Biology subjects

Rafaels, N.

Publications and source records attributed to Rafaels, N..

4 recordsLinked to original sources

bioRxiv2024

Characterizing substructure via mixture modeling of genetic similarity in large-scale summary statistics

Genetic summary data are broadly accessible and highly useful including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into groups masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted substructure limits summary data usability, especially for understudied or admixed populations. Here, we present Summix2, a comprehensive set of methods and software based on a computationally efficient mixture model to estimate and adjust for substructure in genetic summary data. In extensive simulations and application to public data, Summix2 characterizes finer-scale population structure, identifies ascertainment bias, and identifies potential regions of selection due to local substructure deviation. Summix2 increases the robust use of diverse publicly available summary data resulting in improved and more equitable research.

genomics↗

bioRxiv2021

SAIGE-BRUSH: an efficient, user-friendly and low cost cloud implementation for genome-wide association studies

SAIGE-Biobank Re-Usable SAIGE Helper (SAIGE-BRUSH) allows users with little computational expertise to utilize SAIGE for GWAS with parallelization and data collection on biobank data sets. This implementation requires no installation and has additional features not programmed within the original SAIGE framework, such as concurrency, reproducibility, reusability, scalability, association analysis results filtering and output plots. This is all achieved without writing any code from the user. This implementation is currently being utilized by the Biobank at the Colorado Center for Personalized Medicine (CCPM) on Google Cloud but is flexible for a number of architectures available to genetic analysts. Availability: This open source implementation is freely available at https://github.com/tbrunetti/SAIGE-BRUSH and is licensed under the MIT License. Contact: Chris Gignoux at chris.gignoux@cuanschutz.edu & Nick Rafaels at nicholas.rafaels@cuanschutz.edu Supplemental Material: For detailed user documentation, please visit https://saige-brush.readthedocs.io/en/latest/

bioinformatics↗

bioRxiv2019

Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease

Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1 Lowering circulating lipids is an important treatment strategy to reduce risk.2,3 However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6 To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5x) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g. APOB, LPL). A novel LoF variant, ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3x10-8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing of ZNF529 in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition of ZNF529 or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.

genomics↗

bioRxiv2017

Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.\n\nMETHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.\n\nRESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 x 10-9 and 2.97 x 10-8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the \"atopic march\" and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 x10-6 [≤] p [≤] 3.06 x10-6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.\n\nCONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

bioinformatics↗