About

Ani W. Manichaikul is an Associate Professor in the Department of Genome Sciences at the University of Virginia School of Medicine. She holds a PhD from Johns Hopkins University. Her research focuses on statistical genetics and genetic epidemiology, with particular emphasis on the analysis of genome-wide association studies in multi-ethnic cohort studies, gene-based analysis of rare variants, quantitative trait mapping in experimental crosses, and translational research bridging mouse and human studies. She is actively involved in genome-wide association analysis of cardiovascular and pulmonary phenotypes through the Multi-Ethnic Study of Atherosclerosis (MESA). Her work includes post-GWAS research such as gene-environment interaction studies, fine mapping, and candidate gene investigations conducted in collaboration with experts in animal models and in vitro studies of genetic pathways. Additionally, she works on integrative 'omics' approaches, combining genomic, transcriptomic, proteomic, and other high-dimensional data sets from projects like NHLBI TOPMed and GTEx to identify causal genes and pathways influencing diseases.

Research topics

• Biology
• Genetics
• Evolutionary biology
• Computational biology
• Medicine
• Environmental health
• Bioinformatics
• Computer Science
• Demography
• Internal medicine
• Surgery
• Endocrinology

Selected publications

• Polygenic risk score for type 2 diabetes shows context-dependent effects across populations

  UNC Libraries · 2025-11-07

  articleOpen access1st authorCorresponding
  PublisherDOI

• Associations of interstitial lung disease subtype and CT pattern with lung function and survival

  Thorax · 2025-06-08 · 7 citations

  articleOpen access

  BACKGROUND: Prior work suggests different interstitial lung diseases (ILDs) that share the radiological usual interstitial pneumonia (UIP) pattern have an overall worse prognosis. However, epidemiological data with longitudinal sampling and replication remains lacking. METHODS: Data was used from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=932) and a meta-cohort of ILD research studies (n=1579). Linear mixed-effects models and Cox proportional hazard models were used to determine forced vital capacity (FVC) slopes and 5-year transplant-free survival, respectively, by ILD diagnosis and UIP radiological pattern. Secondarily, we examined FVC and survival by diagnosis and radiological fibrosis quantified by data-driven texture analysis (DTA) in the PFF-PR. Models were adjusted for age, sex, smoking and antifibrotic and immunosuppression medication use. RESULTS: The proportions of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease (CTD)-ILD were the following for PFF-PR (70%, 11%, 19%) and meta-cohort (21%, 32%, 47%). In the PFF-PR, CTD-ILD with UIP CT pattern was associated with slower FVC decline (-34.4 mL/year) compared with IPF (-158.4 mL/year) and longer transplant-free survival (HR 0.50, 95% CI 0.29 to 0.85). This was replicated in the meta cohort for FVC (-53.1 vs -185.9 mL/year, p<0.0001) and survival (HR 0.38, 95% CI 0.27 to 0.53). A similar pattern was seen using DTA to objectively categorise patients into higher and lower radiological fibrosis. Between IPF and FHP-UIP, FVC decline was not significantly different in the PFF-PR (-203.4 vs -158.4 mL/year, p=0.58) and meta-cohort (-124.0 vs -185.9 mL/year, p=0.25). CONCLUSIONS: Even in the presence of a UIP CT pattern, there may still be differences in lung function over time and survival, particularly for CTD-ILD.

  PublisherOA PDFDOI

• Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids

  Translational Psychiatry · 2025-06-19

  reviewOpen access

  Abstract Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations ( P &lt; 10 −5 ) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings ( P &lt; 5 × 10 −8 ) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 ( MACROD2 ), rs59808825 ( GRAMD1B ), and rs11702544 ( RRP1B ). Notably, one of the genes in identified loci ( RRP1B ) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.

  PublisherOA PDFDOI

• Table S1 from Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility

  2025-11-26

  articleOpen access

  &lt;p&gt;Table S1. Summary statistics of 7 cancer types tested with ARIC plasma proteome models, FDR&lt;0.05, with single- and multi-variant COLOC results.&lt;/p&gt;

  PublisherDOI

• Table S4 from Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility

  2025-11-26

  articleOpen access

  &lt;p&gt;Table S4. PWAS meta-FDR&lt;0.05 proteins with endometrial cancer associations.&lt;/p&gt;

  PublisherDOI

• D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study

  UNC Libraries · 2025-09-10

  articleOpen access

  OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near <em>F3</em> was associated with higher D-dimer (rs2022030, &beta;=0.284, <em>P</em>=3.24&times;10^-11). The rs2022030 effect size was nearly 3&times; larger among women (&beta;=0.373, <em>P</em>=9.06&times;10^-13) than among men (&beta;=0.135, <em>P</em>=0.06; <em>P</em> interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10&thinsp;808 multiethnic men and women (<em>P</em> interaction =0.001). Finally, the African ancestral sickle cell variant (<em>HBB</em> rs334) was significantly associated with higher D-dimer in JHS (&beta;=0.507, <em>P</em>=1.41&times;10^-14), and this association was successfully replicated in 1933 AAs (<em>P</em>=2.3&times;10^-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the <em>F3</em> and <em>HBB</em> loci contribute to the higher levels of D-dimer among women and AAs.

