Schizophrenia and HLA: a review

A number of reports of genetic association of human leucocyte antigens (HLA) and alleles with schizophrenia have recently been published. A schizophrenia locus on chromosome 6p near the HLA region has also been reported, on the basis of linkage studies. We have therefore reviewed the investigations of association of HLA with schizophrenia published from 1974 to date, and have also briefly reviewed the chromosome 6p linkage studies. Two or more groups of investigators have reported association of each of the following HLA antigens or alleles with schizophrenia - A9 or its A24 subspecificity, A28, A10, DRB1*01 and DRw6. However, these results may represent Type I errors caused by small sample size, inappropriate diagnostic, laboratory and/or statistical methodology, and/or incorrectly chosen comparison subjects. Hypothesis-driven negative associations of DRB1*04 and DQB1*0602 with schizophrenia have also been reported. Taken together, however, HLA association investigations provide only weak evidence for the existence of either resistance or susceptibility loci for schizophrenia close to the HLA region at the 6p21.3 band and, indeed, recently reported investigations that controlled for most of these confounders found no evidence of association. Linkage studies suggest that a susceptibility locus may exist and that it may be within the HLA region, but again the evidence is far from conclusive. Further HLA association investigations should employ operational diagnostic criteria, comparison subjects screened for illness and HLA genotyping, and should include both association studies of candidate alleles and transmission disequilibrium and haplotype relative risk studies.     

Neurotropic Infectious Agents and Cognitive Impairment in Schizophrenia

The links between infectious agents and risk for schizophrenia have been widely debated, but few investigations have focused on “epidiagnostic” effects, eg, whether exposures to infectious agents alter key clinical aspects of the disorder, such as cognitive impairment. The present theme issue evaluates epidiagnostic cognitive effects of two common infectious agents, namely Herpes Simplex Virus, type 1 and Toxoplasma gondii.Key words: schizophrenia, cognition, herpes, virus, Toxoplasma gondiiThe first article of the theme issue indicates that exposure to Herpes Simplex Virus, type 1 (HSV-1) may not be entirely benign for patients with SZ, even though it has not been implicated as a risk factor for schizophrenia (SZ) per se. The word herpes, derived from the Greek “herpein” (“to creep”), describes an unusual characteristic of HSV-1, ie, its proclivity to “creep” along sensory nerves following primary infection in mucosal membranes or in the skin.¹ The retrograde transport takes it to sensory nerve ganglia as well as cortical regions, where it establishes lifelong infection. HSV-1 evades and even hijacks the body’s cellular processes to lie in a relatively dormant state in the nuclei of host neurons. Sporadic reactivation culminates in anterograde transport to sensory nerve endings in mucosal and skin membranes, where typical lytic eruptions reappear. Thus, HSV-1 establishes persistent, ineradicable, lifelong cycles of latency and lytic reactivation. The infection has wide ranging clinical effects, including asymptomatic states, mucosal lesions or devastating encephalitis in immune-compromised individuals and rarely, in otherwise immune competent persons. Whether the repeated latency/reactivation cycles impair neuronal survival, particularly in the brain is not known. In the first article of the theme issues, Prasad et al suggest ominous effects of persistent infection that are particularly notable in SZ patients exposed to HSV-1: (1) structural damage in the cortical gray matter; (2) cognitive impairment; (3) cognitive deterioration over time. The review suggests small to medium effect sizes for the associations between exposure and cognitive impairment, but the population attributable fraction is likely to be 15% or higher, based on a recent association study² and exposure rates over 70% even in middle-aged US adults (http://www.cdc.gov/nchs/nhanes.htm).Genome-wide association studies (GWAS) indicate that HLA variants are associated with SZ risk predominantly in Caucasian ancestry samples, but the basis for the associations is uncertain.³ In the second article of this issue, Bamne et al report nominal associations with the Caucasian-GWAS SNPS in an African American case-control sample. As HLA molecules play a critical role in host immune responses to infection, Bamne and colleagues also investigated the SZ associated SNPs in relation to HSV-1 exposure. No significant associations were found, apart from a curious nominal association with rs3130297. One allele of this SNP elevates risk for SZ, while the other allele is associated with HSV-1 exposure. Analysis of additional replicative samples could clarify whether the epidiagnostic effects reviewed by Prasad et al are related to such host genetic variation. Toxoplama gondii (TOX), the focus of the third theme issue article is a protozoan with unusual clinical features. It infects diverse warm-blooded animals (including rodents), with cats serving as the definitive host for sexual reproduction of the parasite. Presumably to facilitate transfer from rodents to feline species, TOX reduces feline fear in infected rodents.^4,5 TOX infections also occur in 10%–20% of US adults, with exposure rates that approach 50% in other countries. Humans are considered accidental hosts for TOX as further transmission of the parasite to feline species ceases, except for unlikely but plausible cases of infected humans becoming preys of tigers and lions. Reminiscent of its effects on rodent behavior, TOX exposure has also been associated with elevated risk for accidents in humans in addition to its well-known devastating prenatal effects.^6,7 More important for SZ research, meta-analysis of over 30 case-control studies indicates elevated SZ risk in association with TOX infection.⁸ The basis for the association is not known. Kannan and Pletnikov (this issue) show that TOX infection impairs measures of spatial learning and memory in rodents. Because analogous variables are also impaired in SZ patients, it would be important to see whether TOX exposure explains some of the cognitive impairments in SZ patients.The associations discussed in the theme issue do not conclusively prove causal links between HSV-1 or TOX exposure and cognitive impairment. Cohort-based studies and treatment studies are needed. Recently, a double-blind placebo-controlled study of HSV-1 exposed SZ patients revealed significant improvement in verbal memory, working memory, and visual object learning following treatment with valacylcovir, a drug used to treat reactivated HSV-1 infection.⁹ Such studies may indicate novel remedies for cognitive impairment in SZ. They will also establish paradigms that may help us sift through the trove of data that are being generated by the NIH-funded Human Microbiome Project, which aims to characterize trillions of microorganisms harbored in the human body (http://commonfund.nih.gov/hmp/index.aspx).     

