Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson's disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity.

Background: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases.

Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study.

Importance: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk.

Objective: To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls.

Design, Setting, And Participants: Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set.

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

Importance: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.

Objective: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.

Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.

Introduction: African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g.

Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.

Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood.

Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

Importance: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.

Objective: To identify genetic loci associated with late-onset Alzheimer disease in African Americans.

Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure.

Background: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ).

Association between family risk of stroke and myocardial infarction with prevalent risk factors and coexisting diseases.

Background And Purpose: Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.

Methods: A cross-sectional association between the stratified log-rank family score for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

Objective: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls.

Methods: African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests.

Comparison of measures of marker informativeness for ancestry and admixture mapping.

Background: Admixture mapping is a powerful gene mapping approach for an admixed population formed from ancestral populations with different allele frequencies. The power of this method relies on the ability of ancestry informative markers (AIMs) to infer ancestry along the chromosomes of admixed individuals. In this study, more than one million SNPs from HapMap databases and simulated data have been interrogated in admixed populations using various measures of ancestry informativeness: Fisher Information Content (FIC), Shannon Information Content (SIC), F statistics (FST), Informativeness for Assignment Measure (In), and the Absolute Allele Frequency Differences (delta, δ).

A comprehensive genetic association study of Alzheimer disease in African Americans.

Objectives: To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites.

Design: We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population.

Incident cognitive impairment is elevated in the stroke belt: the REGARDS study.

Objective: To determine whether incidence of impaired cognitive screening status is higher in the southern Stroke Belt region of the United States than in the remaining United States.

Methods: A national cohort of adults age ≥45 years was recruited by the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from 2003 to 2007. Participants' global cognitive status was assessed annually by telephone with the Six-Item Screener (SIS) and every 2 years with fluency and recall tasks.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients.

Objective: Neurocognitive impairments in schizophrenia are well replicated and widely regarded as candidate endophenotypes that may facilitate understanding of schizophrenia genetics and pathophysiology. The Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) aims to identify genes underlying liability to schizophrenia. The unprecedented size of its study group (N=1,872), made possible through use of a computerized neurocognitive battery, can help further investigation of the genetics of neurocognition.

Database mining for selection of SNP markers useful in admixture mapping.

Background: New technologies make it possible for the first time to genotype hundreds of thousands of SNPs simultaneously. A wealth of genomic information in the form of publicly available databases is underutilized as a potential resource for uncovering functionally relevant markers underlying complex human traits. Given the huge amount of SNP data available from the annotation of human genetic variation, data mining is a reasonable approach to investigating the number of SNPs that are informative for ancestry information.

Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples.

Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414).

Candidate gene discovery procedure after follow-up confirmatory analyses of candidate regions of interests for Alzheimer's disease in the NIMH sibling dataset.

The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs) identified in our original genome scan in the NIMH Alzheimer's diseases (AD) Initiative families (Blacker et al. [1]). There were six CRIs identified that met the threshold of multipoint lod score (MLS) of >or= 2.

Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Background: The association between kidney function and cognitive impairment has not been assessed in a national sample with a wide spectrum of kidney disease severity.

Study Design: Cross-sectional.

Setting & Participants: 23,405 participants (mean age, 64.

Regional differences in diabetes as a possible contributor to the geographic disparity in stroke mortality: the REasons for Geographic And Racial Differences in Stroke Study.

Background And Purpose: Diabetes and hypertension impart approximately the same increased relative risk for stroke, although hypertension has a larger population-attributable risk because of its higher population prevalence. With a growing epidemic of obesity and associated increasing prevalence of diabetes that disproportionately impacts the southeastern Stroke Belt states, any potential contribution of diabetes to the geographic disparity in stroke mortality will only increase.

Methods: Racial and geographic differences in diabetes prevalence and diabetes awareness, treatment, and control were assessed in the REasons for Geographic And Racial Differences in Stroke study, a national population-based cohort of black and white participants older than 45 years of age.

A genomic scan for age at onset of Alzheimer's disease in 437 families from the NIMH Genetic Initiative.

We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis.

Genetic association of neurotrophic tyrosine kinase receptor type 2 (NTRK2) With Alzheimer's disease.

Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long-term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin-3 (NT-3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimer's disease (AD).

Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease.

Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs).

Effects of chronic stress and interleukin-10 gene polymorphisms on antibody response to tetanus vaccine in family caregivers of patients with Alzheimer's disease.

Objective: To assess the effects of psychological stress on the antibody response to tetanus vaccine adjusting for cytokine gene polymorphisms and other nongenetic factors in caregivers of patients with Alzheimer's disease (AD).

Methods: A family-based follow-up study was conducted in 119 spouses and offspring of community-dwelling patients with AD. Psychological stress was measured by the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D) scale at baseline and 1 month after the vaccination.

Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Background And Purpose: Vascular disorders that increase risk for stroke may be accompanied by decrements in cognitive functioning and by stroke symptoms in the absence of diagnosed stroke or transient ischemic attack. This study evaluates relationships among cognitive status, stroke symptom reports, and cardiovascular and behavioral factors.

Methods: REasons for Geographic and Racial Differences in Stroke (REGARDS), a prospective population study of stroke incidence, assesses stroke risk with telephone interviews and in-home physicals.