Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) has emerged as one of the leading cardiometabolic diseases. Friend of GATA2 (FOG2) is a transcriptional co-regulator that has been shown to regulate hepatic lipid metabolism and accumulation. Using meta-analysis from several different biobank datasets, we identified a coding variant of FOG2 (rs28374544, A1969G, S657G) predominantly found in individuals of African ancestry (minor allele frequency~20%), which is associated with liver failure/cirrhosis phenotype and liver injury. To gain insight into potential pathways associated with this variant, we interrogated a previously published genomics dataset of 38 human induced pluripotent stem cell (iPSCs) lines differentiated into hepatocytes (iHeps). Using Differential Gene Expression Analysis and Gene Set Enrichment Analysis, we identified the mTORC1 pathway as differentially regulated between iHeps from individuals with and without the variant. Transient lipid-based transfections were performed on the human hepatoma cell line (Huh7) using wild-type FOG2 and FOG2^S657G and demonstrated that FOG2S^657G increased mTORC1 signaling, de novo lipogenesis, and cellular triglyceride synthesis and mass. In addition, we observed a significant downregulation of oxidative phosphorylation in FOG2^S657G cells in fatty acid-loaded cells but not untreated cells, suggesting that FOG2^S657G may also reduce fatty acid to promote lipid accumulation. Taken together, our multi-pronged approach suggests a model whereby the FOG2^S657G may promote MAFLD through mTORC1 activation, increased de novo lipogenesis, and lipid accumulation. Our results provide insights into the molecular mechanisms by which FOG2^S657G may affect the complex molecular landscape underlying MAFLD.

Background: Coronary Microvascular Disease (CMVD) contributes to the large burden of ischemic heart disease, and there is a need for mechanistic insight and targeted therapies. Perfusion cardiac PET allows for the quantitative assessment of myocardial blood flow reserve (MBFR), which reflects coronary microvascular function. Here we perform the first genome-wide association study (GWAS) using cardiac PET MBFR as a measure of CMVD. Methods: MBFR was measured using Rubidium-82 cardiac perfusion PET obtained as part of routine clinical care. GWAS was performed using datasets from individuals genetically similar to EUR and AFR populations within the Penn Medicine Biobank (PMBB), followed by comprehensive downstream analyses including fine-mapping and transcriptome-wide association study (TWAS). We used gene set enrichment analysis (GSEA) to investigate associated molecular pathways and TIMI Frame Count to validate the association between the identified variants and CMVD. Finally, we assessed associations between key loci and proteins in the NF- к B pathway in the UK Biobank Pharma Proteome pGWAS dataset and with individual-level OLINK proteomic data in PMBB. Results: Among 241 targeted CAD loci, 17 in the AFR, 14 in the EUR, and 16 shared across both populations were significant (p<2e-04). A subsequent discovery GWAS identified 1 genome-wide significant association. Fine mapping identified a signal near ERC1 . Sex-stratified TWAS identified C APN2 in females and PLA2G5 in males. GSEA identified inflammatory and NF- к B pathways as the top pathways associated with these loci, and TIMI frame count confirmed that these loci were protective. Using proteomic data, we found IL-1B was increased in individuals with CAPN2 variant, and NEMO was differentially regulated by CAPN2 and ERC1 variants. Conclusions: Our study identified variants associated with MBFR in populations of EUR and AFR ancestry and converged on two independent loci that are near genes known to regulate the NF- к B pathway. Our multi-omic analyses support a role for NF- к B pathway in CMVD.

