Biology subjects

Bouland, G. A.

Publications and source records attributed to Bouland, G. A..

5 recordsLinked to original sources

bioRxiv2025

scAGG: Sample-level embedding and classification of Alzheimer's disease from single-nucleus data

Identifying key cell types and genes in Alzheimers Disease (AD) is crucial for understanding its pathogenesis and discovering therapeutic targets. Single-cell RNA sequencing technology (scRNAseq) has provided unprecedented opportunities to study the molecular mechanisms that underlie AD at the cellular level. In this study, we address the problem of sample-level classification of AD using scRNAseq data, where we predict the disease status of entire samples from the gene expression profiles of their cells, which are not necessarily all affected by the disease. We introduce scAGG (single-cell AGGregation), a sample-level classification model that uses a sample-level pooling mechanism to aggregate single-cell embeddings, and show that it can accurately classify AD individuals and healthy controls. We then investigate the latent space learnt by the model and find that the model learns an ordering of the cells corresponding to disease severity. Genes associated with this ordering are enriched in AD-linked pathways, including cytokine signalling, apoptosis, and metal ion response. We also evaluate two attention-based models that perform on par with scAGG, but entropy analysis of their attention scores reveals limited interpretability value. As scRNAseq is increasingly applied to large cohorts and cell-level disease association annotations do not exist, our approach provides a way to classify phenotypes from single-cell measurements. The yielded cell- and sample-level severity scores may enable identification of AD-associated cell subtypes, paving the way for targeted drug development and personalized treatment strategies in AD. Code is available at: http://github.com/timoverlaan/scAGG

bioinformatics↗

bioRxiv2024

gsQTL: Associating genetic risk variants with gene sets by exploiting their shared variability

To investigate the functional significance of genetic risk loci identified through genome-wide association studies (GWASs), genetic loci are linked to genes based on their capacity to account for variation in gene expression, resulting in expression quantitative trait loci (eQTL). Following this, gene set analyses are commonly used to gain insights into functionality. However, the efficacy of this approach is hampered by small effect sizes and the burden of multiple testing. We propose an alternative approach: instead of examining the cumulative associations of individual genes within a gene set, we consider the collective variation of the entire gene set. We introduce the concept of gene set QTL (gsQTL), and show it to be more adept at identifying links between genetic risk variants and specific gene sets. Notably, gsQTL experiences less susceptibility to inflation or deflation of significant enrichments compared with conventional methods. Furthermore, we demonstrate the broader applicability of shared variability within gene sets. This is evident in scenarios such as the coordinated regulation of genes by a transcription factor or coordinated differential expression.

bioinformatics↗

bioRxiv2022

The rise of sparser single-cell RNAseq datasets; consequences and opportunities

There is an exponential increase in the number of cells measured in single-cell RNA sequencing (scRNAseq) datasets. Concurrently, scRNA-seq datasets become increasingly sparser as more zero counts are measured for many genes. We discuss that with increasing sparsity the binarized representation of gene expression becomes as informative as count-based expression. We show that downstream analyses based on binarized gene expressions give similar results to analyses based on count-based expressions. Moreover, a binarized representation scales to 17-fold more cells that can be analyzed using the same amount of computational resources. Based on these observations, we recommend the development of specialized tools for bit-aware implementations for downstream analyses tasks, creating opportunities to get a more fine-grained resolution of biological heterogeneity.

bioinformatics↗

bioRxiv2021

Differential dropout analysis captures biological variation in single-cell RNA sequencing data

Single-cell RNA sequencing data is characterized by a large number of zero counts, yet there is growing evidence that these zeros reflect biological variation rather than technical artifacts. We propose differential dropout analysis (DDA) to identify the effects of biological variation in single-cell RNA sequencing data. Using 16 publicly available and simulated datasets, we show that DDA accurately detects biological variation and can assess the relative abundance of transcripts more robustly than methods relying on counts. DDA is available at https://github.com/gbouland/DDA.

bioinformatics↗

bioRxiv2020

Understanding functional consequences of type 2 diabetes risk loci using the universal data integration and visualization R package CONQUER

BackgroundNumerous large genome-wide association studies (GWASs) have been performed to understand the genetic factors of numerous traits, including type 2 diabetes. Many identified risk loci are located in non-coding and intergenic regions, which complicates the understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci. ResultsHere, we developed the R-package CONQUER. Data for SNPs of interest (build GRCh38/hg38) were acquired from static- and dynamic repositories, such as, GTExPortal, Epigenomics Project, 4D genome database and genome browsers such as ENSEMBL. CONQUER modularizes SNPs based on the underlying co-expression data and associates them with biological pathways in specific tissues. CONQUER was used to analyze 403 previously identified type 2 diabetes risk loci. In all tissues, the majority of SNPs (mean = 13.50, SD = 11.70) were linked to metabolism. A tissue-shared effect was found for four type 2 diabetes-associated SNPs (rs601945, rs1061810, rs13737, rs4932265) that were associated with differential expression of HLA-DQA2, HSD17B12, MAN2C1 and AP3S2 respectively. Seven SNPs were identified that influenced the expression of seven ribosomal proteins in multiple tissues. Finally, one SNP (rs601945) was found to influence multiple HLA genes in all twelve tissues investigated. ConclusionWe present an universal R-package that aggregates and visualizes data in order to better understand functional consequences of GWAS loci. Using CONQUER, we showed that type 2 diabetes risk loci have many tissue-shared effects on multiple pathways including metabolism, the ribosome and HLA pathway.

genomics↗