Cell Genomics

The Genome Informed Risk Assessment (GIRA) report from eMERGE has become a standard approach to implement genomic precision medicine at scale. Here, we assess GIRAs utility and impact in a health care system independent of eMERGE, focusing on 9 adult conditions using the Penn Medicine Biobank (PMBB, n=48,279). We find a large number of patients - 50.1% (n=24,185) - were deemed by GIRA as high-risk for at least one of the 9 conditions with 30.4% (n=14,676) due to polygenic and/or monogenic risk. ...

AbstractGenome-wide studies (GWAS) on asthma have identified nearly 200 genomic loci. However, the underlying mechanisms remain mostly elusive. While functional profiling of blood immune cell types has helped interpret asthma GWAS signals, high-resolution functional genomic data of lung immune cells, which differ from circulating immune cells, are lacking. We thus profiled single-cell multi-omics (RNA-seq and ATAC-seq) on lymphocytes of lung and spleen tissues from 9 donors. Cross-tissue compari...

The Clinical Pharmacogenetics Implementation Consortium (CPIC) bases its drug-gene recommendations on the assignment of star alleles, which map known genotypes to defined functional categories and corresponding drug dosage guidelines. The star allele framework, first proposed in 1996 for the CYP gene family and later formalized with CPICs establishment in 2010 [1, 2], remains foundational to pharmacogenomics. However, this system has notable limitations. Its dependence on a restricted set of ben...

The genetic relationship between asthma and lung function may be dependent on age-at-onset (AAO) of asthma. We investigated whether the shared genetics between asthma AAO and lung function is dependent on AAO. Asthma cases from UK Biobank were subset according to their AAO and genetic correlation was used to obtain genetically homogeneous groups, i.e., [≤]20 (LT20), 20-40, and >40 (GT40) years. Association analysis and fine-mapping were performed to identify shared genetics between AAO groups...

Methods that analyze single-cell RNA-seq+ATAC-seq multiome data have shown promise in linking enhancers to target genes by correlating chromatin accessibility with gene expression across cells. However, correlations among ATAC-seq peaks may induce non-causal tagging peak-gene links (analogous to tagging associations in GWAS); indeed, we confirm that tagging effects induced by peak co-accessibility are pervasive in peak-gene linking. We defined two scores for each ATAC-seq peak: co-accessibility ...

Drug repurposing offers the opportunity to identify promising drug targets efficiently using existing data, but there are currently limitations to these efforts; there is a particular need for versatile, but rigorous high-throughput approaches. As such, we developed a flexible, high-throughput, Mendelian randomization (MR)-based drug repurposing pipeline with three stages: 1) MR-based identification, 2) MR-based validation and prioritization, and 3) application. This pipeline can be applied to a...

We assessed the impact of plasma protein quantitative trait loci (pQTL) on therapeutic hypotheses backed by human genetic evidence. We show that pQTL-supported target-indication pairs were 4.7 times more likely to advance from Phase I to launch, compared to a 2.6-fold increase observed only with human genetic evidence. Moreover, pQTL-based enrichment was prominent in druggable protein families which had limited enrichment from human genetic evidence alone.

Autism spectrum disorder (ASD; MIM 209850) is reported to vary globally from 0.01% in East Asian populations to 4.36% in certain Australian cohorts. Despite high heritability estimates (61-94%), the genetic architecture underlying ASD susceptibility remains poorly characterized across diverse populations, as most genomic studies have initially focused on individuals of European ancestry. To investigate ancestry-specific genetic contributions to ASD, we analyzed whole-genome sequencing data from ...

Inflammatory bowel disease (IBD) frequently co-occurs with immune-mediated and metabolic disorders, but whether these associations reflect shared genetics or causal effects remains unclear. We performed two-sample Mendelian randomization (MR) using large-scale genome-wide association study (GWAS) summary statistics to investigate potential causal effects of immune-mediated diseases and lifestyle traits on IBD, Crohns disease (CD), and ulcerative colitis (UC). SNP-based heritability and genetic c...

BackgroundPersonalized pharmacotherapy requires systematic consideration of genetic factors influencing drug efficacy and safety. The accumulation of large-scale whole-exome sequencing (WES) data provides an opportunity to assess population frequencies of clinically significant pharmacogenetic variants; however, the diagnostic applicability of exome data for pharmacogenomics remains insufficiently studied. Materials and MethodsA retrospective analysis of 6,102 anonymized sequencing datasets obt...

Genome-wide association studies (GWAS) have implicated tens of thousands of genetic variants associated with complex traits and polygenic diseases. Colocalizing GWAS variants with variants that may regulate gene expression, via expression quantitative trait loci (eQTL) mapping, has successfully led to the identification of disease-critical genes and their cell types of action. Recent studies predominantly colocalize proximal cis-eQTLs, which are estimated to regulate [~]10% of variance in gene e...

Mapping the pleiotropic effect of genetic variation on biological processes and complex phenotypes is fundamental to extracting translational insight from genome-wide association studies (GWAS). Here we present The Human Genotype-Phenotype Map (GPMap), a repository of colocalizing genetic associations across 15,997 complex traits and 2.7 million molecular measurements, leveraging common and rare variants and cis-and trans-acting effects across disaggregated tissue types and single cell datasets ...

Biobanks with longitudinal measurements have advanced our understanding of time-to-event (TTE) traits including age-of-onset and disease progression. However, limited work has characterized the heritability of TTE traits, a key parameter for comparisons of total association and predictive power. Here, we present COXMM, a Cox proportional hazard mixed model for estimating TTE heritability. Simulations show our model achieves nearly unbiased results, whereas non-TTE approaches severely underestima...

Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal ...

MotivationFanconi anemia (FA) is a rare disease mainly caused by biallelic pathogenic variants, including structural variants such as large deletions and insertions in FA genes. Currently, variant detection is based on short-read sequencing and probe-based approaches. However, determining the exact genomic breakpoint or achieving allelic discrimination remains challenging. Nanopore-based long-read sequencing enables a comprehensive detection of FA variants, but a unified bioinformatic analysis p...

Polygenic risk scores (PRSs) have emerged as a valuable tool for genetic risk prediction and stratification in human diseases. Over the past decade, extensive methodological efforts have focused on improving the predictive power of PRS, leading to the development of numerous methods for PRS construction. Benchmarking these various methods thus becomes an essential task that is crucial for guiding future PRS applications. While studies have benchmarked subsets of these methods on specific phenoty...

Low-frequency variants (LFVs), defined by minor allele frequencies (MAF) of 1-5%, occupy the gap between common and rare variants in both frequency and effect size. The conventional genome-wide association study (GWAS) significance threshold (5x10-) is overly conservative for LFVs, which account for more than 25% of variants in GWAS. This limitation may obscure meaningful associations in highly heritable yet genetically complex disorders such as autism spectrum disorder (ASD). We hypothesize tha...

BackgroundAmiodarone is a widely used antiarrhythmic which frequently induces thyroid dysfunction, including both amiodarone-induced hypothyroidism (AIH) and thyrotoxicosis (AIT). Whether genetic factors contribute to these adverse drug reactions is unknown. In this study, we aimed to identify genetic variants that influence the risk of amiodarone-induced thyroid dysfunction and to evaluate their potential to support genotype-guided risk screening. MethodsThis pharmacogenetic study comprised tw...

IntroductionFibrosis can affect organs throughout the body and is present in a wide range of diseases. Recent research has suggested that there could be shared biological mechanisms that lead to fibrosis in different organs. MethodsWe performed genome-wide association studies using UK Biobank for fibrosis in 12 different organ-systems and meta-analysed results with previously published studies of fibrotic diseases. We considered genetic associations that colocalised across [≥]3 organs as tho...

Polygenic scores (PGS) show promise for disease risk stratification but suffer from limited portability across populations. American Indians face a disproportionate burden of cardiovascular disease yet remain significantly underrepresented in genomic research, limiting equitable access to precision medicine. Here, we evaluate whether integrating specific lifestyle and clinical context variables with PGS enhances risk prediction for cardiometabolic traits in 424,622 European from UK Biobank (UKB)...