked. New molecular genetic technology has already been used to explore genetic susceptibility hypotheses, as well as novel viral associations. Imaging of brain receptor kinetics in vivo is in progress. Improvements in structured clinical rating scales for quantifying changes in biologically important clusters of symptoms (eg, negative vs positive symptoms) or the defining of prodromal symptoms that lead to relapse are critical to progress in etiological and treatment research. A genetic factor or factors for schizophrenia exist, although whether a "familial" type defines only a subgroup of schizophrenia is controversial. The relative importance of genetic vs environmental variables, and whether there is genetic and environmental heterogeneity, continue to be debated. The most important epidemiological data, the seasonality of birth, and the controversial question of geographical variation in prevalence can be clues to the etiology of schizophrenia and are presently being clarified. The pursuit of new treatments and modifications of present conventional treatments to increase the percentage of patients recovering from psychotic illnesses or lead to more complete recovery states is always of prime importance. An emphasis on clarifying the dopamine hypothesis of schizophrenia with PET continues to be at the forefront of psychiatric research. A focus on patients in a first episode of schizophrenia can clarify major issues.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical features of illness in siblings with schizophrenia or schizoaffective disorder.

Evidence implicating genetic or prenatal-perinatal environmental causes in the familial aggregation of schizophrenia led us to study 53 sets of siblings, two or more of whom had chronic psychosis, either schizophrenia or schizoaffective disorder. We looked for similarities in clinical features and concordance of diagnosis within sibships to test for shared familial causes. Clinical variables, including diagnosis, specific symptoms, age at onset, and nongenetic perinatal factors, were studied. Auditory hallucinations, paranoid delusions, thought disorder, negative symptoms, and poor premorbid social adjustment did not significantly correlate in siblings. Concordance was found for schizoaffective disorder and history of major depressive episodes, suggesting that schizophrenia with a depressive component and Research Diagnostic Criteria schizoaffective illness may represent a specific etiologic subtype(s) of the illness, whereas the other noted symptoms may represent the variable expression of the disorder. Age at onset and at first hospitalization were significantly correlated, consistent with genetic or other familial factors on time of onset. Birth complications were significantly more frequent among the schizophrenic compared with non-psychotic siblings, had a familial component, and tended to be associated with an earlier age at onset. Thus, nongenetic perinatal factors may increase the risk for schizophrenia in a familial form of the illness and contribute to the correlation of ages at onset in siblings.

Increased whole blood serotonin concentrations in chronic schizophrenic patients.

Whole blood serotonin concentrations were studied in 33 chronic schizophrenic patients who previously had computed tomographic (CT) brain scans and in 23 healthy volunteers. The chronic schizophrenic patients had a mean serotonin concentration significantly higher than that of the controls. The patients were subcategorized into a group with abnormal CT scan findings (enlargement of cerebral ventricles, cerebral atrophy, or both) and a group with normal CT scans. The patients with abnormal CT scans had significantly higher serotonin concentrations when compared with schizophrenics with normal CT scans and with controls. The chronic schizophrenic patients with normal CT scans did not have significantly elevated serotonin concentrations compared with controls. Furthermore, ventricular size in the total group was significantly correlated with serotonin concentration.

Plasma phenylalanine, tyrosine, and tryptophan in schizophrenia.

Plasma phenylalanine, tyrosine, and tryptophan concentrations were measured in chronic schizophrenic patients, normal controls, and heterozygotes for phenylketonuria. Schizophrenic patients' plasma concentrations of these amino acids could not be distinguished from those of normal controls, either when fasting or following oral or intravenous (IV) phenylalanine challenge. No neuroleptic effect was observed. Plasma phenylalanine-tyrosine ratios following IV phenylalanine challenge could easily distinguish heterozygotes from schizophrenic and normal control subjects but could not distinguish schizophrenic subjects from normal control subjects. No overlap between heterozygotes' values and those of the schizophrenic and normal subjects was observed. These studies find no evidence of abnormal phenylalanine metabolism in schizophrenic persons. Phenylalanine challenge did not affect the abstraction or judgment capacities of the subjects.

