Long-read sequencing identifies repeat expansions in Parkinson's disease.

Pathogenic GAA repeat expansions in are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease (PD). Given emerging evidence that repeat expansions in ataxia-associated genes like , can contribute to atypical or familial forms of PD, we investigated whether expansions might play a similar role. Using long-read whole-genome sequencing on 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, alongside 1,429 additional controls from the NIH CARD initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations.

Gut-brain nexus: Mapping multimodal links to neurodegeneration at biobank scale.

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. We conducted a biobank-scale study to (i) identify endocrine, nutritional, metabolic, and digestive disorders with potential causal or temporal associations with AD/PD risk before diagnosis; (ii) assess plasma biomarkers' specificity for AD/PD in the context of co-occurring gut related traits and disorders; and (iii) integrate multimodal datasets to enhance AD/PD prediction. Our findings show that several disorders were associated with increased AD/PD risk before diagnosis, with variation in the strength and timing of associations across conditions.

Biobank-scale genetic characterization of Alzheimer's disease and related dementias across diverse ancestries.

Alzheimer's disease and related dementias (AD/ADRDs) pose a significant global public health challenge. To effectively implement personalized therapeutic interventions on a global scale, it is essential to identify disease-causing, risk, and resilience factors across diverse ancestral backgrounds. This study leveraged biobank-scale data to conduct a large multi-ancestry whole-genome sequencing characterization of AD/ADRDs.

Genome-wide association analyses reveal susceptibility variants linked to Parkinson's disease in the South African population using inferred global and local ancestry.

Genome-wide association studies (GWAS) have been successful in identifying over 100 loci associated with Parkinson's disease (PD) susceptibility. However, the majority of these studies have focused on European cohorts with few including diverse ancestries. Using genotyped and imputed data from 691 South African PD cases and 826 controls, we conducted a conventional GWAS, two local ancestry GWAS (LA-GWAS) approaches (one using local ancestry as a covariate and the other separating the dosage per ancestry), and an association analysis to identify regions of homozygosity associated with PD status.

A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance.

Background: Progressive myoclonic epilepsy is a heterogeneous neurodegenerative disorder characterized by early-onset myoclonus, epilepsy, generalized tonic-clonic seizures, and progressive neurological deterioration. Recently, a CGG repeat expansion and increased CSNK1E DNA methylation have been shown to be associated with developmental and epileptic encephalopathies.

Objective: To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.

MEDICATION EXPOSURE AND NEURODEGENERATIVE DISEASE RISK ACROSS NATIONAL BIOBANKS.

Unlabelled: Advanced age, genetics, and environmental exposures are leading contributors to the development of neurodegenerative disorders (NDD). In this study, we used data from the UK Biobank (UKB) and the All of Us (AoU) initiative to determine if exposure to specific medications are associated with an increased or decreased risk of NDD, including Alzheimer's (AD), Parkinson's disease (PD), and all-cause dementia (DEM). We investigated the associations between these diseases and prescription drug exposures through an unbiased analysis, assessing both lifetime risk and risk from exposures occurring more than ten years before diagnosis, while also accounting for comorbid conditions.

The Global Landscape of Genetic Variation in Parkinson's disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance.

Background: The genetic architecture of Parkinson's disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting our insights into the genetic architecture of PD at a global scale.

Methods: We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson's Genetics Program, we analyzed sequencing and genotyping data from 69,881 individuals, including 41,139 affected and 28,742 unaffected, from eleven different ancestries, including ~30% of individuals from non-European ancestries.

Insights into ancestral diversity in Parkinson's disease risk: a comparative assessment of polygenic risk scores.

Risk prediction models play a crucial role in advancing healthcare by enabling early detection and supporting personalized medicine. Nonetheless, polygenic risk scores (PRS) for Parkinson's disease (PD) have not been extensively studied across diverse populations, contributing to health disparities. In this study, we constructed 105 PRS using individual-level data from seven ancestries and compared two different models.

Erratum: The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

[This corrects the article DOI: 10.1212/NXG.0000000000200246.

