Biomedical Informatics Commons^™

Hyperkinetic Movement Disorder Caused By The Recurrent C892c>T Nacc1 Variant, Jonna Komulainen-Ebrahim, Salla M Kangas, Estrella López-Martín, Timothy Feyma, Fernando Scaglia, Beatriz Martínez-Delgado, Outi Kuismin, Maria Suo-Palosaari, Lucinda Carr, Reetta Hinttala, Manju A Kurian, Johanna Uusimaa

Faculty, Staff and Students Publications

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency.

OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level.

METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function …

The Kat Module Of The Saga Complex Maintains The Oncogenic Gene Expression Program In Mycn- Amplified Neuroblastoma, Clare F Malone, Nathaniel W Mabe, Alexandra B Forman, Gabriela Alexe, Kathleen L Engel, Ying-Jiun C Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon Y R Dent, Kimberly Stegmaier

Faculty, Staff and Student Publications

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of …

Variant-Specific Pathophysiological Mechanisms Of Aff3 Differently Influence Transcriptome Profiles, Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree Demille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E L M Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M Butler, Michael J Lyons, Claudia M B Carvalho, Chaofan Zhang, James R Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane Mccormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K Haanpää, Pia Pohjola, Harri Arikka, Anneke J A Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

Faculty, Staff and Students Publications

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

RESULTS: We identified …

Profiling Complex Repeat Expansions In Rfc1 In Parkinson’S Disease, Pilar Alvarez Jerez, Kensuke Daida, Abigail Miano-Burkhardt, Hirotaka Iwaki, Laksh Malik, Guillaume Cogan, Mary B Makarious, Roisin Sullivan, Jana Vandrovcova, Jinhui Ding, J Raphael Gibbs, Androo Markham, Mike A Nalls, Rupesh K Kesharwani, Fritz J Sedlazeck, Bradford Casey, John Hardy, Henry Houlden, Cornelis Blauwendraat, Andrew B Singleton, Kimberley J Billingsley

Faculty, Staff and Students Publications

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

Changes In Walking Function And Neural Control Following Pelvic Cancer Surgery With Reconstruction, Geng Li, Di Ao, Marleny M Vega, Payam Zandiyeh, Shuo-Hsiu Chang, Alexander N Penny, Valerae O Lewis, Benjamin J Fregly

Faculty, Staff and Student Publications

Introduction: Surgical planning and custom prosthesis design for pelvic cancer patients are challenging due to the unique clinical characteristics of each patient and the significant amount of pelvic bone and hip musculature often removed. Limb-sparing internal hemipelvectomy surgery with custom prosthesis reconstruction has become a viable option for this patient population. However, little is known about how post-surgery walking function and neural control change from pre-surgery conditions.

Methods: This case study combined comprehensive walking data (video motion capture, ground reaction, and electromyography) with personalized neuromusculoskeletal computer models to provide a thorough assessment of pre- to post-surgery changes in walking function …

Mustang: Multi-Sample Spatial Transcriptomics Data Analysis With Cross-Sample Transcriptional Similarity Guidance, Seyednami Niyakan, Jianting Sheng, Yuliang Cao, Xiang Zhang, Zhan Xu, Ling Wu, Stephen T C Wong, Xiaoning Qian

Faculty, Staff and Students Publications

Spatially resolved transcriptomics has revolutionized genome-scale transcriptomic profiling by providing high-resolution characterization of transcriptional patterns. Here, we present our spatial transcriptomics analysis framework, MUSTANG (MUlti-sample Spatial Transcriptomics data ANalysis with cross-sample transcriptional similarity Guidance), which is capable of performing multi-sample spatial transcriptomics spot cellular deconvolution by allowing both cross-sample expression-based similarity information sharing as well as spatial correlation in gene expression patterns within samples. Experiments on a semi-synthetic spatial transcriptomics dataset and three real-world spatial transcriptomics datasets demonstrate the effectiveness of MUSTANG in revealing biological insights inherent in the cellular characterization of tissue samples under study.

