Western Australian Family Study Of Schizophrenia Research Articles

SA91 - INCREASED PREDICTED C4A EXPRESSION IS ASSOCIATED WITH COGNITIVE DEFICIT IN BOTH SCHIZOPHRENIA AND ALZHEIMER'S DISEASE

Background Recently, Sekar et al. (Nature, 2016) reported that the top GWAS hit for schizophrenia in the Major Histocompatibility Complex (MHC) locus implicated structural variants in the C4 gene which are associated with C4A expression and may affect synaptic pruning. Synapse loss is associated with cognitive decline in a number of disorders, including Alzheimer's disease and schizophrenia. We hypothesised that C4A expression predicted from C4 structural alleles is associated with cognition. We tested this in the Western Australian Family Study of Schizophrenia (WAFSS) (n=770, including 402 schizophrenia cases and 368 controls), and the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) (n=1,112, including 211 Alzheimer's disease cases, 133 with mild cognitive impairment and 768 controls). Methods Sekar et al. showed that C4 structural alleles could be imputed from GWAS data with an accuracy of ~70%. We used 222 reference haplotypes with C4 structural alleles measured by Sekar et al. to impute C4 alleles in all individuals using Beagle. C4A expression was predicted for each individual using the regression coefficients calculated by Sekar et al. Composite measures of cognition were available for both WAFSS and AIBL (Hallmeyer et al., Am J Hum Genet. 2005; Burnham et al., J Alzheimers Dis. 2015). Linear regression was used to assess their relationship with predicted C4A expression. P values for these relationships were calculated using linear mixed models to account for the relatedness between some WAFSS participants, and repeated measurements in the AIBL dataset. All analyses were adjusted for case status, age, sex, and education. Results Although mean C4A expression was not significantly different between schizophrenia cases and controls in the WAFSS (P=0.7), cases were overrepresented in those with the highest C4A expression levels. There was a small but consistent association between increased cognitive deficit and increased levels of C4A in both the WAFSS and the AIBL samples (P Discussion These data suggest that C4 structural variants previously shown to be associated with schizophrenia may specifically implicate the cognitive deficit which is a core feature of schizophrenia. Further, our finding that a similar relationship between C4A levels and cognition exists in patients with schizophrenia and Alzheimer's disease suggests that the locus may be pleiotropic and have implications for a range of neuropsychiatric disorders.

The longevity gene Klotho is differentially associated with cognition in subtypes of schizophrenia

Cognitive impairment is a core feature of schizophrenia and impacts negatively the functioning of affected individuals. Cognitive decline correlates with aging, and is the primary cause of loss of independence and reduced quality of life. The klotho gene is a key modulator of aging, with expression deficiency resulting in premature aging, while overexpression extends lifespan and enhances cognition. A haplotype and functional human variant of the gene, KL-VS, increases expression and promotes longevity. KL-VS heterozygosity is associated with enhanced cognition and a larger volume of the right dorsolateral prefrontal cortex, a region involved in planning and decision-making, which is especially susceptible to shrinkage with age. We examined the effect of KL-VS heterozygosity on cognition in 497 schizophrenia patients and 316 healthy controls from the Western Australian Family Study of Schizophrenia (WAFSS) who had been comprehensively characterised by neurocognitive tests and classified into cognitively deficient (CD) and cognitively “spared” (CS) clusters. An older, cognitively normal population sample from the Health in Men Study (HIMS) was included to allow assessment of heterozygosity and memory in aged individuals. We show that heterozygosity is associated with better learning and memory in the younger WAFSS healthy controls but not in the aging HIMS sample. However, in schizophrenia patients, KL-VS has a selective effect on memory, with heterozygotes in CD and CS clusters performing worse than non-carriers. This effect was significant and more severe in the CD cluster, reinforcing the utility of subtyping patients into CD and CS clusters that may differ in their genetic underpinnings.

