The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

Compromised neurocognition is a core feature of schizophrenia. Following Heinrichs and Zakzanis's (1998) seminal meta-analysis of middle-aged and predominantly chronic schizophrenia samples, the aim of this study is to provide a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007. The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20). Findings indicate that impairments are reliably and broadly present by the FE, approach or match the degree of deficit shown in well-established illness, and are maximal in immediate verbal memory and processing speed. Larger IQ impairments in the FE compared to the premorbid period, but comparable to later phases of illness suggests deterioration between premorbid and FE phases followed by deficit stability at the group level. Considerable heterogeneity of effect sizes across studies, however, underscores variability in manifestations of the illness and a need for improved reporting of sample characteristics to support moderator variable analyses.

Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores.

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Diffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia, in-vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic and immunochemical studies support the involvement of axonal degeneration and neuroinflammation - ubiquitous components of neurodegenerative disorders - as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation, and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early-diagnosed schizophrenia patients.