ABSTRACT
Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = 1.8×10-7; rs2603462, p = 4×10-7) were significant in the ADNI cohort (rs7902929, p = 0.012; rs2603462, p =0.012). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.
Subject(s)
Alzheimer Disease , Arteriolosclerosis , Aged , Alzheimer Disease/pathology , Arteriolosclerosis/genetics , Brain/pathology , Genome-Wide Association Study , Humans , Polymorphism, Single NucleotideABSTRACT
Alzheimer's disease (AD) is mainly a late-onset neurodegenerative disorder. Substantial efforts have been made to solve the complex genetic architecture of AD as a means to identify therapeutic targets. Unfortunately, to date, no disease-altering therapeutics have been developed. As therapeutics are likely to be most effective in the early stages of disease (ie, before the onset of symptoms), a recent focus of AD research has been the identification of protective factors that prevent disease. One example is the discovery of a rare variant in the 3'-UTR of RAB10 that is protective for AD. Here, we review the possible genetic, molecular, and functional role of RAB10 in AD and potential therapeutic approaches to target RAB10.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/metabolism , 3' Untranslated Regions , Alzheimer Disease/drug therapy , Animals , Drug Discovery , Humans , Protective FactorsABSTRACT
The Opioid Abuse Risk Screener was developed to support well-informed decision-making in opioid analgesic prescribing by extending the breadth of psychiatric risk factors evaluated relative to other non-clinician-administered measures. We examined the preliminary predictive validity of the Opioid Abuse Risk Screener relative to the widely used Screener and Opioid Assessment for Patients with Pain-Revised in predicting aberrant urine drug tests and controlled substance database checks. The Opioid Abuse Risk Screener is significantly different from the Screener and Opioid Assessment for Patients with Pain-Revised in predicting aberrant same-day urine drug tests (Z = 2.912, p = 0.0036) and controlled substance database checks within 1 year of assessment (Z = 3.731, p = 0.0002). Promising preliminary analyses using machine learning methods are also discussed.