Glucose Metabolism in Relation to Schizophrenia and Antipsychotic Drug Treatment

It has been reported in the earlier literature that many patients with psychoses had abnormalities in glucose metabolism as revealed by glucose tolerance testing. This observation is reinforced by the fact that the schizophrenic population appears to have about a 2–3-fold increased risk for Type II diabetes mellitus. However, some uncertainty remains about the relative risk value because there have been numerous case reports of patients who developed hyperglycemia and even Type II diabetes apparently as a consequence of treatment with antipsychotic drugs. Schizophrenic patients with abnormal glucose metabolism have a higher prevalence of drug-induced tardive dyskinesia than patients with a normal glucose profile. Treatment with the new atypical antipsychotics has a much lower risk of movement disorders; however, weight gain, hyperglycemia, and diabetes are emerging as significant side effects. Because glucose is essential for energy metabolism in neurons, any change in the effective glucose levels in brain that result from drug therapy may have significant clinical implications. It is not clear whether the glycemic state of schizophrenics contributes to their psychotic symptoms or modulates the incidence of drug side effects. Basic research shows that the drugs which cause hyperglycemia in patients appear to inhibit neuronal glucose transport which may partly explain their effects. This paper reviews the relevant literature in a preliminary attempt to understand the implications of such clinical findings in the light of basic research.     

Evaluation of Six SNPs of MicroRNA Machinery Genes and Risk of Schizophrenia

MicroRNAs (miRNAs) are small regulatory RNAs that modulate the expression of approximately half of all human genes. Small changes in miRNA expression have been associated with several psychiatric and neurological disorders, but whether the polymorphisms in genes involved in the processing of miRNAs into maturity influence the susceptibility of a person to schizophrenia (SZ) has not yet been elucidated. In this study, we investigated the association between SZ risk and single-nucleotide polymorphisms (SNPs) in microRNA machinery genes. We assessed the associations between SZ as a risk and six potentially functional SNPs from five miRNA processing genes (DROSHA, DGCR8, DICER, AGO1, and GEMIN4) in a case-control study of 256 Chinese SZ patients and 252 frequency-matched (age, gender, and ethnicity) controls. All the SNPs (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) were genotyped by high resolution melting method. We found that two SNPs in the DGCR8 and DICER gene were significantly associated with the altered SZ risk. The genotype or allele frequency of rs3742330 in DICER was significantly different in patients and controls. Moreover, the recessive model of rs3757 in DGCR8 (AA vs. GA/GG) exhibited a significantly increased risk with an odds ratio (OR) of 3.73 [95 % confidence interval (CI), 1.03–13.52, P?=?0.032]; the dominant model of rs3742330 in DICER (AA vs. AG/GG) exhibited a significantly increased risk with OR of 1.49 (95 % CI, 1.04–2.13; P?=?0.028). Other SNPs and the haplotype of GEMIN4 (rs3744741 and rs7813) did not show any association with SZ. Our results suggested that the specific genetic variants in microRNA machinery genes may affect SZ susceptibility.     