Genome-wide assessment identifies novel runs of homozygosity linked to Parkinson's disease etiology across diverse ancestral populations.

Objective: We conducted the first large-scale, multi-ancestral investigation of Parkinson's disease (PD) to examine the impact of genome-wide homozygosity on disease risk and age at onset. Using genotyping, imputed, and whole-genome sequencing (WGS) data from 16,599 PD cases and 13,585 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability.

Methods: We analyzed runs of homozygosity (ROHs) for total length (S), number (N), average length (AV), and genomic inbreeding coefficient (F).

Genetic Contributions to Alzheimer's Disease and Frontotemporal Dementia in Admixed Latin American Populations.

Latin America's diverse genetic landscape provides a unique opportunity to study Alzheimer's disease (AD) and frontotemporal dementia (FTD). The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, or as healthy controls from six countries: Argentina, Brazil, Chile, Colombia, Mexico, and Peru. Participants underwent genomic sequencing and population structure analyses were conducted using Principal Component Analysis and ADMIXTURE.

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, we show that, among those, TAX1BP1 regulates how αSyn interacts with lipids, and ADAMTS19 modulates how αSyn phase separates into inclusions, adding to the growing body of evidence implicating those processes in PD.

Does Play a Role in Parkinson's Disease Susceptibility Across Diverse Ancestral Populations?

Background: The catechol-O-methyltransferase () gene is involved in brain catecholamine metabolism, but its association with Parkinson's disease (PD) risk remains unclear.

Objective: To investigate the relationship between genetic variants and PD risk across diverse ancestries.

Methods: We analyzed variants in 2,251 PD patients and 2,835 controls of European descent using whole-genome sequencing from the Accelerating Medicines Partnership-Parkinson Disease (AMP-PD), along with 20,427 PD patients and 11,837 controls from 10 ancestries using genotyping data from the Global Parkinson's Genetics Program (GP2).

Racial Disparities in Parkinson Disease Clinical Phenotype, Management, and Genetics: Protocol for a Prospective Observational Study.

Background: Parkinson disease (PD) has been described and studied extensively in White populations, with little known about how the disease manifests and progresses in patients from the Black community. Studies investigating disease features in Black populations are uncommon, with some suggesting that the Black population with PD is more disabled and has greater disease severity and different clinical features compared with the White population with PD. These health disparities are likely to influence the quality of care for Black patients with PD.

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease.

Polygenic scores for disease risk are not associated with clinical outcomes in Parkinson's disease.

Polygenic risk scores (PRS) in Parkinson's disease (PD) are associated with disease risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants to biological pathways or cell types. Here, we investigated 8 biological pathways or regions of open chromatin using pathway-specific PRS: alpha-synuclein pathway, adaptive immunity, innate immunity, lysosomal pathway1, endocytic membrane-trafficking pathway, mitochondrial pathway, microglial open chromatin single nucleotide polymorphisms (SNPs), and monocyte open chromatin SNPs.

New insights from a Malaysian real-world deep brain stimulation cohort.

BackgroundThe availability of deep brain stimulation (DBS), a highly efficacious treatment for several movement disorders, remains low in developing countries, with scarce data available on utilization and outcomes.ObjectiveWe characterized the DBS cohort and outcomes at a Malaysian quaternary medical center.MethodsA retrospective chart review was done on DBS-related surgery at the University of Malaya, including clinico-demographic, genetics, and outcomes data focusing on post-operative medication reduction and complications.

CARDBiomedBench: A Benchmark for Evaluating Large Language Model Performance in Biomedical Research: A novel question-and-answer benchmark designed to assess Large Language Models' comprehension of biomedical research, piloted on Neurodegenerative Diseases.

Backgrounds: Biomedical research requires sophisticated understanding and reasoning across multiple specializations. While large language models (LLMs) show promise in scientific applications, their capability to safely and accurately support complex biomedical research remains uncertain.

Methods: We present , a novel question-and-answer benchmark for evaluating LLMs in biomedical research.

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.

Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in .

Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (). 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.

Chromosome X-wide common variant association study in autism spectrum disorder.

Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, 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.