Publications by authors named "Stephen J Newhouse"

Cell culture models are valuable tools to study biological mechanisms underlying health and disease in a controlled environment. Although their genotype influences their phenotype, subtle genetic variations in cell lines are rarely characterised and taken into account for in vitro studies. To investigate how the genetic makeup of a cell line might affect the cellular response to inflammation, we characterised the single nucleotide variants (SNPs) relevant to inflammation-related genes in an established hippocampal progenitor cell line (HPC0A07/03C) that is frequently used as an in vitro model for hippocampal neurogenesis (HN).

View Article and Find Full Text PDF

Loss of function (LoF) mutations in Optineurin can cause recessive amyotrophic lateral sclerosis (ALS) with some heterozygous LoF mutations associated with dominant ALS. The molecular mechanisms underlying the variable inheritance pattern associated with OPTN mutations have remained elusive. We identified that affected members of a consanguineous Middle Eastern ALS kindred possessed a novel homozygous p.

View Article and Find Full Text PDF
Article Synopsis
  • * Additional gene-based analyses revealed links to several genes, including B4GALNT1 and TRIP11-ATXN3, and highlighted the role of ACSL5 and GPX3 in rapid weight loss, a common characteristic in ALS patients that can lead to shorter survival.
  • * Using data from 77 ALS patients and 77 controls, we found a trend indicating that certain genetic variants (SNPs) may impact fat-free mass in patients but not in controls, emphasizing the importance of lipid metabolism in understanding ALS
View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Background: 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.

Objective: Investigate whether incorporating additional related disorders in the classification model development process can lead to the discovery of an AD-specific gene expression signature.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
Article Synopsis
  • - This study investigates the gene expression differences in first episode psychosis patients compared to healthy controls, focusing on how these differences relate to psychosis symptoms.
  • - Using blood samples from 131 patients and 149 healthy individuals, researchers found that 978 genes were differently expressed, with significant pathways linked to immune functions and mitochondria.
  • - The findings reveal that positive symptoms of psychosis are related to immune function changes, while negative symptoms are tied to alterations in mitochondrial pathways, highlighting distinct biological processes involved in psychosis.
View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Background: 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.

Objective: Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains.

View Article and Find Full Text PDF

Amyotrophic lateral sclerosis (ALS, MND) is a neurodegenerative disease of upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two years of first symptoms. Genetic factors are an important cause of ALS, with variants in more than 25 genes having strong evidence, and weaker evidence available for variants in more than 120 genes. With the increasing availability of next-generation sequencing data, non-specialists, including health care professionals and patients, are obtaining their genomic information without a corresponding ability to analyze and interpret it.

View Article and Find Full Text PDF

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder.

View Article and Find Full Text PDF

Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months.

View Article and Find Full Text PDF

Background: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in accounting for >5% of cases.

Objective: To identify rare, causal CNV in patients with RE.

View Article and Find Full Text PDF

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Background: Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology.

Aims: To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD).

Method: Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals.

View Article and Find Full Text PDF

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.

View Article and Find Full Text PDF

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.

View Article and Find Full Text PDF

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes.

View Article and Find Full Text PDF

Variants within the optineurin gene (OPTN) are recognized as causative mutations for primary open angle glaucoma. However, 4 different nonsynonymous and 3 different exonic deletion OPTN mutations have recently been identified in Japanese amyotrophic lateral sclerosis (ALS) patients. We sought to characterize OPTN genetic variation in a British cohort of ALS cases of Northern European origin.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.

View Article and Find Full Text PDF

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples.

View Article and Find Full Text PDF

Background: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.

Methods And Results: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants.

View Article and Find Full Text PDF

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Warning

Message: fopen(/var/lib/php/sessions/ci_sessiongc9ftp4kojhr125bl3pfpqb8ocd6o83m): Failed to open stream: No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 177

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

A PHP Error was encountered

Severity: Warning

Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)

Filename: Session/Session.php

Line Number: 137

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once