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. ...

Most current GWAS-eQTL approaches prioritize genes whose mediating effects on complex traits act through cis-regulation, while trans-acting genes remain largely underexplored. Recent perturbational screening technology provides a novel approach to quantifying trans-effects between gene pairs, but its integration with GWAS data remains largely unexamined. We introduce Mr. PEG, a novel framework that integrates perturbational screens, eQTL, and GWAS summary data to identify mediating genes of comp...

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...

Early failure of antihypertensive medication treatment affects one in four patients, but the underlying mechanisms are poorly understood. We aimed to identify genetic determinants of antihypertensive treatment failure within the first year. Using longitudinal medication data from >400,000 genotyped antihypertensive medication users across 3 cohorts (FinnGen, the UK Biobank, and the Estonian Biobank), we classified short-term antihypertensive use trajectories as Continue, Switch, or Discontinue....

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.

Genetic studies have largely focused on homogeneous populations, limiting our understanding of the genetic architecture of complex traits in admixed individuals. The advent of diverse biobanks like the All of Us Research Program (AoU) and computationally efficient local ancestry inference (LAI) methods now enable admixture mapping (ADM) at biobank scale. Here, we used two orthogonal LAI methods (GNOMIX and FLARE) to characterize local ancestry in the entire AoU v7.1 cohort (n=230,019). We then u...

Understanding genetic architectures of disease is fundamental to partitioning heritability, polygenic risk prediction, and statistical fine-mapping. Genetic architectures of disease in European populations have been shown to depend on European minor allele frequency (MAF): SNPs with lower MAF have larger per-allele effects, due to the action of negative selection. However, we hypothesized that African MAF (defined using African-ancestry segments in African Americans), which is not distorted by t...

Metabolite genome-wide association studies have identified hundreds of variants, many of which play intermediate roles linking genotype and phenotype with downstream diseases. However, the majority of metabolite GWAS have been published in self-identified Non-Hispanic White (NHW) populations, greatly limiting inference to other populations. Here we report the results of a GWAS of 7,522 untargeted metabolite peaks in 2,183 participants of the Coronary Artery Risk Development in Young Adults (CARD...

BackgroundClinical interpretation of LDLR, APOB, and PCSK9 variants is essential for diagnosing familial hypercholesterolemia (FH), yet manual evidence curation is labor-intensive and prone to variability. MethodsWe developed a web-based platform (https://fh-interpret.shinyapps.io/beta/) to automate the synthesis of multi-dimensional evidence. The tool integrates population frequencies (gnomAD), phenotype associations (UK Biobank), AI-based pathogenicity scores (AlphaMissense), high-throughput ...

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) are conventionally conducted in cohorts spanning a wide age-range. These studies typically assume that genetic associations are constant across different ages. Some traits, however, may have age-varying genetic associations. This has implications for the interpretation of genetic effects derived in downstream applications, such as Mendelian randomization (MR) analyses. In this study we conducted a series of age-stratified GWAS on individuals aged 40-69 year...

BackgroundThe 9p21.3 locus was the first genome-wide significant signal for coronary artery disease (CAD) and replicates across multiple non-African populations, yet is absent in African ancestry cohorts. We hypothesized that ancestry-specific linkage disequilibrium (LD) and haplotype structure, rather than allele frequency or power alone, explain this discrepancy. MethodsWe analyzed multi-ancestry data from European, East Asian, South Asian, Middle Eastern, African, and Admixed American groups...

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...

BackgroundInflammatory Bowel Disease (IBD) is characterized by chronic intestinal inflammation and is associated with both altered gut microbiome composition and host genetic risk. Both host genetic variants and the gut microbiome can affect host gene expression in the colon; however, it remains unclear whether interactions between the two (genotype x microbiome, GxM) shape intestinal gene regulation in humans and their contribution to IBD risk. MethodsWe analyzed publicly available data for 86...