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.

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.

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.

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.

Parkinson's Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation.

Background: Known pathogenic variants in Parkinson's disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale.

Objectives: This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries.

Method: We analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson's Genetics Program dataset.

NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations.

Background: 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.

Cluster Buster: A Machine Learning Algorithm for Genotyping SNPs from Raw Data.

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.

NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations.

Genome-wide genotyping platforms have the capacity to capture genetic variation across different populations, but there have been disparities in the representation of population-dependent genetic diversity. The motivation for pursuing this endeavor was to create a comprehensive genome-wide array capable of encompassing a wide range of neuro-specific content for the Global Parkinson's Genetics Program (GP2) and the Center for Alzheimer's and Related Dementias (CARD). CARD aims to increase diversity in genetic studies, using this array as a tool to foster inclusivity.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

Background: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations.

Application of Aligned-UMAP to longitudinal biomedical studies.

High-dimensional data analysis starts with projecting the data to low dimensions to visualize and understand the underlying data structure. Several methods have been developed for dimensionality reduction, but they are limited to cross-sectional datasets. The recently proposed Aligned-UMAP, an extension of the uniform manifold approximation and projection (UMAP) algorithm, can visualize high-dimensional longitudinal datasets.

Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease.

Background: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD.