Publications by authors named "Nalls M"
Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants (SVs); however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs.
View Article and Find Full Text PDFRecently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.
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- - The study highlights the complexity of Alzheimer's disease and related dementias, emphasizing the need to understand genetic and environmental factors that vary across different ancestries for personalized treatment approaches.
- - Utilizing large-scale biobank data, the research characterized genetic variants associated with Alzheimer's across 11 ancestries, identifying 116 potentially linked variants, including 18 known pathogenic ones and 98 new variants.
- - The findings revealed significant ancestry-driven differences in disease risk, including a higher presence of ε4/ε4 carriers in African ancestries, suggesting the importance of considering genetics in diverse populations to enhance understanding and treatment of AD/ADRDs.
Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals.
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- Copy Number Variations (CNVs) are crucial in understanding complex diseases and vary across different populations, necessitating large sample studies for accurate analysis.
- The CNV-Finder pipeline utilizes deep learning, specifically Long Short-Term Memory (LSTM) networks, to streamline the identification of CNVs in specific genomic areas, making subsequent analyses like genome sequencing more efficient.
- The tool has been validated with data from various cohorts, focusing on genes related to neurological diseases, and includes an interactive web application for researchers to visualize and refine their findings based on model predictions.
ProtPipe: A Multifunctional Data Analysis Pipeline for Proteomics and Peptidomics.
Genomics Proteomics Bioinformatics
November 2024
Article Synopsis
- Mass spectrometry (MS) is a key technique used for identifying and understanding proteins, which is important for fields like personalized medicine and systems biology.
- The development of ProtPipe aims to simplify MS data analysis by automating processes like data quality control, sample filtering, and normalization, making it easier to handle complex datasets.
- ProtPipe also offers various downstream analyses, such as identifying differences in protein abundance and visualizing interactions, and is available as an open-source tool with a user-friendly interface at https://github.com/NIH-CARD/ProtPipe.
Article Synopsis
- Latin America's genetic diversity offers a unique opportunity to study Alzheimer's disease (AD) and frontotemporal dementia (FTD), with a focus on identifying related genetic variations.
- The study involved 2,162 participants from six countries who underwent extensive genomic sequencing and analysis to detect genetic factors linked to these dementias.
- Results highlighted a mix of American, African, and European ancestries, discovered 17 pathogenic variants, and revealed specific genetic variations tied to AD and FTD inheritance patterns in affected families.
Background: Alzheimer's disease and related dementias (ADRD) and Parkinson's disease (PD) are the most common neurodegenerative conditions. These central nervous system disorders impact both the structure and function of the brain and may lead to imaging changes that precede symptoms. Patients with ADRD or PD have long asymptomatic phases that exhibit significant heterogeneity.
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- Parkinson's disease (PD) is a progressive movement disorder becoming more common due to an aging population, and researchers aimed to explore rare genetic variants that could help explain its development.
- Whole-exome sequencing was conducted on a large group of PD cases and controls of Asian ancestry, revealing significant links between the genes GBA1 and SMPD1 and the risk of developing PD, confirmed in additional samples.
- The research found that specific SMPD1 variants that reduced enzyme activity were particularly associated with PD risk, with a prominent Asian-specific variant being common among carriers.
Article Synopsis
- GenoTools is a Python package designed to simplify population genetics research by integrating key functions like ancestry estimation, quality control, and genome-wide association studies into streamlined pipelines.
- It allows users to track samples and variants across customizable processes, making it easier to handle genetics data for studies of any size.
- The tool is utilized in major initiatives like the NIH's Alzheimer's program and has successfully processed vast datasets, contributing to new discoveries and ensuring reliable ancestry predictions and robust quality control in genetic studies.
Article Synopsis
- - The paper explores using Large Language Models (LLMs) to streamline data wrangling and automate tasks in data discovery and harmonization, crucial for making biomedical data AI-ready by developing Common Data Elements (CDEs).
- - A human-in-the-loop approach was utilized to ensure the accuracy of generated CDEs from various studies and databases, achieving a high accuracy rate where 94.0% of fields required no manual changes, with an interoperability mapping rate of 32.4%.
- - The resulting CDEs are designed to improve dataset compatibility by measuring how well different data sources align with these standards, ultimately enhancing the efficiency and scalability of biomedical research efforts.
Neurons rely on mRNA transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA binding proteins (RBPs), including those known to be associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP knockdown on mRNA transport and local translation in iPSC-derived neurons.