A family study of the association of increased ventricular size with schizophrenia.

Families with more than one individual of the same generation with the diagnosis of schizophrenia were recruited for studies. Brain lateral ventricular size was quantified in 26 schizophrenic subjects from 12 unrelated families, their available well siblings (N = 10), and 20 nonpsychotic controls. Lateral ventricular size was significantly greater in the schizophrenics than in their well siblings and controls. In addition, an analysis of variance of the data showed a significant familial component to ventricular size. Although histories of head injury and birth complications were also associated with ventricular size, these were not sufficient to explain both the familial aspect of ventricular size and the association of greater ventricular size with schizophrenia within these families.

Computed tomography in schizophreniform disorder and other acute psychiatric disorders.

To assess whether computed tomographic findings are present at the onset of schizophrenia, we evaluated CT scans of 35 patients with first-episode schizophreniform disorder, 17 with chronic schizophrenia, 23 with affective disorders, 27 with other psychiatric disorders, and 26 controls. Both the schizophreniform and the chronic schizophrenic patients had significantly larger cerebral ventricles than did the other psychiatric or control subjects. Ventricular size in the patients with affective disorder was not significantly different than in any of the other groups. Twenty percent of the schizophreniform patients had enlarged ventricles, (ventricular-brain ratio, greater than 10). The only other subjects outside this limit were four chronic schizophrenic patients (24%). Five schizophreniform patients and three with affective disorder had evidence of mild cortical atrophy. The results suggest that, in some schizophrenic patients, ventricular enlargement and less frequently cortical atrophy predate the onset of psychoses and are not a result of psychiatric treatment.

A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder.

Two hundred thirty-seven relatives of 48 patients with chronic psychosis, diagnosed as either schizophrenia or schizoaffective disorder, along with 380 relatives of psychiatrically normal controls, were studied using systematic diagnostic interviews, information from relatives, and review of medical records where appropriate. A variety of nonbipolar psychotic disorders was found in the relatives of the patients. Comparing relatives of patients with schizophrenia with relatives of patients with schizoaffective disorder, there was no tendency for schizoaffective diagnosis or acute psychoses to aggregate separately from schizophrenia. Increased incidence of bipolar disorder was found in relatives of patients with schizoaffective disorder but not in relatives of patients with schizophrenia. Incidence of major affective disorder (bipolar and unipolar) was increased in relatives of probands with both types of psychoses. If we subdivide the ill probands according to whether or not they had a history of substance abuse, relatives of probands with substance abuse had greater frequency of affective disorder and substance abuse, but there were not significant differences in the number of relatives with nonbipolar psychoses.

Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders.

Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.

Serotonin and 5-hydroxyindoleacetic acid in brains of suicide victims. Comparison in chronic schizophrenic patients with suicide as cause of death.

Serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations were determined in various brain areas of nonschizophrenic suicide victims, chronic schizophrenic patients with or without suicide as the cause of death, and normal control subjects without psychiatric or neurologic disorders. Serotonin concentrations in the basal ganglia were significantly elevated in suicide victims and chronic schizophrenic patients, as were 5-hydroxyindoleacetic acid concentrations in the occipital cortex. These differences were not specific to either patient group and may have been caused by neuroleptic or antidepressant treatment. A decreased 5-HT concentration was found in the hypothalamus of nonschizophrenic suicide victims. Among the chronic schizophrenic patients, there was no significant difference in the hypothalamic 5-HT content between the suicide victims and others, indicating that low 5-HT levels in the hypothalamus are not characteristic of schizophrenic patients who died of suicide.

Gender differences in corpus callosum size in first-episode schizophrenics.

Previous studies indicate differences between schizophrenics and normals in thickness and overall size of the corpus callosum, particularly in female subjects. The present study compares the area of the corpus callosum as measured by magnetic resonance imaging (MRI) in men and women experiencing first-episode cases of schizophrenia. The corpus callosum area is also correlated with measures of neuropsychological function. The results of this study suggest that women who are first-episode schizophrenic patients have a smaller total corpus callosum area than female controls, with no difference noted for men. In normal controls, a larger corpus callosum was associated with better cognitive function, whereas in schizophrenics, no such relationship emerged.

