About

Gerard D Schellenberg is a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. He holds a Ph.D. in Biochemistry with a minor in Cell Biology from the University of California at Riverside, obtained in 1978, and a B.S. in Biochemistry with a minor in Cell Biology from the same institution, earned in 1973. His department affiliation is with the Department of Pathology and Laboratory Medicine, and he is part of the Genomics and Computational Biology graduate group. His research focuses on genetic and neuropathological factors related to Alzheimer's disease and other dementias, contributing to the understanding of genetic variants, risk factors, and molecular mechanisms underlying neurodegenerative conditions.

Research topics

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

Selected publications

• Genome-wide association studies of Alzheimer’s disease and related disorders stratified by sex, onset age, and Apolipoprotein E genotype reveal novel risk loci in African Americans

  Alzheimer s Research & Therapy · 2025-07-24 · 1 citations

  articleOpen access

  Abstract Background Alzheimer’s disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE , the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses. Methods We generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE -ε4 carrier status in AA cohorts from MVP and the Alzheimer’s Disease Genetics Consortium (ADGC). Outcomes in MVP were AD and related dementias (ADRD; n = 4073 cases and 19,648 controls) and proxy dementia (i.e., reported dementia in a parent, n = 6216 cases and 21,566 controls) while ADGC analyses examined AD ( n = 2425 cases and 5069 controls). The proxy dementia GWASs were included in the sex-stratified meta-analysis corresponding to the sex of the affected parent. The top genes were tested for differential expression in AA brain tissue. Results In addition to the APOE region, genome-wide significant associations were observed in an intergenic region near the EPHA5 gene (rs141838133, p = 2.19 × 10 –8 ) in individuals with onset < 75 years, in GRIN3B near the known AD risk gene ABCA7 (rs115882880, p = 3.83 × 10 –8 ) in females, and near TSPEAR (rs139130053, p = 4.27 × 10 –8 ) in APOE -ε4 non-carriers. EPHA5 regulates glucose homeostasis, and ephrin receptors modify the strength of existing synapses in the brain and in pancreatic islets. It is unclear whether GRIN3B represents a locus distinct from ABCA7 . Rs115882880 was a significant eQTL for GRIN3B but not ABCA7 in AA brain samples. TSPEAR regulates Notch signaling but has not been linked to neuronal function. Conclusions Age, sex, and APOE -stratified analyses of dementia in AA participants from two cohorts revealed potential new associations. Stratified analyses may yield critical information about the genetic heterogeneity underlying dementia risk and lead to advances in precision medicine.

  PublisherOA PDFDOI

• Copy Number Variation and Haplotype Analysis of <scp>17q21.31</scp> Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

  Movement Disorders · 2025-03-08 · 1 citations

  articleOpen access

  BACKGROUND: The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP). OBJECTIVE: To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP. METHODS: Utilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP. RESULTS: We found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells. CONCLUSIONS: The copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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• Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

  Molecular Neurodegeneration · 2025-12-01 · 1 citations

  articleOpen access

  Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

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• Genome‐wide association studies of TDP‐43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B

  Alzheimer s & Dementia · 2025-11-01 · 2 citations

  articleOpen access

  INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions. METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region. RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy. DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy. HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP-43.

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• Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures

  medRxiv · 2025-02-13 · 1 citations

  preprintOpen access

  Abstract Background Genome-wide association studies (GWAS) have identified over 1,000 blood pressure (BP) loci and over 80 loci for Alzheimer’s disease (AD). Considering BP is an AD risk factor, identifying pleiotropy in BP and cognitive performance measures may indicate mechanistic links between BP and AD. Methods Genome-wide scans for pleiotropy in BP variables—systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP)—and co-calibrated scores for cognitive domains (executive function, language, and memory) were performed using generalized linear mixed models and 116,075 longitudinal measures from 25,726 participants of clinic-based and prospective cohorts. GWAS was conducted using PLACO to estimate each SNP’s main effect and interaction with age, and their joint effect on pleiotropy. Effects of genome-wide significant (GWS) pleiotropic SNPs on cognition as direct or mediated through BP were evaluated using Mendelian randomization. Potential contribution of genes in top-ranked pleiotropic loci to cognitive resilience was assessed by comparing their expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms. Results Pleiotropy GWAS identified GWS associations with APOE and 11 novel loci. In the total sample, pleiotropy was identified for SBP and language with JPH2 ( P Joint =6.09×10 -9 ) and GATA3 ( P G×Age =1.42×10 -8 ), MAP and executive function with PAX2 ( P G×Age =4.22×10 -8 ), MAP and language with LOC105371656 ( P G×Age =1.75×10 -8 ), and DBP and language with SUFU ( P G =2.10×10 -8 ). In prospective cohorts, pleiotropy was found for SBP and language with RTN4 ( P G×Age =1.49×10 -8 ), DBP and executive function with ULK2 ( P Joint =2.85×10 -8 ), PP and memory with SORBS2 ( P G =2.33×10 -8 ), and DBP and memory with LOC100128993 ( P G×Age =2.81×10 -8 ). In clinic-based cohorts, pleiotropy was observed for PP and language with ADAMTS3 ( P G =2.37×10 -8 ) and SBP and memory with LINC02946 ( P G×Age =3.47×10 -8 ). Five GWS pleiotropic loci influence cognition directly, and genes at six pleiotropic loci were differentially expressed between pathologically confirmed AD cases with and without clinical symptoms. Conclusion Our results provide insight into the underlying mechanisms of high BP and AD. Ongoing efforts to harmonize BP and cognitive measures across several cohorts will improve the power of discovering, replicating, and generalizing novel associations with pleiotropic loci.

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

  medRxiv · 2025-06-26 · 1 citations

  preprintOpen access

  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.

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-04

  preprintOpen 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 more 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. To this end, we have constructed the largest and most nationally representative linkage disequilibrium and genotype imputation reference panels in India to date, using high-coverage whole-genome sequencing data of 2,680 Indian 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 (1000G) and TOP-LD panels, respectively. Besides serving as an LD lookup panel, LASI-DAD facilitates various statistical analyses that rely on precise LD estimates. In a polygenic risk score (PRS) analysis, LASI-DAD improved the predictive performance of PRS by 2.1% to 35.1% across traits and studies. As an imputation reference panel, LASI-DAD improved the imputation accuracy by 3% to 101% (mean = 38%) compared to the TOPMed panel (Version R3) and by 3% to 73% (mean = 27%) compared to the Genome Asia Pilot (GAsP) panel across different minor allele frequencies. The LASI-DAD reference panel is publicly available to benefit future studies.

  PublisherOA PDFDOI

• Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults

  medRxiv · 2025-05-27

  preprintOpen access

  Abstract We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer’s disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus, VRK2 (rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired, DCHS2 (rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning, AGA (rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults.

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• Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores

  Neurobiology of Aging · 2025-07-16 · 1 citations

  articleOpen access

  Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets. SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r=0.071) than snRNA-derived ct-ADPRSs (average r=0.19), indicating their heightened cell-type specificity. The association of these ct-ADPRSs with AD endophenotypes was evaluated using logistic and linear regression models. Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028). AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011). SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes. We investigated 1,954 SNPs contributing to this ct-ADPRS and found the strongest association with variants upstream of the neuropeptide Y gene, NPY , particularly rs3940268 (β=-0.13, P=8.2x10 -5 ). This association is significant even after adjusting for diffuse plaque (β=-0.12, P=1.5x10 -4 ) or neurofibrillary tangle burden (β=-0.08, P=3.9x10 -3 ). NPY was expressed in a small subset of neurons, and these findings suggest its strong impact on the association of SST+ GABAergic neurons with early AD pathology. • snATAC-derived cell-type AD polygenic risk score has greater specificity than snRNA • snATAC-seq identified SNPs with cell-type specific effects related to AD pathology • AD SNPs specific to SST+ GABAergic neurons were driven by SST and NPY co-expression

  PublisherDOI

• A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer’s Disease and Related Dementias (ADRD)

  medRxiv · 2024-07-23 · 1 citations

  preprintOpen access

  We developed an imputation panel for Alzheimer's disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genes EXOC3L2 and DMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.

  PublisherOA PDFDOI

Recent grants

• NIH Grant P01AG014382

  NIH · $13.4M · 2009

• NIH Grant UF1AG047133

  NIH · $12.6M · 2019

• Admin Core: Identifying genes and Pathways that impact Tau Toxicity in FTD

  NIH · $12.3M · 2016–2022

• Core C- Biostatistics and Data Analysis Core

  NIH · $23.7M · 2016–2027

• NIH Grant R37AG011762

  NIH · $2.7M · 2014

Frequent coauthors

• Margaret A. Pericak‐Vance

  Dr. John T. Macdonald Foundation

  347 shared

• Lindsay A. Farrer

  Framingham Heart Study

  317 shared

• Jonathan L. Haines

  Case Western Reserve University

  308 shared

• Richard Mayeux

  Columbia University

  288 shared

• Eden R. Martin

  University of Miami

  257 shared

• Gary W. Beecham

  University of Miami

  234 shared

• Thomas D. Bird

  University of Puget Sound

  199 shared

• Brian W. Kunkle

  University of Miami

  194 shared