Investigating the ATN (Amyloid, Tau, Neurodegeneration) framework in Alzheimer’s Disease and its causal genetic‐drivers using Digital‐Twins.

Background: Amyloid, Tau and neurodegeneration (ATN), the hallmark pathologies of Alzheimer’s Disease (AD) translating to measurable biomarkers are important for disease modifying therapeutics.

Method: AD Digital‐Twins were built using AITIA’s patented A.I.

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.

Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals.

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses.

MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study.

Objective: To investigate the feasibility of microRNA (miRNA) levels in CSF as biomarkers for prodromal Huntington disease (HD).

Methods: miRNA levels were measured in CSF from 60 PREDICT-HD study participants using the HTG protocol. Using a CAG-Age Product score, 30 prodromal HD participants were selected based on estimated probability of imminent clinical diagnosis of HD (i.

Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: a longitudinal cohort study and validation.

Background: Better understanding and prediction of progression of Parkinson's disease could improve disease management and clinical trial design. We aimed to use longitudinal clinical, molecular, and genetic data to develop predictive models, compare potential biomarkers, and identify novel predictors for motor progression in Parkinson's disease. We also sought to assess the use of these models in the design of treatment trials in Parkinson's disease.

miR-149 and miR-29c as candidates for bipolar disorder biomarkers.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesicles (EVs) extracted from prefrontal cortex (Brodmann area 9, BA9) of BD patients.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD.

DNM3 and genetic modifiers of age of onset in LRRK2 Gly2019Ser parkinsonism: a genome-wide linkage and association study.

Background: Leucine-rich repeat kinase 2 (LRRK2) mutation 6055G→A (Gly2019Ser) accounts for roughly 1% of patients with Parkinson's disease in white populations, 13-30% in Ashkenazi Jewish populations, and 30-40% in North African Arab-Berber populations, although age of onset is variable. Some carriers have early-onset parkinsonism, whereas others remain asymptomatic despite advanced age. We aimed to use a genome-wide approach to identify genetic variability that directly affects LRRK2 Gly2019Ser penetrance.

The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane.

Genome-wide association studies (GWAS) have identified the GAK/DGKQ/IDUA region on 4p16.3 among the top three risk loci for Parkinson's disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3' clathrin-binding domain of GAK identified by RNA deep-sequencing in post-mortem human brain tissue as having increased expression in PD.

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893).

Correction: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.

[This corrects the article DOI: 10.1371/journal.pone.

Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study.

Rationale: The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated.

Objectives: To determine the risk factors for, and the clinical consequences of, having ILA progression in participants from the Framingham Heart Study.

Methods: ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart.

Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression.

Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types.

microRNA Profiles in Parkinson's Disease Prefrontal Cortex.

Objective: The goal of this study was to compare the microRNA (miRNA) profile of Parkinson's disease (PD) frontal cortex with normal control brain, allowing for the identification of PD specific signatures as well as study the disease-related phenotypes of onset age and dementia.

Methods: Small RNA sequence analysis was performed from prefrontal cortex for 29 PD samples and 33 control samples. After sample QC, normalization and batch correction, linear regression was employed to identify miRNAs altered in PD, and a PD classifier was developed using weighted voting class prediction.

Association Between Interstitial Lung Abnormalities and All-Cause Mortality.

Importance: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.

Objective: To investigate whether interstitial lung abnormalities are associated with increased mortality.

Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease.

Background: Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed "Lewy Bodies" within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking.

Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities.

Rationale: Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis.

Objectives: We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis.

Methods: We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998.

RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.

Huntington's Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing.

Study of plasma-derived miRNAs mimic differences in Huntington's disease brain.

Background: Biomarkers for Huntington's disease progression could accelerate therapeutic developments and improve patient care. Brain microRNAs relating to clinical features of Huntington's disease may represent a potential Huntington's disease biomarker in blood.

Objective: This study was undertaken to examine candidate microRNAs in plasma to determine whether changes observed in HD brains are detectable in peripheral samples.

A comparison of visual and quantitative methods to identify interstitial lung abnormalities.

Background: Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA.

miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement.

Background: MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington's disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD.

Methods: We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains.

Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities.

Objective: To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities.

Materials And Methods: We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT.