Medical Genetics Commons^™

Extending Genome-Wide Association Studies To Admixed Cohorts With High Degrees Of Relatedness, Taotao Tan, Alejandra Vergara-Lope, José Jaime Martínez-Magaña, Nirav N Shah, Yi-Sian Lin, Kai Yuan, Jaime Berumen, Jesus Alegre-Díaz, Pablo Kuri-Morales, Roberto Tapia-Conyer, Joel Gelenter, Janitza L Montalvo-Ortiz, Wei Zhou, Jason M Torres, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

Admixed populations comprise a large portion of the human population worldwide, but are often excluded from genome-wide association studies (GWASs) due to analytic challenges. Our group developed Tractor, a local-ancestry-informed GWAS tool designed for admixed samples that produces accurate ancestry-specific effect sizes and boosts the discovery power to identify ancestry-enriched loci. However, Tractor operates under an assumption of unrelated samples. Here, to address this gap, we propose Tractor-Mix, which allows for well-calibrated association studies in datasets containing admixed samples with relatedness. Extensive simulations show that this method is competitive with other state-of-the-art approaches that do not produce ancestry-specific results. Empirical …

Systems Genetic Dissection Of Brain Gene Expression Reveals Excitotoxic Mechanisms Of Alzheimer’S Disease, Pinghan Zhao, Omar El Fadel, Anh Le, Carl Grant Mangleburg, Justin Dhindsa, Timothy Wu, Jinghan Zhao, Meichen Huang, Bismark Amoh, Aditi Sai Marella, Yarong Li, Nicholas T Seyfried, Allan I Levey, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Gene expression changes likely mediate the impact of Alzheimer's disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers …

Public Attitudes Toward Cascade Genetic Screening In The United States, Hadley Stevens Smith, Emilie S Zoltick, Madison R Hickingbotham, Emily S Bonkowski, Stacey Pereira, Tara A Lavelle, David L Veenstra, Amy L Mcguire, Katherine E Bonini, Leila Jamal

Center for Medical Ethics and Health Policy Staff Publications

Introduction: After a patient receives genetic test results that indicate an actionable health condition, cascade genetic screening (CGS) is the process of evaluating the patient's relatives for a potentially elevated genetic risk of disease. The United States primarily relies on patients to communicate with their relatives, resulting in suboptimal rates of risk communication, familial genetic testing uptake, and risk-reducing interventions. There is ongoing debate about whether and how best to inform relatives of a potentially increased genetic risk.

Methods: We conducted a nationally representative survey of US adults to assess attitudes toward informing at-risk relatives, acceptability of system-mediated communication, and …

Genome-Wide Crispr Screen Identifies A Cytokine-Enhancer Circuit Driving Hif-2Α Activation In Renal Cancer, Jun Fang, Jeremy M Simon, Tao Wang, Yunpeng Gao, Xianju Bi, Lianxin Hu, Chengheng Liao, Cheng Zhang, Yayoi Adachi, Jin Zhou, Hongyi Liu, Qian Liang, James A Nathan, Ram Mani, James Brugarolas, Qing Zhang

Faculty, Staff and Student Publications

Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1-STAT3 signaling pathway. Using a genome-wide CRISPR screen in VHL-deficient ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1-STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of EPAS1 that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in ccRCC patient samples and functionally …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Zilin Li, Derek Shyr, Xihao Li, Haoyu Yang, Rounak Dey, Yushi Tang, Robert Maier, Eric Boerwinkle, Steve Buyske, Mark Daly, Adam Felsenfeld, Richard A Gibbs, Namrata Gupta, Ira M Hall, Tara Matise, Ginger A Metcalf, Albert Smith, Catherine Reeves, Heidi J Sofia, Nathan O Stitziel, Michael C Zody, Nhgri Genome Sequencing Program (Gsp) Consortium, Benjamin Neale, Xihong Lin

Faculty, Staff and Students Publications

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Epigenome-Wide Association Study Meta-Analysis Of Bmi In African Americans, Kendra Ferrier, Mariaelisa Graff, Iain R Konigsberg, Maggie Stanislawski, Heather M Highland, Laura M Raffield, April P Carson, Eric Boerwinkle, Jill M Norris, Chris R Gignoux, Audrey E Hendricks, Sridharan Raghavan, Kari E North, Kristin L Young, Anne E Justice, Matthew A Allison, Mathew J Budoff, Silva Kasela, François Aguet, Joshua J Joseph, Charles Kooperberg, Stephen S Rich, Jerome I Rotter, Ethan M Lange, Leslie A Lange

Faculty, Staff and Student Publications

Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and …

An Integrated Single-Cell And Spatial Transcriptomic Atlas Of Thyroid Cancer Progression Identifies Prognostic Fibroblast Subpopulations, Matthew A Loberg, George J Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C Wahoski, Kailey P Caroland, Megan L Tigue, Heather A Hartmann, Jean-Nicolas Gallant, Courtney J Phifer, Andres A Ocampo, Dayle K Wang, Reilly G Fankhauser, Kirti A Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M Shaddy, James L Netterville, Sarah L Rohde, Carmen C Solórzano, Lindsay A Bischoff, Naira Baregamian, Barbara A Murphy, Jennifer H Choe, Jennifer R Wang, Eric C Huang, Quanhu Sheng, Luciane T Kagohara, Elizabeth M Jaffee, Ryan H Belcher, Ken S Lau, Fei Ye, Ethan Lee, Vivian L Weiss

Faculty, Staff and Student Publications

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts …

Nf2 Loss Malignantly Transforms Human Pancreatic Acinar Cells And Enhances Cell Fitness Under Environmental Stress, Yi Xu, Michael H Nipper, Angel A Dominguez, Chenhui He, Francis E Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation …

Using Genetically Diverse Mice To Examine The Effects Of Environmental Enrichment Of The Transcriptome, Michael Richard Leonardo

Theses, Dissertations and Capstones

Environmental impoverishment is a model of early life stress with direct consequences across a wide range of neurological and physiological conditions. Neuron morphology and density as well as anxiety disorders and addiction have shown to have significant relationships with environmental impoverishment models. Conversely, environmental enrichment confers therapeutic benefits that are protective across these conditions. There is an observed spectrum of resistance or vulnerability to the effects of housing conditions across populations, indicating genetics as an influential factor. Understanding this interaction is critical for deepening our knowledge of how genes and environment interact in ways that confer resistance or vulnerability, and …

Host Modulation Therapy In Periodontitis: From Established Therapies To Emerging Technologies, Aonjittra Phanrungsuwan, Jiaqi Huang, Neeraja Dharmaraj, Alejandra Cobos Perez, Omid Veiseh, Simon Young, Chun-Teh Lee

Faculty, Staff and Student Publications

Periodontitis is a biofilm-induced chronic inflammatory disease, characterized by gingival inflammation and alveolar bone loss. According to a national survey, approximately half of the U.S. adults are affected by periodontal disease. To effectively prevent and treat periodontitis, it is essential to address its underlying causes. The primary etiological factors include polymicrobial synergy and dysbiosis of the oral microbiota, and a dysregulated immune response. The standard therapeutic approach, mechanical removal of biofilm through debridement, sometimes demonstrates limited efficacy, particularly in cases of severe periodontitis, which may require adjunctive or additional therapy. Emerging evidence indicates that periodontal tissue destruction is initiated by …

From Screens To Stress: Public Health Implications Of Cancer Worry In A Digitally Connected World, Shreya Mathur, Ethan Burns, Michael Pokojovy, Tzu-Liang Bill Tseng, Sunil Mathur

Mathematics & Statistics Faculty Publications

Aims:

This study examines how digital information environments, genetic testing experiences, health behaviors, and psychological distress influence cancer-related worry among adults in the United States. It further considers the public health implications of elevated or reduced cancer worry for prevention and risk communication.

Methods:

Data were drawn from a nationally representative survey of 6,252 U.S. adults. Measures included reliance on social media for health decision-making, smoking status, history of genetic testing, and psychological distress. Multivariable analyses assessed associations between these factors and levels of cancer worry.

Results/Findings:

Reliance on social media for health decisions was associated with greater cancer worry, …

Differences Between Government, Consortium, And Private Database Stewards Impacting The Genomic Data Market: A Survey Of U.S. Academic Genetic Researchers., Amanda K Greene, J Denard Thomas, Kaitlyn Jaffe, Luyun Chen, Kerry A Ryan, Brian J Zikmund-Fisher, J Scott Roberts, Amy L Mcguire, Katherine Hendy, Kayte Spector-Bagdady

Center for Medical Ethics and Health Policy Staff Publications

Background: Despite major shifts in U.S. federal government data sharing requirements, their impact, and relation to researcher choice of database, are underexplored. This study surveyed genetic researchers regarding trends, priorities, perceptions of quality, impact on research outcomes, and genomic data sharing and use across government, consortium, and private databases.