Relation of Positive and Negative Symptoms of Schizophrenia to Financial Capacity

The aim of this study was to examine the value of positive and negative symptoms of schizophrenia, as measured on the Positive and Negative Syndrome Scale (PANSS), in classifying outpatients who manage their finances independently (n = 25) from those who do not (n = 24). Logistic regression analysis showed that, unlike the positive symptom subscale of the PANSS, the negative symptom subscale was statistically reliable and demonstrated moderate classification accuracy in distinguishing those who managed their finances independently from those who cannot.     

Exposure to Herpes Simplex Virus Type 1 and Cognitive Impairments in Individuals With Schizophrenia

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes–specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations.     

Reduction of Cerebral Blood Flow in Chronic Schizophrenia: Relation to Age

Abstract: The effect of age on resting-state cerebral blood flow (CBF) was studied in 40 medicated patients with chronic schizophrenia aged 20 to 57 and 32 age- and sex-matched normal Controls, using the regional CBF with the xenon-133 inhalation technique. Global CBF (average of 16 cerebral regions) and the left prefrontal flow ratio (left prefrontal/global CBF) were significantly lower in schizophrenics aged 20–29 than in age-matched controls. Both global CBF and the left prefrontal flow ratio correlated with age in controls, but neither of such correlations was found in schizophrenics. Therefore, the CBF deficits in chronic schizophrenia appear to be unaffected by the aging process.     

Morbidity Risk of Schizophrenia to Parents and Siblings of Schizophrenic Patients

Abstract: In order to estimate the familial morbidity risk of schizophrenia, parents and siblings of 1,691 inpatients meeting the DSM-III criteria for schizophrenia were investigated on the basis of a review of medical records, family history data and/or personal interviews. The morbidity risks of schizophrenia to parents and siblings of the schizophrenic probands were 4.0% and 4.1%, respectively, which were greater than the morbidity risk in the general population. Siblings of 118 probands whose parents suffered from schizophrenia were at a significantly greater risk of schizophrenia than siblings of 1,493 probands whose parents did not have schizophrenic illness. These findings support thenotion of familial transmission of schizophrenia. A total of 16.4% of the schizophrenic probands had at least one first-degree relative with schizophrenia. This is significantly greater in the female probands than in the male probands.     

AKT1 Gene Polymorphisms and Obstetric Complications in the Patients with Schizophrenia

Objective

We performed a genetic association study with schizophrenic patients to investigate whether the V-akt murine thymoma viral oncogene homolog 1 (AKT1) gene plays a role in obstetric complications.

Methods

One-hundred-eighty patients with schizophrenia (male, 113; female, 67) were included. All patients fulfilled DSM-IV criteria for schizophrenia. Obstetric complications were measured by the Lewis scale. Prenatal and perinatal information was retrospectively collected from the patients'' mothers. We selected six single nucleotide polymorphisms (SNPs) for the AKT1 gene: SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs 1130233), SNP5 (rs2494732), and SNPA (rs2498804). The genotype data were analyzed for an association with the Lewis total score in terms of allele, genotype, and haplotype distribution.

Results

The mean total Lewis scores were 1.30±1.61 for males and 1.54±1.87 for females. Higher total score tended to be correlated with an earlier age of onset of schizophrenia in females. In the total sample, no SNP was associated with obstetric complications. However, the additional analyses for male and female subgroups found a significant association between SNPA and SNP4 and Lewis score in females (p=0.02 for SNPA, p=0.04 for SNP4). The SNP5-SNPA haplotype showed a positive association with obstetric complications (p=0.03) in the female patient group.

Conclusion

We found an association between SNPs in the AKT1 gene and total Lewis score measuring obstetric complications in female patients with schizophrenia. Because these findings did not survive a correction for multiple testing, the significance should be interpreted carefully and replication studies are required.     

No Association between PAWR Gene Polymorphisms and Tardive Dyskinesia in Schizophrenia Patients

Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD.     

Dysregulated Brain Dynamics in a Triple-Network Saliency Model of Schizophrenia and Its Relation to Psychosis

Background

Schizophrenia is a highly disabling psychiatric disorder characterized by a range of positive “psychosis” symptoms. However, the neurobiology of psychosis and associated systems-level disruptions in the brain remain poorly understood. Here, we test an aberrant saliency model of psychosis, which posits that dysregulated dynamic cross-network interactions among the salience network (SN), central executive network, and default mode network contribute to positive symptoms in patients with schizophrenia.

Exposure to Antidepressant Medication and the Risk of Incident Dementia

ObjectiveTo test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia.MethodsA prospective national matched cohort study from Israel (N = 71,515) without dementia (2002–2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes.ResultsIn the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47.ConclusionIn this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.     