Phenome-Wide Identification Of Therapeutic Genetic Targets, Leveraging Knowledge Graphs, Graph Neural Networks, And Uk Biobank Data, Lawrence Middleton, Ioannis Melas, Chirag Vasavda, Arwa Raies, Benedek Rozemberczki, Ryan S Dhindsa, Justin S Dhindsa, Blake Weido, Quanli Wang, Andrew R Harper, Gavin Edwards, Slavé Petrovski, Dimitrios Vitsios

Faculty, Staff and Students Publications

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power …

Exome Sequencing Implicates Ancestry-Related Mendelian Variation At Syne1 In Childhood-Onset Essential Hypertension, Ian Copeland, Edmond Wonkam-Tingang, Monesha Gupta-Malhotra, S Shahrukh Hashmi, Yixing Han, Aarti Jajoo, Nancy J Hall, Paula P Hernandez, Natasha Lie, Dan Liu, Jun Xu, Jill Rosenfeld, Aparna Haldipur, Zelene Desire, Zeynep H Coban-Akdemir, Daryl A Scott, Qing Li, Hsiao-Tuan Chao, Ana M Zaske, James R Lupski, Dianna M Milewicz, Sanjay Shete, Jennifer E Posey, Neil A Hanchard

Faculty, Staff and Student Publications

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope …

Data Normalization For Addressing The Challenges In The Analysis Of Single-Cell Transcriptomic Datasets, Raquel Cuevas-Diaz Duran, Haichao Wei, Jiaqian Wu

Faculty, Staff and Student Publications

BACKGROUND: Normalization is a critical step in the analysis of single-cell RNA-sequencing (scRNA-seq) datasets. Its main goal is to make gene counts comparable within and between cells. To do so, normalization methods must account for technical and biological variability. Numerous normalization methods have been developed addressing different sources of dispersion and making specific assumptions about the count data.

MAIN BODY: The selection of a normalization method has a direct impact on downstream analysis, for example differential gene expression and cluster identification. Thus, the objective of this review is to guide the reader in making an informed decision on the most …

Ras G-Domains Allosterically Contribute To The Recognition Of Lipid Headgroups And Acyl Chains, Neha Arora, Huanwen Mu, Hong Liang, Wenting Zhao, Yong Zhou

Faculty, Staff and Student Publications

Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, …

Gain-Of-Function And Loss-Of-Function Variants In Gria3 Lead To Distinct Neurodevelopmental Phenotypes, Berardo Rinaldi, Allan Bayat, Linda G Zachariassen, Jia-Hui Sun, Yu-Han Ge, Dan Zhao, Kristine Bonde, Laura H Madsen, Ilham Abdimunim Ali Awad, Duygu Bagiran, Amal Sbeih, Syeda Maidah Shah, Shaymaa El-Sayed, Signe M Lyngby, Miriam G Pedersen, Charlotte Stenum-Berg, Louise Claudia Walker, Ilona Krey, Andrée Delahaye-Duriez, Lisa T Emrick, Krystal Sully, Chaya N Murali, Lindsay C Burrage, Julie Ana Plaud Gonzalez, Mered Parnes, Jennifer Friedman, Bertrand Isidor, Jérémie Lefranc, Sylvia Redon, Delphine Heron, Cyril Mignot, Boris Keren, Mélanie Fradin, Christele Dubourg, Sandra Mercier, Thomas Besnard, Benjamin Cogne, Wallid Deb, Clotilde Rivier, Donatella Milani, Maria Francesca Bedeschi, Claudia Di Napoli, Federico Grilli, Paola Marchisio, Suzanna Koudijs, Danielle Veenma, Emanuela Argilli, Sally Ann Lynch, Ping Yee Billie Au, Fernando Eduardo Ayala Valenzuela, Carolyn Brown, Diane Masser-Frye, Marilyn Jones, Leslie Patron Romero, Wenhui Laura Li, Erin Thorpe, Laura Hecher, Jessika Johannsen, Jonas Denecke, Vanda Mcniven, Anna Szuto, Emma Wakeling, Vincent Cruz, Valerie Sency, Heng Wang, Juliette Piard, Fanny Kortüm, Theresia Herget, Tatjana Bierhals, Angelo Condell, Bruria Ben-Zeev, Simranpreet Kaur, John Christodoulou, Amelie Piton, Christiane Zweier, Cornelia Kraus, Alessia Micalizzi, Marina Trivisano, Nicola Specchio, Gaetan Lesca, Rikke S Møller, Zeynep Tümer, Maria Musgaard, Benedicte Gerard, Johannes R Lemke, Yun Stone Shi, Anders S Kristensen

Faculty, Staff and Students Publications

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1–GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral.

We collected detailed …

The Clinical Utility And Diagnostic Implementation Of Human Subject Cell Transdifferentiation Followed By Rna Sequencing, Shenglan Li, Sen Zhao, Jefferson C Sinson, Aleksandar Bajic, Jill A Rosenfeld, Matthew B Neeley, Mezthly Pena, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William J Craigen, Gary D Clark, Seema Lalani, Carlos A Bacino, Keren Machol, Hsiao-Tuan Chao, Lorraine Potocki, Lisa Emrick, Jennifer Sheppard, My T T Nguyen, Anahita Khoramnia, Paula Patricia Hernandez, Sandesh Cs Nagamani, Zhandong Liu, Christine M Eng, Brendan Lee, Pengfei Liu

Faculty, Staff and Students Publications

RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 individuals with primary …

De Novo Genome Assembly For The Coppery Titi Monkey (Plecturocebus Cupreus): An Emerging Nonhuman Primate Model For Behavioral Research, Susanne P Pfeifer, Alexander Baxter, Logan E Savidge, Fritz J Sedlazeck, Karen L Bales

Faculty, Staff and Students Publications

The coppery titi monkey (Plecturocebus cupreus) is an emerging nonhuman primate model system for behavioral and neurobiological research. At the same time, the almost entire absence of genomic resources for the species has hampered insights into the genetic underpinnings of the phenotypic traits of interest. To facilitate future genotype-to-phenotype studies, we here present a high-quality, fully annotated de novo genome assembly for the species with chromosome-length scaffolds spanning the autosomes and chromosome X (scaffold N50 = 130.8 Mb), constructed using data obtained from several orthologous short- and long-read sequencing and scaffolding techniques. With a base-level accuracy of ∼99.99% in chromosome-length …

Dlk-Mapk Signaling Coupled With Dna Damage Promotes Intrinsic Neurotoxicity Associated With Non-Mutated Tau, Sanming Li, Ethan R Roy, Yanyu Wang, Trent Watkins, Wei Cao

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine …

Mechanical Venous Thrombectomy For Deep Venous Thrombosis In Cancer Patients: A Single-Center Retrospective Study, Riya M Patel, Koustav Pal, Syed Hadi Ahmed, Joshua D Kuban, Milan Patel, Ketan Shah, Peiman Habibollahi, Zeyad Metwalli, Varshana Gurusamy, Sanjay Gupta, Cristhiam M Rojas-Hernandez, Vahid Afshar-Kharghan, Michael H Kroll, Rahul A Sheth

Faculty, Staff and Student Publications

PURPOSE: Venous thromboembolism (VTE) is a major contributor to the mortality of cancer patients. Mechanical thrombectomy (MT) is an endovascular technique that physically removes a thrombus without thrombolytics. The purpose of this study was to evaluate safety, efficacy, and clinical outcomes following MT for lower extremity DVT in cancer patients.