Methods: As part of an exploratory sequential mixed methods project, we surveyed 294 U.S.-based genomic academic researchers.

Results: Genetic researchers generally have a choice between databases, which allows them to prioritize data quality. This might explain recent trends toward the use of government and consortium databases away from private ones. Respondents …

Multiple Sclerosis: An Ethnically Diverse Disease With Worldwide Equity Challenges Accessing Care, Victor M Rivera

Faculty, Staff and Students Publications

Multiple sclerosis (MS) affects approximately 2.9 million people in the world, exerting a significant economic and societal burden. The disease is increasingly identified among populations considered as uncommonly affected. MS is reported in all regions of the World Health Organization (WHO) member states in Africa, the Americas, South-East Asia, Europe, the Eastern Mediterranean and the Western Pacific, affecting all ethnicities while exhibiting substantially variable prevalences. Countries with high MS prevalence and some with moderate frequencies generally have economically better structured healthcare systems. Nevertheless, health disparities in these countries are accentuated by suboptimal accessibility of care for their minorities, immigrants and …

Improved Allele Frequencies In Gnomad Through Local Ancestry Inference, Pragati Kore, Michael W Wilson, Grace Tiao, Katherine Chao, Philip W Darnowsky, Nicholas A Watts, Jessica Honorato Mauer, Samantha M Baxter, Genome Aggregation Database Consortium, Heidi L Rehm, Mark J Daly, Konrad J Karczewski, Elizabeth G Atkinson

Faculty, Staff and Students Publications

The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (n = 7612) and African/African American (n = 20,250), deriving ancestry-specific allele frequencies. We show that 78.5% and 85.1% of variants in these groups, respectively, exhibit at least a twofold difference in ancestry-specific frequencies. Moreover, 81.49% of variants with LAI information would …

Dominant Negative Atp5f1a Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders, Sara M Fielder, Marisa W Friederich, Daniella H Hock, Jessie R Zhang, Liana M Valin, Jill A Rosenfeld, Kevin T A Booth, Natasha J Brown, Rocio Rius, Tanavi Sharma, Liana N Semcesen, Kim C Worley, Lindsay C Burrage, Kayla Treat, Tara Samson, Sarah Govert, Sara Dacunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Farah A Ladha, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Claudia Soler-Alfonso, Erin Conboy, Francesco Vetrini, Lisa Emrick, William J Craigen, Undiagnosed Diseases Network, Stephen M Sykes, David A Stroud, Johan L K Van Hove, Tim Schedl, Stephen C Pak

Faculty, Staff and Students Publications

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP …

Governance Of Polygenic Embryo Screening: A Qualitative Study On The Perspectives Of Clinicians And Patients, Jason Bach, Jonathan Frumovitz, Dorit Barlevy, Rémy A Furrer, Abigail Martinez, Ana Battaglino, Shai Carmi, Todd Lencz, Gabriel Lázaro-Muñoz, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Objective: To investigate the perspectives of stakeholders on their attitudes toward potential regulation of polygenic embryo screening (PES), a new form of preimplantation genetic testing that is used to screen embryos for the genetic chances of developing medical conditions and nonmedical traits involving hundreds or thousands of genes.

Design: We conducted individual, semistructured interviews and analyzed transcripts using thematic analysis.

Subjects: Twenty-seven US-based reproductive endocrinology and infertility specialists and 26 patients who were currently undergoing in vitro fertilization or had within the past five years.

Main outcome measures: Repeating ideas and patterned responses were organized into themes and subthemes.

Results: …

Atopy-Related Immune Profiles Are Subject To Genetic Influence As Evaluated Using School-Aged Twin Pairs, Jonatan Leffler, James F. Read, Danny Mok, Michael Serralha, Anthony Bosco, Patrick G. Holt, Richard Saffery, Deborah H. Strickland

Research outputs 2022 to 2026

The interaction of genetic and environmental contributions to immunological traits and their association with atopic disease remain unclear. Flow cytometry and in vitro cytokine responses were used to characterize immune profiles from 93 school-aged twin pairs. Using an established twin pair analytical strategy, the genetic and environmental influences on immunological traits were evaluated, along with their association with atopy. Our findings suggest strong genetic influence on several traits, particularly B cell abundance. In contrast, cytokine responses from in vitro stimulations appeared mainly shaped by environmental exposures. Regarding associations with atopy, greater abundance of both B cells and basophils were observed …

Complete Genomic Characterization Of Global Pathogens Respiratory Syntical Virus And Human Norovirus Using Probe Based Capture Enrichment, Sravya V Bhamidipati, Anil Surathu, Hsu Chao, Daniel P Agustinho, Qin Xiang, Kavya Kottapalli, Abirami Santhanam, Zeineen Momin, Kimberly Walker, Vipin K Menon, George Weissenberger, Nathanael Emerick, Faria Mahjabeen, Qingchang Meng, Jianhong Hu, Richard Sucgang, David Henke, Fritz J Sedlazeck, Ziad M Khan, Ginger A Metcalf, Vasanthi Avadhanula, Pedro A Piedra, Sasirekha Ramani, Robert L Atmar, Mary K Estes, Joseph F Petrosino, Richard A Gibbs, Donna M Muzny, Sara Cregeen Javornik, Harsha Doddapaneni

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, while human noroviruses (HuNoV) are a leading cause of epidemic and sporadic acute gastroenteritis. Generating full-length genome sequences for these viruses is crucial for understanding viral diversity and tracking emerging variants. However, obtaining high-quality sequencing data is often challenging due to viral strain variability, quality, and low titers. Here, we present a set of comprehensive oligonucleotide probe sets designed from 1,570 RSV and 1,376 HuNoV isolate sequences in GenBank. Using these probe sets and a capture enrichment sequencing workflow, 85 RSV positive nasal swab …

Variants In Bsn, Encoding The Presynaptic Protein Bassoon, Result In A Distinct Neurodevelopmental Disorder With A Broad Phenotypic Range, Stacy G Guzman, Sarah M Ruggiero, Shiva Ganesan, Colin A Ellis, Alicia G Harrison, Katie R Sullivan, Zornitza Stark, Natasha J Brown, Sajel L Kana, Anabelle Tuttle, Jair Tenorio, Pablo Lapunzina, Julián Nevado, Marie T Mcdonald, Courtney Jensen, Patricia G Wheeler, Lila Stange, Jennifer Morrison, Boris Keren, Solveig Heide, Meg W Keating, Kameryn M Butler, Mike A Lyons, Shailly Jain, Mehdi Yeganeh, Michelle L Thompson, Molly Schroeder, Hoanh Nguyen, Jorge Granadillo, Kari M Johnston, Chaya N Murali, Katie Bosanko, T Andrew Burrow, Chop Birth Defects Biorepository, Penn Medicine Biobank, Syreeta Morgan, Deborah J Watson, Hakon Hakonarson, Ingo Helbig

Faculty, Staff and Students Publications

Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), …

Navigating The Future Of Polygenic Risk Scores: Insights From Child And Adolescent Psychiatrists, Page M Trotter, Amanda R Merner, Lauren A Ginn, Abigail C Martinez, Ana L Battaglino, Kaitlynn P Craig, Jason Bach, Katherine J Freedberg, Takahiro Soda, Eric A Storch, Gabriel Lázaro-Muñoz, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Polygenic risk scores (PRS) are a method of calculating genetic risk for polygenic, or multi-gene, disorders. These scores have potential impacts in the realm of child and adolescent psychiatry, given the high prevalence of psychiatric disorders among youth. However, there are concerns about PRS implementation among key stakeholders, namely child and adolescent psychiatrists (CAP). We conducted interviews with 29 U.S.-based CAP to investigate clinician attitudes toward the use of PRS. The data herein correspond to a future scenario we provided CAP in which PRS are accurate and portable to patients of different racial and ethnic backgrounds. We found that CAP …

Immune Landscape Of Early Liver Metastatic Lesions In A Novel Immunocompetent Murine Colorectal Cancer Metastasis Model, Alaa Mohamed

Dissertations and Theses (Open Access)

Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We …

A Stakeholder-Informed Conceptual Framework For Evaluating Genomics In Precision Oncology, Julie A. Wiedower

All Dissertations

This dissertation explores the value of genomic testing in precision oncology with an emphasis on how US payers conceptualize and prioritize elements of value. This research aims to address gaps in understanding payer perspectives and proposes a stakeholder-informed framework for evaluating genomic testing in oncology. To achieve this aim, the presented research investigates payer perspectives, value-based cancer care priorities, and the conceptual understanding of the value of a genetic diagnosis to establish a framework for value with the payer audience in mind. Chapter 1 outlines relevant background information relating to the genomic revolution and challenges in translating genomic testing technologies …

Genome-Wide Association Meta-Analyses Of Drug-Resistant Epilepsy, Costin Leu, Andreja Avbersek, Remi Stevelink, Helena Martins Custodio, Siwei Chen, Doug Speed, Caitlin A Bennett, Lina Jonsson, Unnur Unnsteinsdóttir, Andrea L Jorgensen, Gianpiero L Cavalleri, Norman Delanty, John J Craig, Chantal Depondt, Michael R Johnson, Bobby P C Koeleman, Emadeldin Hassanin, Maryam Erfanian Omidvar, Roland Krause, Holger Lerche, Anthony G Marson, Terence J O'Brien, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Hreinn Stefansson, Kari Stefansson, Patrick May, Benjamin M Neale, Dennis Lal, Samuel F Berkovic, Epi25 Collaborative, Epipgx Consortium, Sanjay M Sisodiya

Faculty, Staff and Student Publications

Background: Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown.

Methods: We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: …

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

Longitudinal Multi-Omics In Alpha-Synuclein Drosophila Model Discriminates Disease- From Age-Associated Pathologies In Parkinson’S Disease, Justin Moore, Timothy Wu, Justin Dhindsa, Omar El Fadel, Anh Le, Alma Perez, Bismark Amoh, Akash Tarkunde, Katy F Zhu, Matthew Avalos, Eric B Dammer, Duc M Duong, Nicholas T Seyfried, Joshua M Shulman, Ismael Al-Ramahi, Juan Botas

Duncan NRI Faculty and Staff Publications

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated …

2024 Lifetime Achievement Award: Biology Unbalanced: Genes, Gene Dosage, And Disease Susceptibility, James R Lupski

Faculty, Staff and Students Publications

This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.

Genome-Wide Prediction Of Dominant And Recessive Neurodevelopmental Disorder-Associated Genes, Ryan S Dhindsa, Blake A Weido, Justin S Dhindsa, Arya J Shetty, Chloe F Sands, Slavé Petrovski, Dimitrios Vitsios, Anthony W Zoghbi

Duncan NRI Faculty and Staff Publications

Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised …

Excess Of Rare Noncoding Variants In Several Type 2 Diabetes Candidate Genes Among Asian Indian Families, Madhusmita Rout, Deepika Ramu, Mariana Mendez, Juan C. Lopez-Alvarenga, Rector Arya, Roy G. Resendez, Marcio A. Almeida, Srinivas Mummidi, Ravi Duggirala, Juan M. Peralta, John Blangero

School of Medicine Publications

Background

Type 2 diabetes (T2D) etiology is highly complex due to its multiple roots of origin. Polygenic risk scores (PRS) based on genome-wide association studies (GWAS) can partially explain T2D risk. Asian Indian people have up to six times higher risk of developing T2D than European people, and underlying causes of this disparity are unknown.

Methods

We have performed targeted sequencing of ten T2D GWAS/candidate regions using endogamous Punjabi Sikh families and replication studies using unrelated Sikh people and families from three other Indian endogamous ethnic groups (EEGs).

Results

We detect rare and ultra-rare variants (RVs) in KCNJ11-ABCC8 …

Investigating Comorbidities And Heritability Of Chronic Intractable Migraine With Reactive Hypoglycemia, Stella Santa Ana, Alexander Baumann, Benjamin Gordon, Alex Schofield, Sophia Delgado, Catherine Yvonne Russell, Jacob Warner, Christina Nelson, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

Poster at 2025 Roseman Research Symposium

Mbnl Overexpression Rescues Cardiac Phenotypes In A Myotonic Dystrophy Type 1 Heart Mouse Model, Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J Johnson, Ayrea E Hurley, William R Lagor, Zheng Xia, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile …