A5003493606- Genetic Associations and Epidemiology
- Statistical Methods and Inference
- Bioinformatics and Genomic Networks
- Genetic and phenotypic traits in livestock
- Liver Disease Diagnosis and Treatment
- Genomics and Rare Diseases
- Gene expression and cancer classification
- Lipid metabolism and disorders
- Cancer-related molecular mechanisms research
- Genetic Mapping and Diversity in Plants and Animals
- Adipokines, Inflammation, and Metabolic Diseases
- Epigenetics and DNA Methylation
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Adipose Tissue and Metabolism
- Atherosclerosis and Cardiovascular Diseases
- Advanced Causal Inference Techniques
- Genomics and Chromatin Dynamics
- SARS-CoV-2 and COVID-19 Research
- Lipoproteins and Cardiovascular Health
- RNA modifications and cancer
- Plant Pathogens and Resistance
- NF-κB Signaling Pathways
- Molecular Biology Techniques and Applications
- Substance Abuse Treatment and Outcomes
- Single-cell and spatial transcriptomics
Massachusetts Institute of Technology
2021-2024
Broad Institute
2021-2024
Intel (United States)
2024
Stanford University
2017-2023
The University of Tokyo
2017-2018
Tokyo Medical and Dental University
1970
University of Michigan
1970
Kyoto Prefectural University of Medicine
1970
Juntendo University
1970
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus transcriptomes epigenomes across 443 human subjects diverse Alzheimer's (AD) pathological phenotypes. We annotate 12 transcriptional states, including AD-dysregulated homeostatic, inflammatory, lipid-processing states. identify 1,542 AD-differentially-expressed genes, both microglia-state-specific disease-stage-specific alterations. By...
We present WhichTF, a computational method to identify functionally important transcription factors (TFs) from chromatin accessibility measurements. To rank TFs, WhichTF applies an ontology-guided functional approach compute novel enrichment by integrating measurements, high-confidence pre-computed conservation-aware TF binding sites, and putative gene-regulatory models. Comparison with prior sheer abundance-based methods reveals the unique ability of context-specific TFs relevance,...
We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. report 813 sparse PRS models with significant (p < 2.5 x 10 −5 ) incremental predictive performance when compared against covariate-only model that considers age, sex, types genotyping arrays, principal component loadings genotypes. correlation between number variants selected (Spearman’s ⍴ = 0.61, p 2.2 −59 for quantitative traits,...
Exercise training is critical for the prevention and treatment of obesity, but its underlying mechanisms remain incompletely understood given challenge profiling heterogeneous effects across multiple tissues cell types. Here, we address this opposing exercise high-fat diet (HFD)-induced obesity at single-cell resolution in subcutaneous visceral white adipose tissue skeletal muscle mice with interventions. We identify a prominent role mesenchymal stem cells (MSCs) exercise-induced adaptation....
Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating across 135 from UK Biobank find 27 associations between in genes outside major histocompatibility complex. We perform phenome-wide analyses directly measure homozygous carriers, commonly referred...
Abstract Suicide accounts for nearly 800,000 deaths per year worldwide with rates of both and attempts rising. Family studies have estimated substantial heritability suicidal behavior; however, collecting the sample sizes necessary successful genetic has remained a challenge. We utilized two different approaches in independent datasets to characterize contribution common variation suicide attempt. The first is patient reported attempt phenotype asked as part an online mental health survey...
The UK Biobank is a very large, prospective population-based cohort study across the United Kingdom. It provides unprecedented opportunities for researchers to investigate relationship between genotypic information and phenotypes of interest. Multiple regression methods, compared with genome-wide association studies (GWAS), have already been showed greatly improve prediction performance variety phenotypes. In high-dimensional settings, lasso, since its first proposal in statistics, has...
Large biobanks linking phenotype to genotype have led an explosion of genetic association studies across a wide range phenotypes. Sharing the knowledge generated by these resources with scientific community remains challenge due patient privacy and vast amount data. Here, we present Global Biobank Engine (GBE), web-based tool that enables exploration relationship between in biobank cohorts, such as UK Biobank. GBE supports browsing for results from genome-wide studies, phenome-wide...
Population-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses understanding the role in disease predisposition. To characterize latent components of genetic associations, we apply truncated singular value decomposition (DeGAs) to matrices summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured 337,199 White British individuals UK Biobank study. We systematically identify key...
Abstract Clinical laboratory tests are a critical component of the continuum care and provide means for rapid diagnosis monitoring chronic disease. In this study, we systematically evaluated genetic basis 38 blood urine measured in 358,072 participants UK Biobank identified 1,857 independent loci associated with at least one test, including 488 large-effect protein truncating, missense, copy-number variants. We tested these enrichment specific single cell types kidney, liver, pancreas...
Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen 176,899) to conduct a search for protein-altering conferring lower intraocular pressure (IOP) protection glaucoma. Through rare variant association analysis, find missense ANGPTL7 (rs28991009, p.Gln175His, MAF 0.8%, genotyped 82,253 individuals with measured IOP an...
The global pandemic of COVID-19 accounts for more than 14,000 deaths worldwide. However, little is known about the host genetics interaction with infection and progression. To better understand role genetics, we review current literature, aggregate readily available genetic resources, provide some updated analysis relevant to associated phenotypes. Using unrelated individuals in UK Biobank (total n = 337,579 across 5 populations), human leukocyte antigen ABO blood type frequencies. We find...
Abstract Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective American Indians Europeans. However, there is lack of data other Europeans non-Europeans. Also, whether genetically increased plasma TG due ApoC-III causally associated with CAD still unclear inconsistent. The objectives this study were verify the role...
Abstract Dominance heritability in complex traits has received increasing recognition. However, most polygenic score (PGS) approaches do not incorporate non-additive effects. Here, we present GenoBoost, a flexible PGS modeling framework capable of considering both additive and effects, specifically focusing on genetic dominance. Building statistical boosting theory, derive provably optimal GenoBoost scores provide its efficient implementation for analyzing large-scale cohorts. We benchmark...
We develop a scalable and highly efficient algorithm to fit Cox proportional hazard model by maximizing the $L^1$-regularized (Lasso) partial likelihood function, based on Batch Screening Iterative Lasso (BASIL) method developed in Qian others (2019). Our is particularly suitable for large-scale high-dimensional data that do not memory. The output of our full path, parameter estimates at all predefined regularization parameters, as well their validation accuracy measured using concordance...
Immune dysfunctions are believed to contribute bipolar disorder (BD), yet their mechanistic basis remains unclear. To address this, we systematically characterize BD-associated epigenomic and genetic variation in peripheral blood immune cells by profiling integrating 833 genome-wide maps of five histone modification marks across 180 individuals (88 Type I BD patients, 92 controls), coupled with whole-genome sequencing data rich medical records. We annotate 450k candidate cis-regulatory...
Approximately 40% of Alzheimers disease (AD) patients develop psychosis, yet the molecular and cellular processes that govern manifestation psychotic symptoms in dementia remain poorly understood. To define neurobiological correlates distinguish AD with psychosis (AD+P) from never exhibited (AD-P), we performed single-nucleus transcriptome epigenome profiling prefrontal cortex hippocampus 48 postmortem brains subjects segmented by psychiatric diagnosis. Our snRNA-seq uncovered differentially...
Background: The aortic valve is an important determinant of cardiovascular physiology and anatomic location common human diseases. Methods: From a sample 34 287 white British ancestry participants, we estimated functional area by planimetry from prospectively obtained cardiac magnetic resonance imaging sequences the valve. Aortic measurements were submitted to genome-wide association testing, followed polygenic risk scoring phenome-wide screening, identify genetic comorbidities. Results: A...
Abstract Current genome-wide association studies (GWASs) do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas genetic associations non-European populations, we conducted 220 deep-phenotype GWASs (diseases, biomarkers, medication usage) BioBank Japan ( n =179,000), by incorporating past medical history text-mining electronic records. Meta-analyses with the UK Biobank FinnGen total =628,000) identified ∼5,000 novel loci, which improved resolution...