On the interconnectedness and prognostic value of visual and auditory hallucinations in first-episode psychosis

BackgroundVisual hallucinations (VH) are common symptoms in schizophrenia and other psychoses. An understanding of their cross-sectional and longitudinal patterns of association with auditory hallucinations (AH) is essential for developing accurate models of hallucinatory phenomena. ObjectiveThis study presents the most comprehensive examination of the association between VH and AH, and its change over time, in 1303 individuals with first-episode psychosis (FEP) and 469 individuals with chronic schizophrenia. MethodThe samples included data from the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders and the Western Australian Family Study of Schizophrenia (WAFSS). Standardized assessment of symptoms and functioning were used to examine the clinical profile and symptom co-occurrence of hallucinations over time. ResultsVH were approximately half as frequent as AH, almost always co-occurred with AH, and tended to be linked to a more severe psychopathological profile. AH and VH at baseline also predicted higher disability, risk of relapse and duration of psychosis after 1 and 2 years, especially when occurring in combination. ConclusionsThe findings point to three hallucination ‘subtypes’ with different symptom profile. The VH+AH combination signals greater psychopathology and a less favourable prognosis, than hallucinations occurring in isolation, and no hallucinations. This conclusion points to one common mechanism for all hallucinations, which can separate into distinct pathways and modalities. For a more complete clinical picture, clinicians should carefully probe for both auditory and VHs in presenting patients.

Exome array analysis suggests an increased variant burden in families with schizophrenia

The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n=341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS).Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P<2.2E-16). This was pronounced in variants nominally associated (P<0.05) with schizophrenia.Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P=0.05) for membership of the ‘extracellular matrix (ECM) - receptor interaction’ biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease.We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that ‘schizophrenia gene-sets’ were enriched for case-only variants was not replicated in the WAFSS.The higher frequency of moderately rare, exonic variants in these multiplex families compared to a population-based sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples.

Analysis of schizophrenia data using a nonlinear threshold index logistic model.

Genetic information, such as single nucleotide polymorphism (SNP) data, has been widely recognized as useful in prediction of disease risk. However, how to model the genetic data that is often categorical in disease class prediction is complex and challenging. In this paper, we propose a novel class of nonlinear threshold index logistic models to deal with the complex, nonlinear effects of categorical/discrete SNP covariates for Schizophrenia class prediction. A maximum likelihood methodology is suggested to estimate the unknown parameters in the models. Simulation studies demonstrate that the proposed methodology works viably well for moderate-size samples. The suggested approach is therefore applied to the analysis of the Schizophrenia classification by using a real set of SNP data from Western Australian Family Study of Schizophrenia (WAFSS). Our empirical findings provide evidence that the proposed nonlinear models well outperform the widely used linear and tree based logistic regression models in class prediction of schizophrenia risk with SNP data in terms of both Types I/II error rates and ROC curves.

Impact of the Reelin signaling cascade (Ligands–Receptors–Adaptor Complex) on cognition in schizophrenia

Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia.

Normative Data for Rey's Auditory Verbal Learning Test in Individuals with Schizophrenia

Deficits in episodic memory, related to medial temporal lobe dysfunction, are a core component of schizophrenia. Rey's Auditory Verbal Learning Test (RAVLT) is one of the most widely used neuropsychological memory tasks in clinical practice but normative data are limited. Over the last 15 years, the RAVLT has been used to assess verbal episodic memory performance as part of the Western Australian Family Study of Schizophrenia (WAFSS). This study aims to provide RAVLT norms, derived from the WAFSS, for individuals meeting DSM-IV and ICD-10 diagnostic criteria for schizophrenia or schizophrenia-spectrum disorder, for use in clinical settings. Performance on three immediate and one delayed recall trials, and additional measures of encoding and forgetting, is presented for 492 patients and 260 healthy community controls. Results indicated that age and sex (both groups) and IQ (schizophrenia group only) significantly influenced performance. Norms are presented, as means and standard deviations, stratified accordingly. Additional between-groups analysis clearly shows a significant memory deficit in schizophrenia even when patients are matched on IQ, age, and sex with healthy controls.