Brief Report: Clusters and Trajectories Across the Autism and/or ADHD Spectrum.

Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occur and show high genetic correlation. With the introduction of DSM-5, there is a new concept of an ASD and/or ADHD spectrum (ASD/ADHD). This study aimed to identify predictors of severity and need of healthcare within this spectrum. 39 families with multiple individuals affected by ASD/ADHD were recruited from a psychiatric clinic. Diagnoses, functional and demographic characteristics were retrieved from journals while hospital admissions were identified in the Danish health register. An estimated fraction of 31% ASD/ADHD patients had never been hospitalized and 35% remained undiagnosed despite hospitalization. Cluster analysis identified trajectories that discriminate age of diagnosis, educational attainment to degree of severity, need of hospitalization and genetic risk.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia.

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.

OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METHOD: The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

A possible association between schizophrenia and GRIK3 polymorphisms in a multicenter sample of Scandinavian origin (SCOPE).

There is considerable evidence of altered glutamatergic signalling in schizophrenia and a polymorphic variant of the GRIK3 glutamate receptor gene on 1p34-33 has previously been associated to this psychotic disorder. We therefore conducted a systematic association study with 30 HapMap-selected tagging SNPs across GRIK3 in three independent samples of Scandinavian origin from the Scandinavian Collaboration of Psychiatric Etiology (SCOPE), including a total of 839 cases with schizophrenia spectrum and 1473 healthy controls. Four markers (rs6671364, rs17461259, rs472188, and rs535620) attained nominally significant P-values in both the genotypic (0.002, 0.02, 0.03, and 0.05, respectively) and allelic (0.001, 0.006, 0.03, and 0.02, respectively) association tests for the combined sample, and 2 additional markers (rs481047and rs1160751) displayed significance for the genotype (P-values: 0.03 and 0.04). Several haplotypes, that all included at least one of the four SNPs implicated by the single marker analysis, remained significant after adjustment for multiple testing using permutations with 10,000 shuffles. In addition we observed an association for two of the four significant GRIK3 markers (rs472188 and rs535620) to scores for negative symptoms on the PANSS scale. The present results, although not robust, support the importance of more extensive investigations of GRIK3, given its potential role in mediating risk for schizophrenia.

Diagnostic agreement of schizophrenia spectrum disorders among chronic patients with functional psychoses.

BACKGROUND: To investigate whether diagnostic agreement across different diagnostic systems improves in a sample of chronic patients suffering from functional psychosis compared to first-admitted patients. SAMPLING AND METHODS: Among 353 patients with a history of functional psychosis, a subset of 100 individuals (35 women and 65 men) were randomly sampled and assessed using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT). Based on the OPCRIT diagnoses the subjects suffering from schizophrenia and schizophrenia spectrum disorders according to seven diagnostic systems were identified. Diagnostic agreement was assessed using unweighted kappa-statistics and pairwise concordance rates (CR). RESULTS: High diagnostic agreement of schizophrenia was observed across the ICD-10 and DSM systems (CR >0.70, kappa >0.70), which all had a significantly lower concordance to the St. Louis Criteria (SLC), research diagnostic criteria and Schneider's first rank symptoms (FRS) (0.32< CR <0.66; -0.10< kappa <0.51). Agreement on schizophrenia across all systems was observed for one fourth of the subjects. Elimination of the diagnostic impact of 'co-occurrence of psychotic and affective symptoms' excluded FRS standalone individuals from the sample, increased overall homogeneity and resulted in a dichotomized sample according to SLC (46 positive vs. 47 negative). SLC status could be predicted in 78% of cases by four items relating to family history and psychosocial function previous to the onset of illness. Similarly high pairwise CR were observed for schizophrenia spectrum disorders across all diagnostic systems. CONCLUSIONS: This study demonstrates that diagnostic agreement is higher among chronic patients than that observed in subjects with a recent onset of psychosis, although considerable discordance is also observed in this chronic sample. However, the discordance among chronic patients with functional psychosis largely derives from the different emphasis that diagnostic systems place on co-occurrence of psychotic and affective symptoms. This may have serious epistemological consequences, thus underlining the conventional nature of the present schizophrenia diagnoses and the need for biologically founded diagnostic criteria.

Apolipoprotein D is associated with long-term outcome in patients with schizophrenia.

Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find ApoD alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P = 0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.

Stimulation of AIDS lymphocytes with calcium ionophore (A23187) and phorbol ester (PMA): studies of cytoplasmic free Ca, IL-2 receptor expression, IL-2 production, and proliferation.