METHODS: This single-center, retrospective study evaluated outcomes following MT of lower extremity DVT in cancer patients from November 2019 to May 2023. The primary outcome measure was clinical success, defined as a decrease in Villalta score by at least 2 points following the intervention. Secondary outcomes included repeat intervention-free survival …

Modeling Acute Myocardial Infarction And Cardiac Fibrosis Using Human Induced Pluripotent Stem Cell-Derived Multi-Cellular Heart Organoids, Myeongjin Song, Da Bin Choi, Jeong Suk Im, Ye Na Song, Ji Hyun Kim, Hanbyeol Lee, Jieun An, Ami Kim, Hwan Choi, Joon-Chul Kim, Choongseong Han, Young Keul Jeon, Sung Joon Kim, Dong-Hun Woo

Faculty, Staff and Student Publications

Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches to non-clinical animal research. However, most of these approaches struggle to accurately replicate adult human heart conditions, such as myocardial infarction and ventricular remodeling pathology. The intricate interplay between various cell types within the adult heart, including cardiomyocytes, fibroblasts, and endothelial cells, contributes to the complexity of most heart diseases. Consequently, the mechanisms behind heart disease induction cannot be attributed to a single-cell type. Thus, the use of multi-cellular models becomes essential for creating …

Ai-Marrvel - A Knowledge-Driven Ai System For Diagnosing Mendelian Disorders, Dongxue Mao, Chaozhong Liu, Linhua Wang, Rami Ai-Ouran, Cole Deisseroth, Sasidhar Pasupuleti, Seon Young Kim, Lucian Li, Jill A Rosenfeld, Linyan Meng, Lindsay C Burrage, Michael F Wangler, Shinya Yamamoto, Undiagnosed Diseases Network, Michael Santana, Victor Perez, Priyank Shukla, Christine M Eng, Brendan Lee, Bo Yuan, Fan Xia, Hugo J Bellen, Pengfei Liu, Zhandong Liu

Faculty, Staff and Students Publications

BACKGROUND: Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis.

METHODS: AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. The online version of AIM is available at https://ai.marrvel.org. To evaluate AIM, we benchmarked it with diagnosed patients from three independent cohorts.

RESULTS: AIM …

Development Of A Weight-Band Dosing Approach For Vosoritide In Children With Achondroplasia Using A Population Pharmacokinetic Model, Yulan Qi, Ming Liang Chan, Diane R Mould, Kevin Larimore, Elena Fisheleva, Anu Cherukuri, Jonathan Day, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, Michael B Bober, Joshua Henshaw

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was …

Genome-Wide Association Analyses Identify 95 Risk Loci And Provide Insights Into The Neurobiology Of Post-Traumatic Stress Disorder, Caroline M Nievergelt, Adam X Maihofer, Elizabeth G Atkinson, Chia-Yen Chen, Karmel W Choi, Jonathan R I Coleman, Nikolaos P Daskalakis, Laramie E Duncan, Renato Polimanti, Cindy Aaronson, Ananda B Amstadter, Soren B Andersen, Ole A Andreassen, Paul A Arbisi, Allison E Ashley-Koch, S Bryn Austin, Esmina Avdibegoviç, Dragan Babić, Silviu-Alin Bacanu, Dewleen G Baker, Anthony Batzler, Jean C Beckham, Sintia Belangero, Corina Benjet, Carisa Bergner, Linda M Bierer, Joanna M Biernacka, Laura J Bierut, Jonathan I Bisson, Marco P Boks, Elizabeth A Bolger, Amber Brandolino, Gerome Breen, Rodrigo Affonseca Bressan, Richard A Bryant, Angela C Bustamante, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Anders D Børglum, Sigrid Børte, Leah Cahn, Joseph R Calabrese, Jose Miguel Caldas-De-Almeida, Chris Chatzinakos, Sheraz Cheema, Sean A P Clouston, Lucía Colodro-Conde, Brandon J Coombes, Carlos S Cruz-Fuentes, Anders M Dale, Shareefa Dalvie, Lea K Davis, Jürgen Deckert, Douglas L Delahanty, Michelle F Dennis, Frank Desarnaud, Christopher P Dipietro, Seth G Disner, Anna R Docherty, Katharina Domschke, Grete Dyb, Alma Džubur Kulenović, Howard J Edenberg, Alexandra Evans, Chiara Fabbri, Negar Fani, Lindsay A Farrer, Adriana Feder, Norah C Feeny, Janine D Flory, David Forbes, Carol E Franz, Sandro Galea, Melanie E Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F Gillespie, Slavina B Goleva, Scott D Gordon, Aferdita Goçi, Lana Ruvolo Grasser, Camila Guindalini, Magali Haas, Saskia Hagenaars, Michael A Hauser, Andrew C Heath, Sian M J Hemmings, Victor Hesselbrock, Ian B Hickie, Kelleigh Hogan, David Michael Hougaard, Hailiang Huang, Laura M Huckins, Kristian Hveem, Miro Jakovljević, Arash Javanbakht, Gregory D Jenkins, Jessica Johnson, Ian Jones, Tanja Jovanovic, Karen-Inge Karstoft, Milissa L Kaufman, James L Kennedy, Ronald C Kessler, Alaptagin Khan, Nathan A Kimbrel, Anthony P King, Nastassja Koen, Roman Kotov, Henry R Kranzler, Kristi Krebs, William S Kremen, Pei-Fen Kuan, Bruce R Lawford, Lauren A M Lebois, Kelli Lehto, Daniel F Levey, Catrin Lewis, Israel Liberzon, Sarah D Linnstaedt, Mark W Logue, Adriana Lori, Yi Lu, Benjamin J Luft, Michelle K Lupton, Jurjen J Luykx, Iouri Makotkine, Jessica L Maples-Keller, Shelby Marchese, Charles Marmar, Nicholas G Martin, Gabriela A Martínez-Levy, Kerrie Mcaloney, Alexander Mcfarlane, Katie A Mclaughlin, Samuel A Mclean, Sarah E Medland, Divya Mehta, Jacquelyn Meyers, Vasiliki Michopoulos, Elizabeth A Mikita, Lili Milani, William Milberg, Mark W Miller, Rajendra A Morey, Charles Phillip Morris, Ole Mors, Preben Bo Mortensen, Mary S Mufford, Elliot C Nelson, Merete Nordentoft, Sonya B Norman, Nicole R Nugent, Meaghan O'Donnell, Holly K Orcutt, Pedro M Pan, Matthew S Panizzon, Gita A Pathak, Edward S Peters, Alan L Peterson, Matthew Peverill, Robert H Pietrzak, Melissa A Polusny, Bernice Porjesz, Abigail Powers, Xue-Jun Qin, Andrew Ratanatharathorn, Victoria B Risbrough, Andrea L Roberts, Alex O Rothbaum, Barbara O Rothbaum, Peter Roy-Byrne, Kenneth J Ruggiero, Ariane Rung, Heiko Runz, Bart P F Rutten, Stacey Saenz De Viteri, Giovanni Abrahão Salum, Laura Sampson, Sixto E Sanchez, Marcos Santoro, Carina Seah, Soraya Seedat, Julia S Seng, Andrey Shabalin, Christina M Sheerin, Derrick Silove, Alicia K Smith, Jordan W Smoller, Scott R Sponheim, Dan J Stein, Synne Stensland, Jennifer S Stevens, Jennifer A Sumner, Martin H Teicher, Wesley K Thompson, Arun K Tiwari, Edward Trapido, Monica Uddin, Robert J Ursano, Unnur Valdimarsdóttir, Miranda Van Hooff, Eric Vermetten, Christiaan H Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Monika Waszczuk, Heike Weber, Frank R Wendt, Thomas Werge, Michelle A Williams, Douglas E Williamson, Bendik S Winsvold, Sherry Winternitz, Christiane Wolf, Erika J Wolf, Yan Xia, Ying Xiong, Rachel Yehuda, Keith A Young, Ross Mcd Young, Clement C Zai, Gwyneth C Zai, Mark Zervas, Hongyu Zhao, Lori A Zoellner, John-Anker Zwart, Terri Deroon-Cassini, Sanne J H Van Rooij, Leigh L Van Den Heuvel, Murray B Stein, Kerry J Ressler, Karestan C Koenen

Faculty, Staff and Students Publications

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), …

A Phenome-Wide Association And Mendelian Randomisation Study Of Alcohol Use Variants In A Diverse Cohort Comprising Over 3 Million Individuals, Mariela V Jennings, José Jaime Martínez-Magaña, Natasia S Courchesne-Krak, Renata B Cupertino, Laura Vilar-Ribó, Sevim B Bianchi, Alexander S Hatoum, Elizabeth G Atkinson, Paola Giusti-Rodriguez, Janitza L Montalvo-Ortiz, Joel Gelernter, María Soler Artigas, Sarah L Elson, Howard J Edenberg, Pierre Fontanillas, Abraham A Palmer, Sandra Sanchez-Roige

Faculty, Staff and Students Publications

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African …

Core Planar Cell Polarity Genes Vangl1 And Vangl2 In Predisposition To Congenital Vertebral Malformations, Xin Feng, Yongyu Ye, Jianan Zhang, Yuanqiang Zhang, Sen Zhao, Judith C W Mak, Nao Otomo, Zhengye Zhao, Yuchen Niu, Yoshiro Yonezawa, Guozhuang Li, Mao Lin, Xiaoxin Li, Prudence Wing Hang Cheung, Kexin Xu, Kazuki Takeda, Shengru Wang, Junjie Xie, Toshiaki Kotani, Vanessa N T Choi, You-Qiang Song, Yang Yang, Keith Dip Kei Luk, Kin Shing Lee, Ziquan Li, Pik Shan Li, Connie Y H Leung, Xiaochen Lin, Xiaolu Wang, Guixing Qiu, Disco (Deciphering Disorders Involving Scoliosis And Comorbidities) Study Group, Kota Watanabe, Japanese Early Onset Scoliosis Research Group, Zhihong Wu, Jennifer E Posey, Shiro Ikegawa, James R Lupski, Jason Pui Yin Cheung, Terry Jianguo Zhang, Bo Gao, Nan Wu

Faculty, Staff and Students Publications

Congenital scoliosis (CS) is the most common congenital spinal disorder caused by congenital vertebral malformations (CVMs), influenced by genetic and environmental factors and exhibiting diverse clinical presentations. Here, we identified the critical roles of Vangl1 and Vangl2, two core components in the Wnt/planar cell polarity (Wnt/PCP) signaling pathway, in vertebral development and in predisposition to CVMs in CS patients. We found that in Vangl mutant mouse models, the CVMs present in a Vangl gene dose- and gestational hypoxia-dependent manner. Our studies reveal a complex etiology of CS and its association with Wnt/PCP signaling.

Critical Assessment Of Variant Prioritization Methods For Rare Disease Diagnosis Within The Rare Genomes Project, Sarah L Stenton, Melanie C O'Leary, Gabrielle Lemire, Grace E Vannoy, Stephanie Ditroia, Vijay S Ganesh, Emily Groopman, Emily O'Heir, Brian Mangilog, Ikeoluwa Osei-Owusu, Lynn S Pais, Jillian Serrano, Moriel Singer-Berk, Ben Weisburd, Michael W Wilson, Christina Austin-Tse, Marwa Abdelhakim, Azza Althagafi, Giulia Babbi, Riccardo Bellazzi, Samuele Bovo, Maria Giulia Carta, Rita Casadio, Pieter-Jan Coenen, Federica De Paoli, Matteo Floris, Manavalan Gajapathy, Robert Hoehndorf, Julius O B Jacobsen, Thomas Joseph, Akash Kamandula, Panagiotis Katsonis, Cyrielle Kint, Olivier Lichtarge, Ivan Limongelli, Yulan Lu, Paolo Magni, Tarun Karthik Kumar Mamidi, Pier Luigi Martelli, Marta Mulargia, Giovanna Nicora, Keith Nykamp, Vikas Pejaver, Yisu Peng, Thi Hong Cam Pham, Maurizio S Podda, Aditya Rao, Ettore Rizzo, Vangala G Saipradeep, Castrense Savojardo, Peter Schols, Yang Shen, Naveen Sivadasan, Damian Smedley, Dorian Soru, Rajgopal Srinivasan, Yuanfei Sun, Uma Sunderam, Wuwei Tan, Naina Tiwari, Xiao Wang, Yaqiong Wang, Amanda Williams, Elizabeth A Worthey, Rujie Yin, Yuning You, Daniel Zeiberg, Susanna Zucca, Constantina Bakolitsa, Steven E Brenner, Stephanie M Fullerton, Predrag Radivojac, Heidi L Rehm, Anne O'Donnell-Luria

Faculty, Staff and Students Publications

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting.

