Deciphering state-dependent immune features from multi-layer omics data at single-cell resolution.

Current molecular quantitative trait locus catalogs are mostly at bulk resolution and centered on Europeans. Here, we constructed an immune cell atlas with single-cell transcriptomics of >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics and gut metagenomics from 235 Japanese persons, including patients with coronavirus disease 2019 (COVID-19) and healthy individuals.

Unraveling the COVID-19 Severity Hubs and Interplays in Inflammatory-Related RNA-Protein Networks.

The rapid worldwide transmission of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to severe cases of hypoxia, acute respiratory distress syndrome, multi-organ failure, and ultimately death. Small-scale molecular interactions have been analyzed by focusing on several genes/single genes, providing important insights; however, genome-wide multi-omics comprehensive molecular interactions have not yet been well investigated with the exception of GWAS and eQTLm, both of which show genetic risks. From April of 2020 until now, we have created a Japan-wide system, initially named the Japan COVID-19 Task Force.

JOB: Japan Omics Browser provides integrative visualization of multi-omics data.

We present the Japan Omics Browser (JOB), which enables integrative analysis of human omics at different layers. JOB offers visualization of per-variant regulatory effects in the human blood at mRNA and protein level distinctively, quantified from statistical fine-mapping of mRNA-expression quantitative loci (eQTL) and protein QTLs (pQTLs) in 1,405 Japanese, together with fine-mapping results of 94 complex traits in UK Biobank. In addition, JOB shows per-tissue regulatory effect prediction score (EMS), trained via multi-task learning.

Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity.

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC.

Platform-dependent effects of genetic variants on plasma APOL1.

Mutations in apolipoprotein L1 (APOL1) are strongly associated with protection against parasitic infections and increased risk of kidney disease in individuals of African ancestry. To better understand the mechanisms underlying APOL1-related pathologies, we examined genetic drivers of circulating APOL1 in individuals of African and European ancestry from four independent cohorts (UK Biobank, AASK, deCODE, and Health ABC) using three proteomic technologies (Olink, SomaLogic, and mass spectrometry). We found that disease-associated G1 and G2 variants are strong -pQTLs for plasma APOL1 measured by Olink and SomaLogic, but not mass spectrometry.

Functional dissection of complex and molecular trait variants at single nucleotide resolution.

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types.

High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways.

High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse and human kidneys, in healthy and distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in tissue from nine distinct human kidneys, which revealed a cell neighborhood centered around a population of macrophages.

Principles of Spatial Transcriptomics Analysis: A Practical Walk-Through in Kidney Tissue.

Spatial transcriptomic technologies capture genome-wide readouts across biological tissue space. Moreover, recent advances in this technology, including Slide-seqV2, have achieved spatial transcriptomic data collection at a near-single cell resolution. To-date, a repertoire of computational tools has been developed to discern cell type classes given the transcriptomic profiles of tissue coordinates.

Methods for statistical fine-mapping and their applications to auto-immune diseases.

Although genome-wide association studies (GWAS) have identified thousands of loci in the human genome that are associated with different traits, understanding the biological mechanisms underlying the association signals identified in GWAS remains challenging. Statistical fine-mapping is a method aiming to refine GWAS signals by evaluating which variant(s) are truly causal to the phenotype. Here, we review the types of statistical fine-mapping methods that have been widely used to date, with a focus on recently developed functionally informed fine-mapping (FIFM) methods that utilize functional annotations.