  PublisherDOI

• Multi-Trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins

  medRxiv · 2025-08-26

  preprintOpen access

  ABSTRACT Objectives. To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Design Prospective cohort studies. Setting. Genetic Epidemiology of COPD (COPDGene; 2007-present), Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE; 2005-2008), Mass General Brigham Biobank (MGBB; 2010-present), All of Us (2016-present), and UK Biobank (UKB; 2006-present). Participants. 6,647 non-Hispanic White (NHW) and 2,466 African American (AA) participants from COPDGene; 1,858 participants from ECLIPSE; 118,566 from All of Us; 15,142 from MGBB with genetic data. 5,173 COPDGene and 5,012 UKB participants with proteomic data. Main outcome measures. COPD status (GOLD 2-4 vs. GOLD 0) and COPD exacerbation frequency. Results. PRSmix+, a multi-trait PRS framework, selected 7 traits for a composite PRS (PRS multi ). In multivariable models, PRS multi was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRS multi outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions. Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764 ; ECLIPSE: NCT00292552 .

  PublisherOA PDFDOI

• Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study

  Respiratory Research · 2025-07-04 · 1 citations

  articleOpen access

  Abstract Background Pulmonary emphysema occurs frequently in older adults, often without airflow limitation. Its presence predicts symptoms, respiratory hospitalizations and deaths, and all-cause mortality. Proteomics may provide further insights into emphysema pathogenesis and inform therapeutic targets. Objective We performed a proteomic discovery analysis of percent emphysema on computed tomography (CT) in a population-based, multiethnic sample from the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Replication was performed in two chronic obstructive pulmonary disease (COPD)-based studies, the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) and the Genetic Epidemiology of COPD (COPDGene) Study. Methods MESA recruited participants from the general population in 2000–02. The MESA Lung Study performed full-lung CT scans in 2010–12. Percent emphysema was defined as the percentage of lung voxels &lt; -950 Hounsfield units. Over 7,200 plasma aptamers were measured via SomaScan. Cross-sectional linear and least absolute shrinkage and selection operator (LASSO) regression models were adjusted for demographics, anthropometrics, smoking, renal function, and scanner parameters. Statistical significance was defined as a false discovery rate p-value &lt; 0.05. Gene Ontology (GO)/Reactome enrichment analyses were performed. LASSO-selected proteins’ predictive performance was evaluated. Results Among 2,504 participants in the MESA Lung Study, mean age was 69.4 years, 1,291 had ever smoked, and median percent emphysema-like lung was 1.4%. In total, 1,234 aptamers were significantly associated with percent emphysema in the MESA Lung Study, and 35 replicated in the SPIROMICS and COPDGene Studies. Novel associations included protein family with sequence similarity (FAM) 177A1, syntenin-2, ubiquitin carboxyl-terminal hydrolase 25, and uncharacterized protein C20orf173. Previously identified emphysema-associated proteins included soluble advanced glycosylation end product-specific receptor (sRAGE), protein S100-A12, high mobility group protein B1, and roundabout homolog 2. Enrichment analyses identified 40 GO biological processes, including chemokine production and regulation and cell–cell adhesion and regulation, and two Reactome pathways, including RAGE signaling. In tenfold cross-validation, novel proteins were largely retained by LASSO (R 2 = 5.4%), improved overall model performance (R 2 = 24.8%), and uniquely explained greater variance in percent emphysema. Conclusions This analysis in a general population sample identified novel and previously characterized proteins whose functional roles were validated by GO/Reactome enriched pathways, offering new insights into emphysema pathophysiology and therapeutics.

  PublisherOA PDFDOI

• Mosaic Loss of Y chromosome associates with lung function, emphysema and epigenetic aging

  medRxiv · 2025-07-30 · 1 citations

  preprintOpen access

  Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mutation, but its relationship with pulmonary health remains undercharacterized. Leveraging mLOY assessment in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in Trans-Omics for Precision Medicine program, we investigated its association with respiratory outcomes and epigenetic aging. Cross-sectionally, mLOY was associated with airflow obstruction with prevalence increasing with age, particularly in men with a former smoking history. Longitudinally, mLOY associated with lung function decline. Notably, mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Prospectively, in participants with normal lung function at baseline, mLOY was associated with lower future lung function and faster pace of epigenetic aging. These associations remained robust after adjusting for clonal hematopoiesis and telomere length. Collectively, these findings position mLOY as a potential biomarker of respiratory aging and obstructive lung disease.

  PublisherOA PDFDOI

• Polygenic risk score for type 2 diabetes shows context-dependent effects across populations

  Nature Communications · 2025-10-01 · 4 citations

  articleOpen access

  Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.

  PublisherOA PDFDOI

Recent grants

• Genomic and Transcriptomic Analysis of Emphysema and Subclinical ILD

  NIH · $2.0M · 2016–2023

Frequent coauthors

• Philip St. John

  University of Manitoba

  1568 shared

• Natalia S. Rost

  Massachusetts General Hospital

  1477 shared

• Hugh S. Markus

  University of Cambridge

  1473 shared

• Danish Saleheen

  935 shared

• Jing Liu

  Central South University

  905 shared

• Philippe Amouyel

  Université de Lille

  842 shared

• Vincent Thijs

  University of Melbourne

  840 shared

• Stéphanie Debette

  Université de Bordeaux

  835 shared