Nathan O. Stitziel

A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis

In‐Hyuk Jung, Junedh Amrute, Sofia E. Luna, Ryan E. Wagoner et autres

A single-nucleotide missense polymorphism (rs1800449, R158Q) in the propeptide domain of lysyl oxidase (LOX-PP) is associated with increased risk of coronary artery disease (CAD) independent of changes in plasma lipid levels. Although the enzymatic function of LOX has an essential role for …

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Pangenome-based human genome analysis improves trait association and genomic prediction

Shuangjia Lu, Wen‐Wei Liao, Marianne K. DeGorter, Pagé C. Goddard et autres

Abstract The Human Pangenome Reference Consortium has generated 462 open-access reference genomes and a variation graph that represents differences among them, providing a substrate for pangenome-based analysis methods that overcome the longstanding limitation of comparing all genomic data to a single linear …

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Single-Cell Studies Advance Understanding of the Genetic and Molecular Basis of Atherosclerosis

Daniel Yuhang Li, João P Monteiro, Quanyi Zhao, Nathan O. Stitziel et autres

Atherosclerosis is a chronic disease of the arterial wall driven by complex interactions between vascular, immune, and stromal cells. For decades, our understanding of plaque biology relied on bulk assays that masked the underlying cellular heterogeneity. The development of single-cell and spatial …

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Genealogy-based trait association with LOCATER boosts power at loci with allelic heterogeneity

Xinxin Wang, Ryan Christ, Erica P. Young, Chul Joo Kang et autres

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based …

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Comparison of variant callers using 60 532 multi-ancestry whole genome sequences

Hufeng Zhou, Zilin Li, Derek Shyr, Xihao Li et autres

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. …

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Fully T2T pedigree assemblies reveal genetic stability and epigenetic plasticity of human centromeres across inheritance and cell-fate transitions

Shihua Dong, Xiaoyun Xing, Monika Čechová, Hailey Loucks et autres

Centromeres are essential chromosome components yet remain poorly understood due to their highly repetitive sequence architecture. Using fully-phased telomere-to-telomere diploid assemblies from a three-generation pedigree integrated with long-read epigenomes from matched peripheral blood mononuclear cells, induced pluripotent stem cells, and neural progenitor …

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Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy

Junedh Amrute, In‐Hyuk Jung, Tracy Yamawaki, Wen-Ling Lin et autres

Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD), but the mechanisms governing these cell state transitions remain unclear. We applied multiomic single-cell profiling, epitope mapping, and spatial transcriptomics across 27 human coronary arteries, identifying fibroblast activation protein (FAP) …

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Complete genomes of a multi-generational pedigree to expand studies of genetic and epigenetic inheritance

Monika Čechová, Tamara Potapova, Andreas Rechtsteiner, Glenn Hickey et autres

Pedigree analysis remains the gold standard for rare disease diagnostics, yet whole genome sequencing studies typically omit critical regions like centromeres, telomeres, and acrocentric chromosome p-arms. Here, we present telomere-to-telomere (T2T) reference genomes for four self-identified African American individuals of admixed ancestry …

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Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Ryan Welch, Anne Jackson, Annie Kwon, Jean Morrison et autres

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Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Xianyong Yin, Aarno Palotie, Samuli Ripatti, Ketian Yu et autres

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Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

Sanna Gudmundsson, Moriel Singer‐Berk, Sarah L. Stenton, Julia K. Goodrich et autres

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant …

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Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification

Stephen S. Rich, Paul S. de Vries, HarshaVardhan Doddapaneni, David R. Jacobs et autres

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