Biology subjects

Cutler, D.

Publications and source records attributed to Cutler, D..

6 recordsLinked to original sources

bioRxiv2024

CADET: Enhanced transcriptome-wide association analyses in admixed samples using eQTL summary data

A transcriptome-wide association study (TWAS) is a popular statistical method for identifying genes whose genetically-regulated expression (GReX) component is associated with a trait of interest. Most TWAS approaches fundamentally assume that the training dataset (used to fit the gene expression prediction model) and testing GWAS dataset are from the same ancestrally homogenous population. If this assumption is violated, studies have shown a marked negative impact on expression prediction accuracy as well as reduced power of the downstream genetrait association test. These issues pose a particular problem for admixed individuals, whose genomes represent a mosaic of multiple continental ancestral segments. To resolve these issues, we present CADET, which enables powerful TWAS of admixed cohorts leveraging the local-ancestry (LA) information of the cohort along with summary-level eQTL data from reference panels of different ancestral groups. CADET combines multiple polygenic risk score models based on the summary-level eQTL reference data to predict LA-aware GReX components in admixed test samples. Using simulated data, we compare the imputation accuracy, power, and type I error rate of our proposed LA-aware approach to LA-unaware methods for performing TWASs. We show that CADET performs optimally in nearly all settings regardless of whether the genetic architecture of gene expression is dependent or independent of ancestry. We further illustrate CADET by performing a TWAS of 29 common blood biochemistry phenotypes within an admixed cohort from the UK Biobank and identify 18 hits unique to our LA-aware strategy with the majority of hits supported by existing GWAS findings.

genetics↗

bioRxiv2023

Identifying latent genetic interactions in genome-wide association studies using multiple traits

Genome-wide association studies of complex traits frequently find that SNP-based estimates of heritability are considerably smaller than estimates from classic family-based studies. This missing heritability may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. To circumvent these challenges, we propose a new method to detect genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Our approach, Latent Interaction Testing (LIT), uses the observation that correlated traits with shared latent genetic interactions have trait variance and covariance patterns that differ by genotype. LIT examines the relationship between trait variance/covariance patterns and genotype using a flexible kernel-based framework that is computationally scalable for biobank-sized datasets with a large number of traits. We first use simulated data to demonstrate that LIT substantially increases power to detect latent genetic interactions compared to a trait-by-trait univariate method. We then apply LIT to four obesity-related traits in the UK Biobank and detect genetic variants with interactive effects near known obesity-related genes. Overall, we show that LIT, implemented in the R package lit, uses shared information across traits to improve detection of latent genetic interactions compared to standard approaches.

genetics↗

bioRxiv2021

Structure modeling hints at a granular organization of the Vertebrate Golgi ribbon

Vertebrate cells display a specific Golgi apparatus architecture, known as the "ribbon", where the functional subunits, the mini-stacks, are linked into a tridimensional network. The importance of the ribbon architecture is underscored by evidence of its disruption in a host of diseases, but just how it relates to the biological Golgi functions remains unclear. Are all the connections between mini-stacks functionally equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, due to the lack of a secretory cargo providing a quantifiable readout of the functional output of ribbon-embedded mini-stacks. Endothelial cells produce rod-shaped secretory granules, the Weibel-Palade bodies (WPB), whose von Willebrand Factor (VWF) cargo is central to hemostasis. In these cells, the Golgi apparatus exerts a dual control on WPB size at both mini-stack and ribbon levels. Mini-stack dimensions delimit the size of VWF boluses" while the ribbon architecture allows their linear co-packaging at the trans-Golgi network generating WPBs of different lengths. This Golgi/WPB size relationship lends itself to mathematical analysis. Here, different ribbon structures were modeled and their predicted effects on WPB size distribution compared to the ground truth of experimental data. Strikingly, the best-fitting model describes a Golgi ribbon made by linked subunits corresponding to differentially functioning monomer and dimer ministacks. These results raise the intriguing possibility that the fine-grained structure of the Golgi ribbon is more complex than previously thought.

cell biology↗

bioRxiv2020

Methylation Quantitative Trait Loci are Largely Consistent across Disease States in Crohns disease

BackgroundIn a recent study, we identified 1189 CpG sites whose DNA methylation (DNAm) level in blood distinguished Crohns disease (CD) cases from controls. We also demonstrated that the vast majority of these differences were a consequence of disease, rather than a cause of CD. Since methylation can be influenced by both genetic and environmental factors, here we focus on CpGs under demonstrable genetic control (methylation quantitative trait loci, or mQTLs). By comparing mQTL patterns across disease states and tissue (blood vs. ileum), we may distinguish patterns unique to CD. Such DNAm patterns may be relevant for the developmental origins of CD. MethodsWe investigated three datasets: (i) 402 blood samples from 164 newly diagnosed pediatric CD patients taken at two time points, and 74 non-IBD controls (ii) 780 blood samples from a non-CD adult population and (iii) 40 ileal biopsies (17 CD cases and 23 non-IBD controls) from group (i). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were tested via linear models adjusted for age, gender, disease status, disease subtype, estimated cell type and three genotype-based principal components. We used a Bonferroni-adjusted significance threshold to identify significantly associated SNP-CpG pairs, but also considered larger sets identified by a false discovery rate criterion ResultsIn total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P<8.21x10-14). These associations and their effects are highly consistent across different ages, races, disease states, and tissue types, suggesting that the vast majority of these mQTLs participate in common gene regulation. However, genes near CpGs associated with IBD SNPs were enriched for 18 KEGG pathways relevant to IBD-linked immune function and inflammatory responses. We observed suggestive evidence for a small number of tissue-specific associations and disease-specific ileal associations in ileum, though larger studies will be needed to confirm these results. ConclusionThe vast majority of blood derived mQTLs are commonly shared across individuals. However, we have identified a subset of such, which may be involved in processes related to CD. Independent cohort studies will be required to validate these findings.

genomics↗

bioRxiv2020

Coding de novo mutations identified by WGS reveal novel orofacial cleft genes

While de novo mutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

genetics↗

bioRxiv2017

New mutations, old statistical challenges

Based on targeted sequencing of 208 genes in 11,730 neurodevelopmental disorder cases, Stessman et al. report the identification of 91 genes associated (at a False Discovery Rate [FDR] of 0.1) with autism spectrum disorders (ASD), intellectual disability (ID), and developmental delay (DD)--including what they characterize as 38 novel genes, not previously reported as connected with these diseases1.\n\nIf true, this would represent a substantial step forward. Unfortunately, each of the two discovery analyses (1. De novo mutation analysis and, 2. a comparison of private mutations with public control data) contain critical statistical flaws. When one accounts for these problems, fewer than half of the genes--and very few, if any, of the novel findings--survive. These errors have implications for how future analyses should be conducted, for understanding the genetic basis of these disorders, and for genomic medicine.\n\nWe discuss the two main ana ...

genetics↗