About

Daniel J Rader, MD, is the Seymour Gray Professor of Molecular Medicine at the University of Pennsylvania's Perelman School of Medicine. He serves as the Director of the Penn Medicine BioBank and is the Associate Director of the Institute for Translational Medicine and Therapeutics. Dr. Rader is also the Chief of the Division of Translational Medicine and Human Genetics in the Department of Medicine and the Chair of the Department of Genetics. His research expertise focuses on molecular medicine, with particular interests in genetics, genomics, and translational medicine. He is involved in various academic departments and centers, contributing to the advancement of biomedical research and personalized medicine.

Research topics

• Biology
• Genetics
• Medicine
• Internal medicine
• Evolutionary biology
• Computational biology
• Endocrinology
• Computer Science
• Pathology
• Cell biology
• Virology
• Cardiology
• Bioinformatics
• Psychiatry
• Cancer research
• Demography
• Surgery
• Immunology
• Audiology
• Environmental health
• Data science
• Clinical psychology

Selected publications

• Population-scale repeat expansions elucidate disease risk and brain atrophy

  Nature · 2026-04-08 · 1 citations

  articleOpen access

  Pathogenic expansions of short tandem repeats (STRs) cause over 70 neurological diseases1–3. Here we performed a population-scale survey of pathogenic repeat expansions by analysing repeat length in 37 disease-associated STR loci in a diverse set of 1,020,833 samples using short-read sequencing whole-exome and whole-genome data. Consistent with previous findings, we found that the frequency of pathogenic repeats is higher than the prevalence of corresponding diseases for most loci4,5. Associations of repeat length with 7,671 binary traits captured known locus–trait associations, including HTT and Huntington’s disease, DMPK and myotonic disorders and C9orf72 and motor neuron disease, among others. Finally, we found that, even before disease diagnosis, repeat expansions in several loci strongly associate with increased levels of neurofilament light chain (NfL) and a loss of brain volume in specific disease-associated regions. For example, carriers of HTT expansions exhibited a 22.1% loss of putamen volume, and carriers of CACNA1A expansions showed a 24.6% loss of cerebellar volume. These observations suggest that both decreased brain volumes and increased NfL levels occur earlier than disease diagnosis. This study demonstrates the use of characterizing repeat expansions from short-read sequencing data in diverse population-scale cohorts and its application to epidemiology and clinical biomarker development. Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

  PublisherOA PDFDOI

• Proteomic risk score for early prediction of kidney disease progression in individuals with APOL1 high-risk genotypes

  Nature Medicine · 2026-04-15

  articleOpen access

  Abstract Individuals of African ancestry carrying APOL1 (apolipoprotein L1) high-risk genotypes face a markedly increased risk of kidney failure, yet tools to identify those individuals likely to progress to chronic kidney disease are lacking. Here we profiled plasma proteomes of 851 Penn Medicine BioBank participants of African ancestry (285 males and 566 females) with APOL1 high-risk genotypes and preserved estimated glomerular filtration rate (eGFR) (≥60 ml min −1 1.73 m −2 ). Using elastic net Cox regression adjusted for age, sex, eGFR and albuminuria, we derived a nine-protein APOL1 Proteomic Risk Score (APRS) that predicts a composite outcome of ≥40% eGFR decline, kidney failure or death. APRS achieved a time-dependent area under the receiver operating characteristic curve (tAUC) of 86.5%, outperforming the Kidney Failure Risk Equation (66.1%) and polygenic risk scores, with 10-year event rates of 62.5% versus 3.3% across risk quintiles. External validation in Atherosclerosis Risk in Communities and UK Biobank cohorts confirmed robust accuracy (tAUC 82–85%) and consistent performance across demographic and clinical subgroups. Plasma levels of APRS component proteins correlated with kidney tissue fibrosis and tubular injury pathways, indicating strong biological plausibility. By enabling early and accurate prediction of disease progression in APOL1 high-risk individuals, APRS bridges the gap between genetic susceptibility and clinical translation. This scalable and biologically informed approach provides a precision medicine framework for early intervention and may accelerate development of APOL1-targeted therapies to reduce kidney disease disparities.

  PublisherDOI

• Lipoprotein(a) Is Associated With Increased Risk of Abdominal Aortic Aneurysm

  JACC Basic to Translational Science · 2026-01-06 · 1 citations

  articleOpen access

  Lp(a) is a genetically determined lipoprotein targeted by emerging therapies. In a UK Biobank analysis (1,026 abdominal aortic aneurysm [AAA] cases, 469,989 controls), elevated Lp(a) was associated with increased risk of AAA, including at clinically relevant thresholds while controlling for traditional risk factors, including ApoB. Multivariable Mendelian randomization confirmed a causal relationship between lipoprotein(a) [Lp(a)] and AAA independent of apolipoprotein B. These findings support Lp(a) as a modifiable risk factor and potential therapeutic target for AAA, a condition with limited medical treatment options. AAA should be considered as an outcome in future clinical trials of Lp(a)-lowering therapies.

