Biology subjects

Leslie, E. J.

Publications and source records attributed to Leslie, E. J..

6 recordsLinked to original sources

bioRxiv2024

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis

Orofacial cleft (OFC) is a common human congenital anomaly. Epithelial-specific RNA splicing regulators ESRP1 and ESRP2 regulate craniofacial morphogenesis and their disruption result in OFC in zebrafish, mouse and humans. Using esrp1/2 mutant zebrafish and murine Py2T cell line models, we functionally tested the pathogenicity of human ESRP1/2 gene variants. We found that many variants predicted by in silico methods to be pathogenic were functionally benign. Esrp1 also regulates the alternative splicing of Ctnnd1 and these genes are co-expressed in the embryonic and oral epithelium. In fact, over-expression of ctnnd1 is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants. Additionally, we identified 13 CTNND1 variants from genome sequencing of OFC cohorts, confirming CTNND1 as a key gene in human OFC. This work highlights the importance of functional assessment of human gene variants and demonstrates the critical requirement of Esrp-Ctnnd1 acting in the embryonic epithelium to regulate palatogenesis.

genetics↗

bioRxiv2022

POIROT: A powerful test for parent-of-origin effects in unrelated samples leveraging multiple phenotypes

MotivationThere is widespread interest in identifying genetic variants that exhibit parent-of-origin effects (POEs) wherein the effect of an allele on phenotype expression depends on its parental origin. POEs can arise from different phenomena including genomic imprinting and have been documented for many complex traits. Traditional tests for POEs require family data to determine parental origins of transmitted alleles. As most genome-wide association studies (GWAS) instead sample unrelated individuals (where allelic parental origin is unknown), the study of POEs in such datasets requires sophisticated statistical methods that exploit genetic patterns we anticipate observing when POEs exist. We propose a method to improve discovery of POE variants in large-scale GWAS samples that leverages potential pleiotropy among multiple correlated traits often collected in such studies. Our method compares the phenotypic covariance matrix of heterozygotes to homozygotes based on a Robust Omnibus Test. We refer to our method as the Parent of Origin Inference using Robust Omnibus Test (POIROT) of multiple quantitative traits. ResultsThrough simulation studies, we compared POIROT to a competing univariate variance-based method which considers separate analysis of each phenotype. We observed POIROT to be well-calibrated with improved power to detect POEs compared to univariate methods. POIROT is robust to non-normality of phenotypes and can easily adjust for population stratification and other confounders. Finally, we applied POIROT to a GWAS of quantitative anthropometric measures at birth. We identified two loci of suggestive significance for follow-up investigation.

genetics↗

bioRxiv2021

Efficient Estimation of Indirect Effects in Case-Control Studies Using a Unified Likelihood Framework

Mediation models are a set of statistical techniques that investigate the mechanisms that produce an observed relationship between an exposure variable and an outcome variable in order to deduce the extent to which the relationship is influenced by intermediate mediator variables. For a case-control study, the most common mediation analysis strategy employs a counterfactual framework that permits estimation of indirect and direct effects on the odds ratio scale for dichotomous outcomes, assuming either binary or continuous mediators. While this framework has become an important tool for mediation analysis, we demonstrate that we can embed this approach in a unified likelihood framework for mediation analysis in case-control studies that leverages more features of the data (in particular, the relationship between exposure and mediator) to improve efficiency of indirect effect estimates. One important feature of our likelihood approach is that it naturally incorporates cases within the exposure-mediator model to improve efficiency. Our approach does not require knowledge of disease prevalence and can model confounders and exposure-mediator interactions, and is straightforward to implement in standard statistical software. We illustrate our approach using both simulated data and real data from a case-control genetic study of lung cancer.

genetics↗

bioRxiv2019

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

Orofacial clefts (OFCs) are one of the most common birth defects worldwide and create a significant health burden. The majority of OFCs are non-syndromic, and the genetic component has been only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. Part of the Gabriella Miller Kids First Pediatric Research Program, this is the first large-scale WGS study of OFC in parent-offspring trios. WGS provides deeper and more specific genetic data than currently available using imputation on single nucleotide polymorphic (SNP) marker panels. Here, association analysis of genome-wide single nucleotide variants (SNV) and short insertions and deletions (indels) identified a new locus on chromosome 21 in Colombian families, within a region known to be expressed during craniofacial development. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and the need for larger samples when for studying OFCs and other birth defects in admixed populations.

genetics↗

bioRxiv2019

Leveraging Family History in Case-Control Analyses of Rare Variation

Standard methods for case-control association studies of rare variation often treat disease outcome as a dichotomous phenotype. However, both theoretical and experimental studies have demonstrated that subjects with a family history of disease can be enriched for risk variation relative to subjects without such history. Assuming family history information is available, this observation motivates the idea of replacing the standard dichotomous outcome variable used in case-control studies with a more informative ordinal outcome variable that distinguishes controls (0), sporadic cases (1), and cases with a family history (2), with the expectation that we should observe increasing number of risk variants with increasing category of the ordinal variable. To leverage this expectation, we propose a novel rare-variant association test that incorporates family history information based on our previous GAMuT framework (Broadaway et al., 2016) for rare-variant association testing of multivariate phenotypes. We use simulated data to show that, when family history information is available, our new method outperforms standard rare-variant association methods like burden and SKAT tests that ignore family history. We further illustrate our method using a rare-variant study of cleft lip and palate.

genetics↗

bioRxiv2018

Detection of de novo copy number deletions from targeted sequencing of trios

De novo copy number deletions have been implicated in many diseases, but there is no formal method to date however that identifies de novo deletions in parent-offspring trios from capture-based sequencing platforms. We developed Minimum Distance for Targeted Sequencing (MDTS) to fill this void. MDTS has similar sensitivity (recall), but a much lower false positive rate compared to less specific CNV callers, resulting in a much higher positive predictive value (precision). MDTS also exhibited much better scalability, and is available as open source software at github.com/JMF47/MDTS.

bioinformatics↗