Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes

Feasibility and preliminary effects of exercise interventions on plasma biomarkers of Alzheimer’s disease in the FIT-AD trial: a randomized pilot study in older adults with Alzheimer’s dementia

Abstract Background Alzheimer’s disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-β42 and Aβ40 (Aβ42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). Methods This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20–50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aβ42, Aβ40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen’s d, and linear mixed models. Resultss The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and −0.001 (0.010) for Aβ42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and −0.020 (0.279) pg/mL and −0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [−0.33, 1.19]) and t-tau in cycling (−0.35 [−0.87, 0.17]). Conclusions Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. Trials registration ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 201

Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOE[epsilon]4 carriers

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) [straight epsilon]4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOE[straight epsilon]4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOE[straight epsilon]4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOE[straight epsilon]4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk

Validation Phase: Comparison of Pooled Sample NGS with Individual Genotyping Results and Genetic Association Analyses in EU cohort.

<p><i>145 cases</i>, <i>150 controls; 195 males</i>, <i>100 females</i>.</p><p>Pooled EU.</p

Validation Phase: Comparison of Pooled Sample NGS with Individual Genotyping Results and Genetic Association Analyses in AA cohort.

<p><i>42 cases</i>, <i>50 controls; 49 males</i>, <i>43 females</i>.</p><p>Pooled AA.</p

Minor Allele Frequency Differences in EU and AA.

<p>Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the <i>EGR3</i> locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the <i>ARC</i> locus, hg18 coordinates chr8:143,682,474–143,697,026</p

Replication of <i>ARC</i> SNP Association with Schizophrenia in Han Chinese Population.

<p><i>491 cases</i>, <i>491 controls; 525 males</i>, <i>457 females</i>.</p><p>Replication CH <i>ARC</i>.</p

Replication Phase: Genetic Association Between Schizophrenia and SNPs in <i>EGR3</i> and <i>ARC</i> in AA Population.

<p><i>185 cases</i>, <i>50 controls; 127 males</i>, <i>108 females</i>.</p><p>Replication AA.</p