  PublisherDOI

• Response by Daugherty et al to Letter Regarding Article, “Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies

  UNC Libraries · 2026-03-20

  articleOpen access

  In Response: The <em>ATVB</em> editors appreciate the comments of Ramirez and Hibbert on the recently published article &ldquo;Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies: A Statement From the Arteriosclerosis, Thrombosis, and Vascular Biology Council.&rdquo; They provide distinctive insight into the rationale of the focus that is needed to systematically modify the scientific literature in addressing important issues of defining the role of sex in vascular pathologies

  PublisherDOI

• Abstract 4362033: <i>APOH</i> plays a distinct role in lipid trait dysregulation and increased CVD risk

  Circulation · 2025-11-03

  articleSenior author

  Background: Variants at the APOH genomic locus have been associated with lipid traits, Lp(a), coagulation traits, coronary artery disease, and fatty liver disease. The mechanisms by which the ApoH protein influences these cardiometabolic phenotypes are not understood. An APOH missense variant C325G (rs1801689) has a minor allele frequency of 2.8% and is predicted to impact protein structure, making it a potential genetic tool for understanding ApoH biology. Hypothesis: We hypothesize that the association of APOH C325G with clinical phenotypes and circulating proteins and metabolites will provide new insights into the relationship between APOH and cardiometabolic traits. Methods: We accessed internal data from the Penn Medicine BioBank (PMBB) and publicly available data from the UK Biobank, the Million Veteran Program, and the All of Us cohort for these analyses. In addition, siRNA was used to knock down APOH in HuH-7 hepatocytes. Results: PheWAS of APOH C325G in the PMBB identified association with a number of cardiometabolic conditions, several of which were replicated in the other cohorts. Analyses of lab data indicated that APOH C325G was associated with lower triglyceride (TG) levels and higher LDL-C, apoB, and Lp(a) levels (p &lt; 0.01). Analysis of NMR-derived plasma metabolites in UKB showed that APOH C325G is associated with highly significant reductions in the larger VLDL particle subclasses, increases in the small VLDL particle subclasses, and increases in all LDL subclasses. Analysis of UKB proteomic data revealed that APOH C325G is associated with significantly reduced plasma levels of the ApoH protein and changes in other circulating proteins that are related to lipid metabolism and cardiometabolic traits (p &lt; 5 x 10 -8 ). Mendelian randomization analysis suggested that genetically determined lower ApoH plasma levels causally decrease plasma TG levels (p &lt; 5 x 10 -8 ). Finally, siRNA silencing of APOH in human Huh7 cells led to reduced TG secretion (two-sample t-test, p &lt; 0.05). Conclusions: The APOH missense variant C325G is associated with reduced TGs, large VLDLs, and increased LDL, apoB, Lp(a), and cardiometabolic conditions. It may serve as a useful genetic tool to understand the biology of APOH . Silencing of APOH in hepatocytes reduces TG production. Recall-by-genotype deep phenotyping of APOH C325G carriers in the PMBB is underway.

  PublisherDOI

• Expanded Chromatin Accessibility Mapping Explains Genetic Variation Associated with Complex Traits in Liver

  medRxiv · 2025-09-15

  preprintOpen access

  Genome-wide association studies (GWAS) have identified thousands of loci associated with a variety of common, complex human traits. Recent efforts have focused on characterizing chromatin accessibility to discover regulatory elements that modify the expression of nearby genes, suggesting that trait associations are mediated through changes in gene regulation. Genetic variants associated with differences in chromatin accessibility, known as chromatin accessibility quantitative trait loci (caQTLs), are established contributors to gene expression differences, providing mechanistic hypotheses for signals identified by GWAS. Using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), we assessed chromatin accessibility in 189 diverse human liver samples, identifying over two million accessible chromatin regions enriched for gene regulatory features and, in 175 of these samples, over 14,000 caQTLs. Focusing subsequently on liver-relevant complex traits, we obtained publicly available blood lipids GWAS data and identified 157 loci where caQTLs, expression quantitative trait loci (eQTLs), and GWAS signals colocalized. This generated specific molecular hypotheses about regulatory elements, affected genes, and, in some cases, implicated transcription factors. Finally, we enumerated the set of blood lipid trait signals that lack an obvious proposed mechanism beyond catalogs of liver caQTLs and eQTLs. After integrating 10 multi-omic QTL regulatory mechanism datasets whilst considering limitations in statistical power, we found that approximately 20% of blood lipid GWAS signals lacked a statistical link to a proposed mechanism. Our results demonstrate the value of integrating multiple genomic datasets to improve understanding of GWAS signals, while emphasizing the need for additional experimental approaches to fully characterize complex trait associations.