Cigarette Smoking and Mortality Risk in People With Schizophrenia

This study examined effects of cigarette smoking on mortality risk in 1213 persons aged 19–69 years with schizophrenia-related psychotic disorders admitted to State of Maryland Hospitals between 1994 and 2000. Inpatient medical records from 7 hospitals were reviewed to obtain demographic information, diagnosis, medication use, as well as smoking and other substance use. Social Security Death Index data were used to identify deaths in the study group between 1994 and 2004. Death records were reviewed to obtain manner of death and underlying disorders. Of the 1213, 55% were smokers and 71% abused substances. There was an age × smoking interaction (χ² = 14.6, df = 1, P = .0001) for mortality, with estimated hazard ratios (HRs) for smokers vs nonsmokers of 2.1 among 35- to 54-year olds and HR of 0.7 among those aged 55–69 years. Five- and 10-year mortality rates for smokers aged 35–54 years were 7.0% and 14.2%, compared with 3.3% and 10.0% for nonsmokers, respectively (χ² = 5.53, df = 1, P = .019). Cardiac causes were identified in 43% of deaths in smokers but only 19% of deaths in nonsmokers (P < .006). For those aged 35–54 years, the odds of cardiac related death was increased by 12 fold in smokers relative to nonsmokers (HR = 12.4, χ² = 12.0, df = 1, P = .0005). Among people aged 35–54 years, those smoking greater than one pack daily have a significantly increased total mortality risk (HR = 2.7) vs nonsmokers. Cigarette smoking, particularly in people aged 35–54 years, contributes to an increased risk of death. Greater smoking severity significantly increases this risk. Smoking cessation in people with schizophrenia deserves significant attention.     

Brain Circuits That Link Schizophrenia to High Risk of Cigarette Smoking

Schizophrenia is associated with a high prevalence of smoking. Functional connectivity between the dorsal anterior cingulate (dACC) and limbic regions including the ventral striatum, extended amygdala and parahippocampal areas has been previously implicated in the genetics and clinical severity of smoking. In this study, we test the hypothesis that dACC functional circuits are key paths for the high risk of smoking comorbidity in schizophrenia. Resting state functional magnetic resonance imaging (fMRI) was performed using the dACC as a seed region in smoking and nonsmoking patients with schizophrenia (n = 54), matched controls (n = 65), and nonpsychotic first-degree relatives (n = 24). Multiple regions had decreased connectivity with the dACC in schizophrenia patients when compared with matched controls (n = 65). Several of these functional circuits were also associated with nicotine addiction severity; the largest cluster included limbic areas such as the parahippocampal, extended amygdala, ventral striatal, and posterior insula regions, indicating an overlap of schizophrenia and nicotine addiction on to this circuit. These same functional connectivity–defined circuits were also significantly impaired in schizophrenia nonsmokers compared with control nonsmokers and in nonpsychotic first-degree relatives. Functional connectivity between the dACC and limbic regions is inherently abnormal in schizophrenia, related to its genetic liability regardless of smoking, and overlaps with a nicotine addiction–related circuit. Our findings establish a biologically defined brain circuit mechanism that contributes to the high prevalence of smoking.Key words: nicotine, anterior cingulate, functional connectivity, limbic     

Schizophrenia Risk and Handedness: A Mixed Picture

Numerous previous studies have reported on handedness differences among schizophrenics, as well as in normal subjects who are high in “schizotypal” traits, and hence putatively at risk for schizophrenia. Results have varied, but there is evidence of a shift away from dextrality, especially consistent among schizotypal individuals. Using both a conventional three-category and Annett's seven-category classification of handedness, we re-examined the question in 681 general population subjects assessed for schizotypy. The three-category analysis confirmed previous findings of increased schizotypy in mixed-handers. However, the more fine-grained analysis showed that, although mild degrees of mixed handedness were indeed associated with increased schizotypy, this trend was reversed in the most mixed-handed subjects whose schizotypy scores did not differ significantly from right-handers. Independently of our work, this subgroup of mixed-handers are also reported to show superior intellectual function, especially on some spatial tasks. We concluded that previous studies of schizophrenia and schizotypy have failed to distinguish different reasons for shifts from dextrality. It is argued that the latter's association with schizophrenia might come about through exogenous, neurodevelopmental, influences, whereas some—possibly genetically based—forms of mixed handedness could reflect a variety of cerebral organisation that protects against, rather than enhances, the risk for mental disorder.     

Autism Spectrum Disorders and Childhood-Onset Schizophrenia: Clinical and Biological Contributions to a Relation Revisited

ObjectiveTo highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS).MethodClinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed.ResultsIn the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism.ConclusionsBiological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.