METHODS: …

The Swi/Snf Atp-Dependent Chromatin Remodeling Complex In Cell Lineage Priming And Early Development, Dhurjhoti Saha, Srinivas Animireddy, Blaine Bartholomew

Faculty, Staff and Student Publications

ATP dependent chromatin remodelers have pivotal roles in transcription, DNA replication and repair, and maintaining genome integrity. SWI/SNF remodelers were first discovered in yeast genetic screens for factors involved in mating type switching or for using alternative energy sources therefore termed SWI/SNF complex (short for SWItch/Sucrose NonFermentable). The SWI/SNF complexes utilize energy from ATP hydrolysis to disrupt histone-DNA interactions and shift, eject, or reposition nucleosomes making the underlying DNA more accessible to specific transcription factors and other regulatory proteins. In development, SWI/SNF orchestrates the precise activation and repression of genes at different stages, safe guards the formation of specific cell …

A Tetravalent Nanovaccine That Inhibits Growth Of Hpv-Associated Head And Neck Carcinoma Via Dendritic And T Cell Activation, Romano Josi, Daniel E Speiser, Simone De Brot, Anne-Cathrine Vogt, Eva M Sevick-Muraca, Genrich V Tolstonog, Martin F Bachmann, Mona O Mohsen

Faculty, Staff and Student Publications

The global incidence of human papillomavirus (HPV) associated head and neck carcinoma is on the rise, in response to this a tetravalent therapeutic vaccine named Qβ-HPVag was developed. This vaccine, utilizing virus-like particles (VLPs) loaded with toll-like receptor ligands and chemically coupled to four HPV16-derived peptides, demonstrated strong anti-tumor effects in a murine head and neck cancer model. Qβ-HPVag impeded tumor progression, increased infiltration of HPV-specific T cells, and significantly improved survival. The vaccine`s efficacy was associated with immune repolarization in the tumor microenvironment, characterized by expanded activated dendritic cell subsets (cDC1, cDC2, DC3). Notably, mice responding to treatment exhibited …

Cdk8/Cdk19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation And Can Phenotypically Suppress Pink1 Deficiency In Drosophila, Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen

Faculty, Staff and Students Publications

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. …

Jennifer A Wargo, Nadim J Ajami, And Carrie R Daniel-Macdougall, Jennifer A Wargo, Nadim J Ajami, Carrie R Daniel-Macdougall

Faculty, Staff and Student Publications

Dr. Jennifer A. Wargo, Dr. Nadim J. Ajami, and Dr. Carrie R. Daniel-MacDougall describe their academic and clinical work on the role of the microbiome to determine response to immunotherapies and discuss current challenges and potential needs to integrate their findings into clinical practice.

Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.

METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD). …

Cd24 Negativity Reprograms Mitochondrial Metabolism To Pparα And Nf-Κb-Driven Fatty Acid Β-Oxidation In Triple-Negative Breast Cancer, Divya Murthy, Debasmita Dutta, Kuldeep S Attri, Tagari Samanta, Sukjin Yang, Kwang Hwa Jung, Sarah G Latario, Vasanta Putluri, Shixia Huang, Nagireddy Putluri, Jun Hyoung Park, Benny Abraham Kaipparettu

Faculty, Staff and Students Publications

CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. …

Human Brain Glycoform Coregulation Network And Glycan Modification Alterations In Alzheimer's Disease, Qi Zhang, Cheng Ma, Lih-Shen Chin, Sheng Pan, Lian Li

Faculty, Staff and Student Publications

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain …

The Saga Of E Faecium, Rishika Prasad, Robert R Jenq

Faculty, Staff and Student Publications

An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.