We have studied whether the decreased lymphocyte proliferative responses of AIDS lymphocytes to stimulation by mitogens and antigens may be overcome when challenged with a combination of calcium ionophore A23187 and phorbol ester PMA. Comparison of the proliferative response of lymphocytes from nine patients with AIDS with the response of lymphocytes from nine control subjects showed that the response of AIDS lymphocytes was severely decreased when stimulated with PHA and no further response could be achieved by stimulation with A23187/PMA. On the other hand, no significant difference between the PHA-induced rise of cytoplasmic free calcium concentration ([Ca2+]1) in normal and AIDS lymphocytes was observed. The percentage of cells expressing IL-2 receptors (CD25) was also normal both after addition of PHA and after addition of A23187/PMA and the expression was normal on both CD4 and CD8 cells. The production of IL-2 in normal lymphocytes stimulated with A23187/PMA was 33 times higher than that after stimulation with PHA. In AIDS lymphocytes the production of IL-2 induced by all activators was severely decreased compared to control subjects, although the production of IL-2 after stimulation with A23187/PMA was higher than that in control lymphocytes after stimulation with PHA. The present study shows that a direct activation of protein kinase C combined with mobilization of cytoplasmic calcium does not overcome the lymphocyte proliferative deficiency of AIDS lymphocytes.

HIV-induced immunodeficiency. Relatively preserved phytohemagglutinin as opposed to decreased pokeweed mitogen responses may be due to possibly preserved responses via CD2/phytohemagglutinin pathway.

We studied the proliferative response of PBL to the mitogens PHA and PWM and Candida albicans Ag in 301 HIV seropositive homosexual men, of whom 55 had AIDS. The responses to PHA were reduced only in the clinically ill HIV seropositive subjects. In contrast, the responses to PWM were profoundly reduced in most HIV seropositive subjects including the asymptomatic group. Further analysis of 16 HIV seropositive subjects showed that the proliferative responses were reduced in both CD4 and CD8 T cell subsets. A total of 15 HIV seropositive individuals with low responses to PWM, of whom seven had AIDS and eight controls were chosen for the following studies. Expression of T3, Ti, delta receptors, and CD2 was investigated and showed an increased percentage of CD2 receptors positive cells in HIV seropositive subjects without AIDS. The proliferative responses of PBL to stimulation with PHA, PWM, antibodies to CD3, or antibodies to CD2 were investigated and showed significant correlation in controls, whereas in contrast, only the responses to PHA and CD2ab correlated in patients with AIDS. The proliferative responses to CD2ab and CD3ab in controls were larger than the responses to both PHA and PWM. In patients, these responses were less suppressed than the responses to PWM indicating that stimulation with mitogens is more complex than a simple stimulation of Ti/T3 and CD2 receptors. Further investigations were done on resting T cells, i.e., lymphocytes depleted of macrophages and pre-activated cells. Addition of PHA to these cells resulted in preactivation with expression of IL-2R (CD25) but not in proliferation. In contrast, addition of PHA plus SRBC, which bind to the CD2 receptors caused IL-2R expression, IL-2 production, and proliferation. Addition of PWM + SRBC did not result in proliferation. A comparison of the responses to PHA + SRBC of resting T cells from 26 HIV seropositive individuals, of whom seven had AIDS and 12 seronegative controls, showed that these responses were normal or only slightly decreased in the 19 seropositive men without AIDS whereas it was decreased in AIDS patients. Nevertheless, all AIDS patients showed clear-cut responses in this assay. Thus, the discrepancy between responses to PHA and PWM may be explained by an at least partially preserved function of the PHA/CD2-dependent pathway. We suggest that the defect induced by the HIV infection primarily concerns T3/Ti-induced responses.

Prognostic value of immunologic abnormalities and HIV antigenemia in asymptomatic HIV-infected individuals: proposal of immunologic staging.

The prognostic value of various immunologic tests was investigated in 150 HIV-seropositive homosexual men, who were initially without HIV-related symptoms or AIDS and who were followed for a median of 12 months (range 3-28 months). The laboratory investigations included HIV antigen in serum, total lymphocyte count, T-helper (CD4) and T-cytotoxic/suppressor (CD8) counts, and lymphocyte transformation responses to the mitogens phytohemagglutinin (PHA) and pokeweed mitogen (PWM), and to antigenic extracts from Candida albicans and cytomegalovirus. 24 individuals developed HIV-related symptoms or AIDS (11 cases). All parameters except the CD8 count were of prognostic value, but a multivariate analysis of symptom-free survival showed that HIV antigenemia, a CD4 count less than 0.5 x 10(9)/l, and relative response to PWM below 25% of controls contained all the prognostic information. Individuals abnormal at entry for these 3 variables had a theoretical 36 times as high hazard of developing symptoms within the observation period as had individuals with normal parameters. There was no significant covariation between HIV antigenemia on the one hand and CD4 count and response to PWM on the other. Although, the latter 2 variables covaried, each of them provided independent information, and both were used to classify the degree of the immunodeficiency in 3 stages: Im-0 with normal values, Im-1 with one, and Im-2 with both tests abnormal. Individuals in stage Im-2 had a 10 times increased risk of developing symptoms. The immunologic staging correlated significantly with the clinical grouping (CDC criteria). This staging improved in only 1, but deteriorated in half of 36 individuals observed for at least 18 months. Thus, the staging is likely to prove useful when attempts to arrest the immunodeficiency of HIV-infected individuals has to be monitored.