About

Yuk Yee Leung, PhD, is a Research Assistant Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the genetics and genomics of Alzheimer's disease and other neurodegenerative diseases, with particular expertise in non-coding variants, small RNA biomarkers, and translational bioinformatics. Dr. Leung's work involves the discovery of biomarkers, machine learning applications, and the exploration of molecular mechanisms underlying neurodegeneration. He holds a BEng in Medical Engineering and a PhD in Electrical and Electronic Engineering (Bioinformatics) from the University of Hong Kong. His contributions include developing genomic variant calling pipelines, creating databases of genetic findings for Alzheimer's disease, and advancing functional genomics data integration. Dr. Leung has authored numerous publications in high-impact journals, contributing significantly to the understanding of Alzheimer's disease genetics and bioinformatics.

Research topics

• Biology
• Medicine
• Genetics
• Gerontology
• Bioinformatics
• Internal medicine
• Neuroscience
• Psychiatry
• Psychology
• Pathology

Selected publications

• Genomic stewardship in Alzheimer’s disease: a decade of insights from the NIAGADS platform

  npj Dementia · 2026-03-09

  articleOpen access

  Fourteen years ago, Alzheimer’s disease (AD) genetics entered an era of exponential data growth, but the infrastructure to support and steward that data had yet to catch up. Large-scale genomic discovery demands more than storage; it requires coordination, ethical rigor, and a platform architecture that transforms raw data into shared knowledge. In response, the National Institute on Aging launched the Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), not simply to house genetic data for AD and AD-related dementias (ADRD), but to enable its responsible reuse. What began in 2012 as a repository has evolved into an integrated system for policy-aligned access, harmonized data production, and broad community engagement. A detailed overview of NIAGADS was recently published as a Perspective in Alzheimer’s & Dementia1. In this Commentary, we reflect on key lessons from building and operating NIAGADS at national scale, with the goal of informing the next generation of genomic platforms.

  PublisherOA PDFDOI

• Indian‐enriched genetic variants are associated with cognitive function

  Alzheimer s & Dementia · 2026-01-29

  articleOpen access

  INTRODUCTION: Little is known about genetic risk factors for dementia in South Asians. Examining genetic variants that occur at higher frequency in India compared to other ancestries (i.e., Indian enriched variants) may identify genetic associations with cognitive function that are potentially unique to the Indian population. METHODS: We examined whether 3.43 million variants enriched in India compared to European (EA), East Asian (EAS), and African (AFR) ancestries were associated with seven measures of cognitive function in 2680 older adults from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). RESULTS: Identified Indian-enriched variants were largely near loci previously associated with neuropsychiatric traits, N-acetyltaurine levels, educational attainment, and cardiovascular risk factors for dementia. Several variants near genes previously associated with intellectual disabilities and synaptic function exhibited sex-specific effects. DISCUSSION: Indian-enriched variants may play a significant role in cognitive function in South Asians living in India. HIGHLIGHTS: Some cognitive function-associated variants are unique to, or more common in, India. Implicated genes were in cardiovascular, neurocognitive, and inflammatory pathways. Some Indian-enriched genetic variants demonstrate sex-specific effects.

  PublisherOA PDFDOI

• Rare coding variants from ADSP R5 whole-genome sequencing implicate novel genes in Alzheimer’s disease

  Research Square · 2026-03-31

  preprintOpen access
  PublisherOA PDFDOI

• Comprehensive adjudication identifies 111 high-confidence loci for Alzheimer's disease and related dementias

  medRxiv · 2026-05-19

  articleOpen access1st authorCorresponding

  Background: The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality. Methods: Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci. Results: Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/. Conclusion: This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.

  PublisherOA PDFDOI

• A reference panel for linkage disequilibrium and genotype imputation using whole-genome sequencing data from 2,680 participants across India

  Human Genetics and Genomics Advances · 2026-02-07 · 1 citations

  articleOpen access

  India is the most populous country globally, yet genetic studies involving Indian individuals remain limited. The Indian population is composed of many founder groups and has a mixed genetic ancestry, including an ancestral component not observed anywhere outside of India. This presents a unique opportunity to uncover novel disease variants and develop tailored medical interventions. To facilitate genetic research in India, a crucial first step is to create a foundational resource that serves as a benchmark for future population studies and methods development. Thus, we constructed the largest and most nationally representative linkage disequilibrium (LD) and genotype imputation reference panels in India to date, using high-coverage whole-genome sequencing data of 2,680 participants from the Longitudinal Aging Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD). As an LD reference panel, LASI-DAD includes 69.5 million variants, representing 170% and 213% increases relative to the 1000 Genomes Project and TOP-LD South Asian panels, respectively. Besides serving as an LD lookup panel, LASI-DAD facilitates various statistical analyses relying on precise LD estimates. In polygenic risk score (PRS) analyses, LASI-DAD improved the PRS predictive performance by 2.1%-35.1% across traits and studies. As an imputation reference panel, LASI-DAD enhanced imputation accuracy, measured by the Pearson correlation between imputed and true genotypes, by 3%-101% (mean 38%) compared with the TOPMed panel and by 3%-73% (mean 27%) compared with the Genome Asia Pilot panel across different allele frequencies. The LASI-DAD reference panel is publicly available to benefit future studies.

  PublisherDOI

• Multi-ancestry exome-wide study identifies variants associated with Alzheimer's disease protection

  Journal of Alzheimer s Disease · 2025-12-22

  articleOpen access

  Background Previous whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted the need for larger samples. Objective Identify associations of rare coding variants with AD risk in a large-scale, multi-ancestry exome-wide. Methods We combined non-overlapping portions of the Alzheimer's Disease Sequencing Project (ADSP) WES (n = 18 717) and WGS (n = 35 014) datasets obtaining a sample (n = 34 202) including participants ages ≥ 60 from four genomic similarity clusters consistent with European ancestry (EA, 9 744 AD cases and 9 095 controls), African American (AA, 1 944 AD cases and 4 215 controls), Caribbean Hispanic (CH 2 344 AD cases and 3 465 controls), and Native American Hispanic (NAH 743 AD cases and 2 652 AD controls) populations. Association of AD with 253,421 bi-allelic variants with minor allele count ≥ 20 in the total sample and each population group was evaluated using GENESIS. Gene-based tests comprising predicted moderate and high-impact variants were performed using SAIGE. Results Novel study-wide significant associations (p < 1.97 × 10 −7 ) were identified with variants enriched among the Amish in BTBD8 (rs927193859, p = 1.58 x10 −10 ), LINGO1 (rs150289554, p = 8.60 × 10 −8 ), and KCNG2 (rs140218057, p = 1.77 × 10 −7 ) in the total sample. Population-specific analyses confirmed significant associations with APOE in all groups and detected an association in CH individuals with the PSEN1 missense mutation G206A (p = 3.07 × 10 −7 ), a variant that was previously linked to early-onset AD in Hispanics. Gene-based tests highlighted significant associations with LINGO1 (p = 2.75 × 10 −8 ), DYNLT4 (p = 2.80 × 10 −7 ), and ADCY4 (p = 7.43 × 10 −7 ). Conclusions We identified rare variants in novel genes which provide new insights into AD pathogenesis.

  PublisherOA PDFDOI

• NIAGADS: A data repository for Alzheimer's disease and related dementia genomics

  Alzheimer s & Dementia · 2025-06-01 · 3 citations

  articleOpen access

  The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is the National Institute on Aging-designated national data repository for human genetics research on Alzheimer's disease and related dementias (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis, including whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project and other genotype/phenotype data, encompassing 211,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a Federal Information Security Modernization Act moderate compliant cloud-based platform that fully supports the National Institutes of Health Genomic Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. As a one-stop access portal for Alzheimer's disease (AD) genetics, NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of AD. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a data repository for the storage of genetics and genomics data. NIAGADS houses data for Alzheimer's disease, related dementias, and healthy aging. NIAGADS offers open and qualified access data and knowledgebases to explore open access data. The Alzheimer's Disease Sequencing Project dataset is the largest Alzheimer's disease and related dementias joint called whole genome sequencing dataset (≈ 58,000 whole genomes).

  PublisherOA PDFDOI

• Integrated genomic analysis and CRISPRi implicates <i>EGFR</i> in Alzheimer’s disease risk

  medRxiv · 2025-06-26 · 1 citations

  preprintOpen access1st authorCorresponding

  Abstract Genome-wide association studies (GWAS) have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), but the pan-brain regional effects of these loci remain largely uncharacterized. To address this, we systematically analyzed all LOAD-associated regions reported by Bellenguez et al. using the FILER functional genomics catalog across 174 datasets, including enhancers, transcription factors, and quantitative trait loci. We identified 42 candidate causal variant-effector gene pairs and assessed their impact using enhancer-promoter interaction data, variant annotations, and brain cell-type-specific gene expression. Notably, the LOAD risk allele of rs74504435 at the SEC61G locus was computationally predicted to increase EGFR expression in LOAD related cell types: microglia, astrocytes, and neurons. Functional validation using promoter-focused Capture C, ATAC-seq, and CRISPR interference in the HMC3 human microglia cell line confirmed this regulatory relationship. Our findings reveal a microglial enhancer regulating EGFR in LOAD, suggesting EGFR inhibitors as a potential therapeutic avenue for the disease.

  PublisherOA PDFDOI

• Region-Based Analysis with Functional Annotation Identifies Genes Associated with Cognitive Function in South Asians from India

  Genes · 2025-05-27 · 2 citations

  articleOpen access

  Background/Objectives: The prevalence of dementia among South Asians across India is high among those who are 65 years and older, yet little is known about genetic risk factors for dementia in this population. Methods: Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis on the missense/loss-of-function (LoF) and brain-specific promoter/enhancer variants of 84 genes, previously associated with AD in European Ancestry (EA). These analyses were performed separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores), using the variant-Set Test for Association using Annotation infoRmation (STAAR). We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. Results: In the missense/LoF analysis, without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes were associated with at least one measure of cognitive function (FDR q &lt; 0.1). APOE was associated with four measures of cognitive function, PICALM was associated with HMSE score, and TSPOAP1 was associated with executive function. The most strongly associated variants in each gene were rs429358 (APOE ε4), rs779406084 (PICALM), and rs9913145 (TSPOAP1). Rs779406084 is a rare missense mutation that is enriched in LASI-DAD compared to EA (minor allele frequency = 0.075% vs. 0.0015%). Conclusions: Missense/LoF variants in some genes previously associated with AD in EA are associated with measures of cognitive function in South Asians from India. Analyzing genome sequence data allows the identification of potential novel causal variants enriched in South Asians.

  PublisherOA PDFDOI

• Clinical Features and Management of Odontogenic Keratocysts in Gorlin Goltz Syndrome

  International Journal of Oral and Maxillofacial Surgery · 2025-06-24

  article
  PublisherDOI

Frequent coauthors

• Li‐San Wang

  University of Pennsylvania

  105 shared

• Otto Valladares

  74 shared

• Adam C. Naj

  72 shared

• Gerard D. Schellenberg

  Computational Physics (United States)

  66 shared

• Margaret A. Pericak‐Vance

  Dr. John T. Macdonald Foundation

  61 shared

• Eden R. Martin

  University of Miami

  61 shared

• Jonathan L. Haines

  Case Western Reserve University

  57 shared

• Brian W. Kunkle

  University of Miami

  57 shared

Labs

• Pathology and Laboratory MedicinePI