Curation and validation of electronic medical record-based dementia diagnoses in the VA Million Veteran Program.

Background: The age distribution and diversity of the VA Million Veteran Program (MVP) cohort make it a valuable resource for studying the genetics of Alzheimer's disease (AD) and related dementias (ADRD).

Objective: We present and evaluate the performance of several International Classification of Diseases (ICD) code-based classification algorithms for AD, ADRD, and dementia for use in MVP genetic studies and other studies using VA electronic medical record (EMR) data. These were benchmarked relative to existing ICD algorithms and AD-medication-identified cases.

Role of the X Chromosome in Alzheimer Disease Genetics.

Importance: The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.

Objectives: To perform the first large-scale X chromosome-wide association study (XWAS) of AD.

Design, Setting, And Participants: This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program.

No Replication of Alzheimer's Disease Genetics as a Moderator of Combat Exposure's Association with PTSD risk in 138,592 Combat Veterans.

Large-scale cohort and epidemiological studies suggest that posttraumatic stress disorder (PTSD) confers risk for late-onset Alzheimer's disease (AD) and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military Veterans have reported that carriers of the apolipoprotein E () ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. This cohort study was designed to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD.

Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting.

Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

Background: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g.

The Role of X Chromosome in Alzheimer's Disease Genetics.

Importance: The X chromosome has remained enigmatic in Alzheimer's disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.

Objectives: Perform the first large-scale X chromosome-wide association study (XWAS) of AD. Primary analyses are non-stratified, while secondary analyses evaluate sex-stratified effects.

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol.

A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors.

A novel principal component based method for identifying differentially methylated regions in Illumina Infinium MethylationEPIC BeadChip data.

Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance.

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence.

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression.

Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease.

Importance: Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.

Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.

Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.

Background And Objectives: Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed.

Genome-wide association study of stimulant dependence.

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls).

Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes.

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively).

Identifying factors associated with opioid cessation in a biracial sample using machine learning.

Aim: Racial disparities in opioid use disorder (OUD) management exist, however, and there is limited research on factors that influence opioid cessation in different population groups.

Methods: We employed multiple machine learning prediction algorithms least absolute shrinkage and selection operator, random forest, deep neural network, and support vector machine to assess factors associated with ceasing opioid use in a sample of 1,192 African Americans (AAs) and 2,557 individuals of European ancestry (EAs) who met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for OUD. Values for nearly 4,000 variables reflecting demographics, alcohol and other drug use, general health, non-drug use behaviors, and diagnoses for other psychiatric disorders, were obtained for each participant from the Semi-Structured Assessment for Drug Dependence and Alcoholism, a detailed semi-structured interview.

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Association of OPRM1 Functional Coding Variant With Opioid Use Disorder: A Genome-Wide Association Study.

Importance: With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD).

Objectives: To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits.

Design, Setting, And Participants: A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls.