•Asymptomatic AD subjects show increased transcriptomic activity in frontal cortex.•Disruption in brain energy pathway detected in Asymptomatic AD brains.•Overactivation of “glutamate-glutamine ...cycle” detected in Asymptomatic AD and AD.
Individuals with intact cognition and neuropathology consistent with Alzheimer’s disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain “glutamate-glutamine cycle”, and disturbances in the brain energy pathways in both AsymAD and AD subjects, while the connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention.
Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across ...individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations.
Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains.
Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington's disease, two major depressive disorder, and one Parkinson's disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p-value method known as Adaptively Weighted with One-sided Correction.
Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains.
This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets.
Many common diseases are accompanied by disturbances in biochemical traits. Identifying the genetic determinants could provide novel insights into disease mechanisms and reveal avenues for developing ...new therapies. Here, we report a genome-wide association analysis for commonly measured serum and urine biochemical traits. As part of the WTCCC, 500,000 SNPs genome wide were genotyped in 1955 hypertensive individuals characterized for 25 serum and urine biochemical traits. For each trait, we assessed association with individual SNPs, adjusting for age, sex, and BMI. Lipid measurements were further examined in a meta-analysis of genome-wide data from a type 2 diabetes scan. The most promising associations were examined in two epidemiological cohorts. We discovered association between serum urate and
SLC2A9, a glucose transporter (p = 2 × 10
−15) and confirmed this in two independent cohorts, GRAPHIC study (p = 9 × 10
−15) and TwinsUK (p = 8 × 10
−19). The odds ratio for hyperuricaemia (defined as urate >0.4 mMol/l) is 1.89 (95% CI = 1.36–2.61) per copy of common allele. We also replicated many genes previously associated with serum lipids and found previously recognized association between LDL levels and SNPs close to genes encoding
PSRC1 and
CELSR2 (p = 1 × 10
−7). The common allele was associated with a 6% increase in nonfasting serum LDL. This region showed increased association in the meta-analysis (p = 4 × 10
−14). This finding provides a potential biological mechanism for the recent association of this same allele of the same SNP with increased risk of coronary disease.
The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most ...people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10
). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10
) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.
A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we ...have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.
•We performed an epigenome-wide assessment of DNA methylation in Alzheimer's disease, mild cognitive impairment, and control whole blood.•We observed hypermethylation of HOXB6 in AD, which was validated via pyrosequencing.•Network analysis (weighted gene correlation network analysis) showed differences in immune system pathways in disease.
Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide ...association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.
Context:
Aldosterone-producing adenomas (APA) are heterogeneous. The recent finding of somatic KCNJ5 mutations suggests a genetic explanation.
Objectives:
The objectives of this study were the ...following: 1) to compare transcriptional profiles in APA and adjacent adrenal gland (AAG); 2) to test whether gene expression profile clusters with different cell histology; and 3) to measure the frequency of KCNJ5 mutations and determine the genotype-phenotype relationship.
Design/Setting:
The design of the study included laboratory analyses of 46 unselected APA.
Patients:
The patients in this study had primary hyperaldosteronism with unilateral APA.
Interventions:
The objectives of this study were the following: 1) Illumina beadchip analysis of RNA from eight paired APA-AAG; 2) a blinded review of cell histology for 46 APA; 3) laser capture microdissection of zona glomerulosa (ZG) and zona fasciculata (ZF) cells; and 4) sequencing of KCNJ5 in 46 APA.
Main Outcome Measures:
The main outcome measures of this study were the following: 1) a difference in gene expression profile and a correlation with histological markers of ZF; 2) a frequency of KCNJ5 mutations and phenotypic comparisons of wild type with mutant APA.
Results:
The results of the study were the following: 1) a cluster analysis of microarray data separated APA from AAG. APA at opposite ends of the APA cluster had an approximately 800-fold difference in CYP17A1 mRNA expression, whereas histology showed 0% ZF-like cells in one vs. 100% in the other. A heat map ranking APA by CYP17A1 expression correctly predicted several genes (e.g. KCNK1, SLC24A3) to be enriched in laser capture microdissection samples of ZG; 2) known or novel mutations of KCNJ5 were found in 20 of 46 consecutive APA 43% (95% confidence interval CI (29, 58)%). The APA with KCNJ5 gene mutations were larger compared with tumors harboring the wild type, 1.63 95% CI (1.37, 1.88) vs. 1.14 0.97, 1.30 cm (P = 0.0013), had predominantly ZF-like cells, and their CYP17A1 (log2-fold change) was higher than in wild type: −0.96 95% CI (−0.07, −1.85) vs. −2.54 −1.61, −3.46, (P = 0.017).
Conclusions:
KCNJ5 mutations are common in APA, particularly those arising from ZF. The long-recognized heterogeneity among APA may have a genetic basis.
The typical approach to identify blood-derived gene expression signatures as a biomarker for Alzheimer's disease (AD) have relied on training classification models using AD and healthy controls only. ...This may inadvertently result in the identification of markers for general illness rather than being disease-specific.
Investigate whether incorporating additional related disorders in the classification model development process can lead to the discovery of an AD-specific gene expression signature.
Two types of XGBoost classification models were developed. The first used 160 AD and 127 healthy controls and the second used the same 160 AD with 6,318 upsampled mixed controls consisting of Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, bipolar disorder, schizophrenia, coronary artery disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and cognitively healthy subjects. Both classification models were evaluated in an independent cohort consisting of 127 AD and 687 mixed controls.
The AD versus healthy control models resulted in an average 48.7% sensitivity (95% CI = 34.7-64.6), 41.9% specificity (95% CI = 26.8-54.3), 13.6% PPV (95% CI = 9.9-18.5), and 81.1% NPV (95% CI = 73.3-87.7). In contrast, the mixed control models resulted in an average of 40.8% sensitivity (95% CI = 27.5-52.0), 95.3% specificity (95% CI = 93.3-97.1), 61.4% PPV (95% CI = 53.8-69.6), and 89.7% NPV (95% CI = 87.8-91.4).
This early work demonstrates the value of incorporating additional related disorders into the classification model developmental process, which can result in models with improved ability to distinguish AD from a heterogeneous aging population. However, further improvement to the sensitivity of the test is still required.
Psychosis is a condition influenced by an interaction of environmental and genetic factors. Gene expression studies can capture these interactions; however, studies are usually performed in patients ...who are in remission. This study uses blood of first episode psychosis patients, in order to characterise deregulated pathways associated with psychosis symptom dimensions.
Peripheral blood from 149 healthy controls and 131 first episode psychosis patients was profiled using Illumina HT-12 microarrays. A case/control differential expression analysis was performed, followed by correlation of gene expression with positive and negative syndrome scale (PANSS) scores. Enrichment analyses were performed on the associated gene lists. We test for pathway differences between first episode psychosis patients who qualify for a Schizophrenia diagnosis against those who do not.
A total of 978 genes were differentially expressed and enriched for pathways associated to immune function and the mitochondria. Using PANSS scores we found that positive symptom severity was correlated with immune function, while negative symptoms correlated with mitochondrial pathways.
Our results identified gene expression changes correlated with symptom severity and showed that key pathways are modulated by positive and negative symptom dimensions.
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association ...between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients’ fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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•Cross-ethnic meta-analysis finds an association between the ACSL5-ZDHHC6 locus and ALS•The ACSL5-ZDHHC6 association is replicated in an independent Australian cohort•ACSL5-ZDHHC6 lead SNP is in ACSL5 and is an eQTL of ZDHHC6 in brain tissues•ACSL5 SNPs might have an effect on fat-free mass in ALS patients
Using meta-analysis of European and Chinese ALS GWAS data, Iacoangeli et al. find an association between ACSL5-ZDHHC6 and ALS risk, with replication in an Australian cohort. They identify B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 using a gene-based analysis. They also find a suggestive association between ACSL5 SNPs and lower fat-free mass in patients.
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