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Background: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms., Methods: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios., Results: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10 -4 ) and NMDAR (p = 1.7 × 10 -5 ) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10 -4 )., Conclusions: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways., Methods: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume., Results: The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment (P = 1.44 × 10 -4 ). Immune response (P = .016) and clathrin/AP2 adaptor complex pathway (P = 3.55 × 10 -3 ) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction (P = 9.09 × 10 -4 )., Discussion: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)