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Conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of late onset sporadic Alzheimers disease (LOAD). Mutations and/or differential expression of microglial specific receptors such as TREM2, CD33, and CR3 have been associated with strong increased risk for developing Alzheimers disease (AD). DAP12 (DNAX-activating protein 12)/TYROBP, a molecule localized to microglia, is a direct partner/adapter for TREM2, CD33, and CR3. We and others have previously shown that TYROBP expression is increased in AD patients and in mouse models. Moreover, missense mutations in the coding region of TYROBP have recently been identified in some AD patients. These lines of evidence, along with computational analysis of LOAD brain gene expression, point to DAP12/TYROBP as a potential hub or driver protein in the pathogenesis of AD. Using a comprehensive panel of biochemical, physiological, behavioral, and transcriptomic assays, we evaluated in a mouse model the role of TYROBP in early stage AD. We crossed an Alzheimers model mutant APP KM670/671NL /PSEN1 Δexon9 (APP/PSEN1) mouse model with Tyrobp -/- mice to generate AD model mice deficient or null for TYROBP (APP/PSEN1; Tyrobp +/- or APP/PSEN1; Tyrobp -/-). While we observed relatively minor effects of TYROBP deficiency on steady-state levels of amyloid-β peptides, there was an effect of Tyrobp deficiency on the morphology of amyloid deposits resembling that reported by others for Trem2 -/- mice. We identified modulatory effects of TYROBP deficiency on the level of phosphorylation of TAU that was accompanied by a reduction in the severity of neuritic dystrophy. TYROBP deficiency also altered the expression of several AD related genes, including Cd33. Electrophysiological abnormalities and learning behavior deficits associated with APP/PSEN1 transgenes were greatly attenuated on a Tyrobp-null background. Some modulatory effects of TYROBP on Alzheimers-related genes were only apparent on a background of mice with cerebral amyloidosis due to overexpression of mutant APP/PSEN1. These results suggest that reduction of TYROBP gene expression and/or protein levels could represent an immune-inflammatory therapeutic opportunity for modulating early stage LOAD, potentially leading to slowing or arresting the progression to full-blown clinical and pathological LOAD.

BackgroundTherapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.MethodsWe defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.FindingsWe combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).InterpretationOur results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.FundingUS National Institutes of Health.

Off-label drug use, defined as use of a drug in a manner that deviates from its approved use defined by the drug's FDA label, is problematic because such uses have not been evaluated for safety and efficacy. Studies estimate that 21% of prescriptions are off-label, and only 27% of those have evidence of safety and efficacy. We describe a data-mining approach for systematically identifying off-label usages using features derived from free text clinical notes and features extracted from two databases on known usage (Medi-Span and DrugBank). We trained a highly accurate predictive model that detects novel off-label uses among 1,602 unique drugs and 1,472 unique indications. We validated 403 predicted uses across independent data sources. Finally, we prioritize well-supported novel usages for further investigation on the basis of drug safety and cost.