Summary: Electronic health record (EHR)-linked biobanks generate unprecedented genomic and phenotypic datasets, but their scientific utility is constrained by data fragmentation across institutional silos and incompatible computing infrastructures, forcing researchers to rewrite ad-hoc scripts for each new environment. We present the PMBB Geno-Pheno Toolkit, a suite of modular Nextflow pipelines for biobank-scale association analyses. This note focuses on the toolkit’s SAIGE family of pipelines — supporting genome-wide (GWAS), exome-wide (ExWAS), and phenome-wide (PheWAS) association testing — together with the companion GWAMA and ExWAS meta-analysis pipelines that enable cross-biobank replication. All components are containerized (Docker/Apptainer) and orchestrated with Nextflow, allowing the same workflows to run unmodified on local HPC clusters, cloud platforms, and the All of Us Research Workbench. Complementary toolkit pipelines for PLINK-based GWAS, polygenic scoring, LD-based clumping, and phenotype harmonization are also available and briefly noted. Availability: The PMBB Geno-Pheno Toolkit is freely available at https://github.com/PMBB-Informatics-and-Genomics/pmbb-geno-pheno-toolkit under MIT open-source license.

BACKGROUND: The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD. METHODS: We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling. RESULTS: We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2 ^S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate. CONCLUSIONS: A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.

Background: Polycystic ovary syndrome (PCOS), recently renamed as polyendocrine metabolic ovarian syndrome (PMOS), is a prevalent endocrine disorder in women, often accompanied by various symptoms, including significant pain, such as dysmenorrhea, abdominal, and pelvic pain, which remains underexplored. Methods: This retrospective study examines electronic health records (EHR) data to assess the prevalence of pain in women with PMOS. Conducted in January 2026, using data from 120 Health Care Organizations within the TriNetX Global Network, the study involved 103,675,738 women from diverse racial backgrounds. The analysis focused on the prevalence of pain among women with PMOS, both overall and in those prescribed PMOS-related medications. Relative risk ratios (RR) were calculated for future health outcomes and stratified by self-reported race. Results: The study found that 20.67% of women with PMOS experienced pain, with the highest prevalence among Black or African American (32.70%) and White (30.78%) populations. Both the PMOS and PMOS and Pain cohorts exhibited increased RR for various health conditions, with significant differences noted across racial groups for infertility, ovarian cysts, obesity, and respiratory diseases. Additionally, women with PMOS who were treated with PMOS-related medications showed a decrease in pain diagnoses following treatment. Conclusions: This study highlights the critical need to address pain in the diagnosis and management of PMOS due to its significant impact on patient health outcomes. Funding: Tess Cherlin was supported by NIH | National Institute of General Medical Sciences (NIGMS) (grant # K12GM081259 (HHS)).

Small non-coding RNAs (sncRNAs) have garnered considerable attention in recent years, following accumulating evidence of their critical roles in many cellular processes. Among sncRNAs, microRNAs (miRNAs) and their isoforms (isomiRs), tRNA-derived fragments (tRFs), rRNA-derived fragments (rRFs), and Y RNA-derived fragments (yRFs) account for more than 95% of all sncRNAs found in cells. Despite their critical regulatory roles, most sncRNAs remain uncharacterized because their functionalization is a lengthy and challenging undertaking. Knowing an sncRNA’s abundance helps prioritize among the various choices, while knowing where it localizes in the cell greatly limits the number and identity of its potential targets and helps understand its function. Most studies to date have assumed that the subcellular localization of the various sncRNA classes is understood and remains unchanged across cell types. However, as we have recently demonstrated, the subcellular distribution of sncRNAs follows complex patterns that depend on the sequence of the sncRNA, the presence or absence of post-transcriptionally added non-templated nucleotides, and the cell type. To determine the subcellular localization and abundance of sncRNAs and aid the design of targeted experimental studies of sncRNA function, we developed “Fraction-seq.” The method combines an experimental and an analytical component to remove cross-fraction contamination and reconstruct the true abundance of sncRNAs in each considered fraction. Fraction-seq can be applied to any adherent cells from any organism without modifications and can reconstruct the abundance of all categories of sncRNAs. Accompanying this detailed protocol is a newly developed port of the original SAS codes to the widely used R programming language. The codes and an example are freely available through our center’s GitHub page.