  PublisherOA PDFDOI

• Contextualizing molecular and structural aging across human organs

  medRxiv · 2025-05-27

  preprintOpen access

  Organ-specific aging clocks have shown promise as predictors of disease risk and aging trajectories; however, the underlying biological mechanisms they reflect remain largely unexplored. Here, we use large-scale proteomic and imaging data to investigate the relationships among organ-specific and modality-specific aging clocks and to uncover the biological processes they represent. By estimating paired protein-based and imaging-based aging clocks across 8 major organs, we demonstrate that these omics and structural profiles exhibit distinct phenotypic and genetic signatures, each potentially quantifying different stages and playing complementary roles within a unified biological aging process. Furthermore, context-specific aging clocks from multiple organs often converge and jointly capture established biological and disease pathways. For example, 65.7% of the KEGG Alzheimer's disease pathway is enriched by at least one of 11 protein- and imaging-based aging clocks, with each clock representing different components of the pathway. These results underscore the importance of a pan-organ multi-modal perspective for quantifying the mechanisms underlying age-related diseases. Additionally, we identify modality-specific links between aging clocks and complex diseases and lifestyle factors. In summary, we uncover intricate relationships among molecular and structural aging clocks across human organs, providing novel insights into their context-specific roles in capturing consequences of aging biology and their implications for disease risk.

  PublisherOA PDFDOI

• Reporting Sex and Sex Differences in Preclinical Studies

  UNC Libraries · 2025-08-15

  articleOpen access

  ATVB publishes research work that advances scientific fields in a rigorous and reproducible manner. We have implemented multiple approaches to follow the National Institutes of Health guidelines for rigor and reproducibility. In 2013, ATVB developed a checklist in the peer review process to facilitate comments on multiple technical requirements, including the sex of animals used in preclinical studies. We have also emphasized the National Institutes of Health guidelines that encourage researchers to study both sexes in preclinical animal models. These include publishing a review entitled &ldquo;Sex Differences in the Development of Cardiovascular Diseases&rdquo; and an ATVB Council statement to encourage authors to consider sex differences in designing and reporting experimental arterial pathology studies that detail the mode by which ATVB complies with the National Institutes of Health guidelines. The journal appointed a technical review editor, Dr Hong Lu, who assumed the role in September 2017 to assess the many elements required for adherence to the National Institutes of Health guidelines. These include issues such as the rigor of statistical analyses and animal background strain, age, and sex. The designation of sex of origin in studies of primary cells derived from cell culture is not as common as it is in animal studies. This is probably because of the unproven assumption that the lack of the hormonal environment in cell culture eliminates the need for designation of sex. However, because the differences of X and Y sex chromosomes and possibly sex-related differences in genomic imprinting are preserved in cultured cells, these cells could theoretically retain the ability to respond in a sex-dependent manner. Therefore, we also encourage and will monitor the reporting of sex in primary cell isolation and culture.

  PublisherDOI

• Targeting triglyceride-rich lipoproteins in cardiovascular disease

  Nature Medicine · 2025-07-24 · 1 citations

  articleSenior author
  PublisherDOI

• Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

  UNC Libraries · 2025-09-07

  articleOpen access
  PublisherDOI

Recent grants

• NIH Grant P01HL059407

  NIH · $37.7M · 2021

• Trib1 regulation of hepatic lipid metabolism and atherogenesis

  NIH · $1.6M · 2016–2021

• NIH Grant R37HL055323

  NIH · $4.0M · 2019

• NIH Grant P50HL070128

  NIH · $16.7M · 2007

• NIH Grant RC1TW008485

  NIH · $500k · 2011

Frequent coauthors

• Muredach P. Reilly

  Columbia University Irving Medical Center

  1974 shared

• Nilesh J. Samani

  Glenfield Hospital

  1510 shared

• Ruth McPherson

  University of Ottawa

  1490 shared

• John C. Chambers

  University of Cambridge

  1485 shared

• Jaspal S. Kooner

  Imperial College London

  1481 shared

• Ruth J. F. Loos

  Novo Nordisk (United States)

  1473 shared

• Håkon Håkonarson

  University of Pennsylvania

  1449 shared

• Nicholas J. Wareham

  MRC Epidemiology Unit

  1431 shared

Education

• B.A.

  Lehigh University

  1981

• M.D.

  Medical College of Pennsylvania

  1984

Awards & honors

• Seymour Gray Professor of Molecular Medicine
• Director, Penn Medicine BioBank
• Associate Director, Institute for Translational Medicine and…
• Chief, Division of Translational Medicine and Human Genetics…
• Chair, Department of Genetics