A geometric morphometric assessment of change in midline brain structural shape following a first episode of schizophrenia.

BACKGROUND: Previous reports indicate that brain structural abnormalities may be progressive in some patients with schizophrenia. Our study was designed to determine deviations in the shape of midline brain structures at the time of onset of symptoms of schizophrenia and 3-5 years later. METHODS: Eleven landmarks were located on the midsagittal magnetic resonance imagery brain scans of 55 patients with schizophrenia and 22 nonpsychiatric control individuals. Geometric morphometric methods were used for the extraction of shape variables from landmark coordinates. Permutation tests were used to test the effects of gender, diagnosis, time elapsed since illness onset, and age on brain shape. RESULTS: The diagnosis-by-time interaction and the effect of gender were significantly different from zero (p<.027 and p <.039, respectively). The effect of time was significant in patients (p <.002), but not in control subjects. Some anatomical abnormalities in mean patient brain morphology seem to be present both at the time of diagnosis and at follow-up. These are similar to anomalies reported by previous geometric morphometrics studies. CONCLUSIONS: Some previously identified brain abnormalities are detectable at the time of first hospitalization. The rapid change in midline brain morphology in patients with schizophrenia during the subsequent 3-5 years is consistent with either a neurodegenerative disease process or an effect of treatment with psychiatric drugs. There is a sexual dimorphism in brain morphology that might be reduced by schizophrenia.

Cerebral ventricular size in major depressive disorder: association with delusional symptoms.

Computerized tomograms (CT scans) and neuroendocrine challenges (TRH stimulation test and dexamethasone suppression test) were completed in 38 melancholic depressed hospitalized patients. There were no significant differences in ventricular size between delusional and nondelusional depressives. However, 5 of 20 delusional depressives (25%) in contrast to none of 18 nondelusional depressives had ventricular brain ratios greater than 2 standard deviations from the mean of 26 neurological controls. There were no demographic, clinical, or neuroendocrine differences between patients with enlarged ventricles and those with normal CT scans. Two of 5 patients with large ventricles were rehospitalized within the 1st year of ascertainment in contrast to 3 of the other 15 delusional depressed patients. The possible relevance of cerebral ventricular size for depressive disorder is discussed.

Corpus callosum dimensions measured by magnetic resonance imaging in bipolar affective disorder and schizophrenia.

Magnetic resonance imaging (MRI) brain scans were performed on 24 schizophrenic patients, 22 bipolar affective patients, and 25 normal control subjects without medical or psychiatric illness using a Picker Vista 0.5 tesla scanner. Specific callosal regions and the cerebral area on the midsagittal slice were measured utilizing the technique described by Nasrallah et al. (1986). No significant differences were found among diagnostic groups in anterior, mid, or posterior callosal width, callosal area, cerebral area, callosal to cerebral area ratio, or the genu (first quartile) to splenium (fourth quartile) ratio. However, male subjects had a significantly greater callosal and cerebral area than female subjects. Gender differences were shown in the genu to splenium ratio in the control groups, but not the affective or schizophrenic groups. The implications of these gender differences are discussed in relation to other studies.

Glucose utilization in the temporal cortex of affectively ill patients: positron emission tomography.

As temporal lobe dysfunction has been postulated in the affective disorders, the authors investigated glucose utilization in the temporal lobes of 13 affectively ill patients in comparison with 18 normal volunteer controls and 17 previously reported schizophrenic patients, following injections of fluorine 18-2-deoxy-D-glucose (FDG) during somatosensory stimulation to the right forearm. Using a boundary-finding algorithm to outline each temporal lobe, maximum glucose use relative to maximums elsewhere in the same positron emission tomography (PET) slice were calculated. In a small group of moderately to severely depressed patients, this relative measure was significantly reduced in the right (with a similar trend in the left) temporal lobe compared to normal volunteers and the other comparison groups. The lack of a significant increase in glucose utilization, measured either as a maximum or in relation to other areas in the PET scan slice, suggests that a temporal lobe activation or a seizure-like process is not generally occurring during active depressive phases of the illness.