View Article and Find Full Text PDFPathogenic variants in the gene represent the most common cause of autosomal dominant Parkinson's disease (PD) worldwide. We identified the p.L1795F variant in 14 White/European ancestry PD patients, including two families with multiple affected carriers and seven additional affected individuals with familial PD using genotyping and sequencing data from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and CENTOGENE.
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- Multiple studies have identified genetic factors linked to Alzheimer's and Parkinson's diseases, mostly in European populations, but evidence shows genetic variations exist across different ancestries.
- There are concerns that treatments developed based on European genetics may not be effective for Latino, Black/African American, and East Asian populations due to differing disease mechanisms.
- This study investigates the Population Attributable Risk (PAR) for Alzheimer's and Parkinson's by analyzing genetic data from various ancestries to promote inclusive and effective treatment strategies for neurodegenerative diseases.
Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. Using data from UK Biobank, SAIL Biobank, and FinnGen, we conducted an unbiased, population-scale study to: 1) Investigate how 155 endocrine, nutritional, metabolic, and digestive system disorders are associated with AD and PD risk prior to their diagnosis, considering known genetic influences; 2) Assess plasma biomarkers' specificity for AD or PD in individuals with these conditions; 3) Develop a multi-modal classification model integrating genetics, proteomics, and clinical data relevant to conditions affecting the gut-brain axis. Our findings show that certain disorders elevate AD and PD risk before AD and PD diagnosis including: insulin and non-insulin dependent diabetes mellitus, noninfective gastro-enteritis and colitis, functional intestinal disorders, and bacterial intestinal infections, among others.
View Article and Find Full Text PDFBackground: Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations.
Objective: We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies.
Methods: We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples.
Article Synopsis
- Genome-wide association studies have found numerous genetic loci linked to glycemic traits, but connecting these loci to specific genes and biological pathways remains a challenge.
- Researchers conducted meta-analyses of exome-array studies across four glycemic traits, analyzing data from over 144,000 participants, which led to the identification of coding variant associations in more than 60 genes.
- The study revealed significant pathways related to insulin secretion, zinc transport, and fatty acid metabolism, enhancing understanding of glycemic regulation and making data available for further research.
Genotyping single nucleotide polymorphisms (SNPs) is fundamental to disease research, as researchers seek to establish links between genetic variation and disease. Although significant advances in genome technology have been made with the development of bead-based SNP genotyping and Genome Studio software, some SNPs still fail to be genotyped, resulting in "no-calls" that impede downstream analyses. To recover these genotypes, we introduce Cluster Buster, a genotyping neural network and visual inspection system designed to improve the quality of neurodegenerative disease (NDD) research.
View Article and Find Full Text PDFInfections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe.
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- * Our research included looking at both common and rare gene variants connected to the NLRP3 inflammasome, as well as assessing the potential effects of related cytokines (IL-1β and IL-18) on PD.
- * The results showed no significant link between NLRP3 variations and PD, suggesting that the NLRP3 inflammasome may not be a viable target for treatment or play a role in the disease's development.
Background: Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at a global scale.
Objective: To identify the multi-ancestry spectrum of monogenic PD.
Methods: The first systematic approach to embrace monogenic PD worldwide, The Michael J.
Article Synopsis
- Parkinson's disease (PD) is influenced by genetics, but much of its heritability is still unclear due to previous focus on single nucleotide variants, while more complex genetic variations have been less studied.
- A specific CT-rich region in the SNCA gene may connect to PD risk, but its detailed role has not been explored until now.
- The study utilized advanced sequencing techniques on a large participant group, confirming existing associations and identifying new ones, while suggesting that the CT-rich region's disease association may not be solely driven by SNCA gene expression.
Article Synopsis
- Many studies on brain diseases mostly involve people of European descent, which makes it hard to understand these diseases for everyone.
- Out of 123 studies, 82% mainly included European participants, finding many genetic markers, while only a few were found in studies with non-European participants.
- It’s super important to include more diverse backgrounds in future research to improve treatments and knowledge about these brain diseases.
Article Synopsis
- * A study analyzed 4,685 sporadic FTD cases and found significant genetic variants at the MAPT and APOE loci that increase the risk for the disease, indicating potential genetic overlap with other neurodegenerative diseases.
- * The genetic risk factors appear to vary by population, with MAPT and APOE associations predominantly found in Central/Nordic and Mediterranean Europeans, suggesting a need for further research into these population-specific features for better understanding of sporadic FTD.