Medical Sciences Commons^™

Xcvatr: Detection And Characterization Of Variant Impact On The Embeddings Of Single -Cell And Bulk Rna-Sequencing Samples, Arif Harmanci, Akdes Serin Harmanci, Tiemo J Klisch, Akash J Patel

Student and Faculty Publications

BACKGROUND: RNA-sequencing has become a standard tool for analyzing gene activity in bulk samples and at the single-cell level. By increasing sample sizes and cell counts, this technique can uncover substantial information about cellular transcriptional states. Beyond quantification of gene expression, RNA-seq can be used for detecting variants, including single nucleotide polymorphisms, small insertions/deletions, and larger variants, such as copy number variants. Notably, joint analysis of variants with cellular transcriptional states may provide insights into the impact of mutations, especially for complex and heterogeneous samples. However, this analysis is often challenging due to a prohibitively high number of variants and …

Determinism V. Free Will & Genetic Evidence Of Addiction In Plea Bargaining And Sentence Mitigation: Conversion Of Incarceration To Probation And Rehabilitation Based On Genetic Addiction Risk Severity (Gars) Test, Kenneth Blum, Paul Mullen, Richard Green

St. Mary's Law Journal

In this Article, Dr. Kenneth Blum and his team present the case of a presently abstinent, thirty-five year old alcoholic (“AG”) who has several convictions for DWI. AG has undergone and continues to be engaged in out-patient substance abuse treatment. He entered treatment before adjudication and was mandated by the court to continue treatment to assist in maintaining sobriety. Treatment included the administration of the Genetic Addiction Risk Severity (“GARS”) Test.

AG was facing a probable five-year sentence for his fifth DWI conviction in Bexar County, Texas. However, because AG’s genetic risk results indicated a genetically induced dopamine dysfunction, hypodopaminergia, …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Janet Van Eersel, Lars M Ittner

Student and Faculty Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Distinct Germline Genetic Susceptibility Profiles Identified For Common Non-Hodgkin Lymphoma Subtypes, Sonja I Berndt, Joseph Vijai, Yolanda Benavente, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Karin E Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F Skibola, Lindsay M Morton, Angela R Brooks-Wilson, Lauren R Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C Anderson, Stephen M Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M Birmann, Paolo Boffetta, Paige M Bracci, Paul Brennan, Elizabeth E Brown, Laurie Burdett, Lisa A Cannon-Albright, Ellen T Chang, Brian C H Chiu, Charles C Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V Conti, David G Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W Ryan Diver, Ahmet Dogan, Christopher K Edlund, Lenka Foretova, Joseph F Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M Habermann, Christopher A Haiman, Corinne Haioun, Jonathan N Hofmann, Theodore R Holford, Elizabeth A Holly, Amy Hutchinson, Aalin Izhar, Rebecca D Jackson, Ruth F Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K Link, Corrado Magnani, Marc Maynadie, James Mckay, Mads Melbye, Lucia Miligi, Roger L Milne, Thierry J Molina, Alain Monnereau, Rebecca Montalvan, Kari E North, Anne J Novak, Kenan Onel, Mark P Purdue, Kristin A Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W Sborov, Richard K Severson, Tait D Shanafelt, Martyn T Smith, Alexandra Smith, Kevin W Song, Lei Song, Melissa C Southey, John J Spinelli, Anthony Staines, Deborah Stephens, Heather J Sutherland, Kaitlyn Tkachuk, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Ruth C Travis, Jenny Turner, Celine M Vachon, Claire M Vajdic, Anke Van Den Berg, David J Van Den Berg, Roel C H Vermeulen, Paolo Vineis, Sophia S Wang, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R Cerhan, Stephen J Chanock, Susan L Slager, Nathaniel Rothman

Student and Faculty Publications

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9,505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P<5 >× 10−8) for subsets of NHL subtypes, …

Consensus Subtypes Of Hepatocellular Carcinoma Associated With Clinical Outcomes And Genomic Phenotypes, Sung Hwan Lee, Sun Young Yim, Yun Seong Jeong, Qi-Xiang Li, Sang-Hee Kang, Bo Hwa Sohn, Shwetha V Kumar, Ji-Hyun Shin, You Rhee Choi, Jae-Jun Shim, Hayeon Kim, Ji Hoon Kim, Shin Kim, Sheng Guo, Randy L Johnson, Ahmed Kaseb, Koo Jeong Kang, Yun Shin Chun, Hee Jin Jang, Byoung Gill Lee, Hyun Goo Woo, Min Jin Ha, Rehan Akbani, Lewis R Roberts, David A Wheeler, Ju-Seog Lee

Student and Faculty Publications

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes.

APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male …

Structural Variants Drive Context-Dependent Oncogene Activation In Cancer, Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C Akdemir, Selene Tyndale, P Andrew Futreal, Graham Mcvicker, Geoffrey M Wahl, Jesse R Dixon

Student and Faculty Publications

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific …

Tceal1 Loss-Of-Function Results In An X-Linked Dominant Neurodevelopmental Syndrome And Drives The Neurological Disease Trait In Xq222 Deletions, Hadia Hijazi, Linda M Reis, Davut Pehlivan, Jonathan A Bernstein, Michael Muriello, Erin Syverson, Devon Bonner, Mehrdad A Estiar, Ziv Gan-Or, Guy A Rouleau, Ekaterina Lyulcheva, Lynn Greenhalgh, Marine Tessarech, Estelle Colin, Agnès Guichet, Dominique Bonneau, R H Van Jaarsveld, A M A Lachmeijer, Lyse Ruaud, Jonathan Levy, Anne-Claude Tabet, Rafal Ploski, Małgorzata Rydzanicz, Łukasz Kępczyński, Katarzyna Połatyńska, Yidan Li, Jawid M Fatih, Dana Marafi, Jill A Rosenfeld, Zeynep Coban-Akdemir, Weimin Bi, Richard A Gibbs, Grace M Hobson, Jill V Hunter, Claudia M B Carvalho, Jennifer E Posey, Elena V Semina, James R Lupski

Student and Faculty Publications

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving …

A Cloning-Free Recyclable System For Crispr-Cas9 Mediated Mutant And Reversion Construction In Candida Albicans Clinical Isolates, Amanda K. Vogel

Theses and Dissertations (ETD)

Candida albicans is a ubiquitous opportunistic fungal pathogen and one of the most prevalent causes of fungal diseases worldwide. The reference isolate SC5314 is one of the most widely used strains for both experimental and genetic studies, but it is becoming increasingly evident that genetic diversity in clinical isolates plays an important role in antifungal resistance, virulence, and pathogenicity. These recent discoveries highlight the need for genetic tools that are capable of investigating genes in multiple strain backgrounds. Here we build on the SAT1-flipper method and combine it with CRISPR-Cas9 technology to achieve cloning-free homozygous deletion in a single transformation …

Methods Development In Inflammatory Bowel Disease, Andrew B. Steimke

Theses and Dissertations (ETD)

Inflammatory bowel disease (IBD) is a disease that is classified into two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). Symptoms can range from mild discomfort to requiring surgical intervention and affects approximately 1-in-200 adults in America alone, with global incidence rates increasing. While many treatments exist for IBD, perhaps the main reason for the lack of a cure is that there are many different pathogeneses that all lead to a very similar expression of symptoms. Over 240 IBD loci have been identified to date, yet the causative allele that drives the association has only been identified in ~60 of …

The Circadian E3 Ligase Fbxl21 Regulates Myoblast Differentiation And Sarcomere Architecture Via Myoz1 Ubiquitination And Nfat Signaling, Ji Ye Lim, Eunju Kim, Collin M Douglas, Marvin Wirianto, Chorong Han, Kaori Ono, Sun Young Kim, Justin H Ji, Celia K Tran, Zheng Chen, Karyn A Esser, Seung-Hee Yoo

Faculty and Staff Publications

Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3β, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from …

Identifying And Minimizing Underspecification In Breast Cancer Subtyping, Jonathan Cheuk-Kiu Tang

Master's Theses

In the realm of biomedical technology, both accuracy and consistency are crucial to the development and deployment of these tools. While accuracy is easy to measure, consistency metrics are not so simple to measure, especially in the scope of biomedicine where prediction consistency can be difficult to achieve. Typically, biomedical datasets contain a significantly larger amount of features compared to the amount of samples, which goes against ordinary data mining practices. As a result, predictive models may fail to find valid pathways for prediction during training on such datasets. This concept is known as underspecification.

Underspecification has been more accepted …

North American Genetic Counselors' Approach To Collecting And Using Ancestry In Clinical Practice, Alexandra Hubbel, Elizabeth Hogan, Anne Matthews, Aaron Goldenberg

Student Scholarship

Current guidelines from the National Society of Genetic Counselors (NSGC) recommend that patients' ancestry be obtained when taking a family history. However, no study has explored how consistently genetic counselors obtain or utilize this information. The goals of this study included assessing how genetic counselors collect their patients' ancestry, what factors influence this decision, and how they view the utility of this information. Genetic counselors working in a direct patient care setting in the US or Canada were recruited to participate in an anonymous survey via an NSGC email blast. Most participants (n = 115) obtain information about their patients' …

Privacy-Aware Estimation Of Relatedness In Admixed Populations, Su Wang, Miran Kim, Wentao Li, Xiaoqian Jiang, Han Chen, Arif Harmanci

Student and Faculty Publications

BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization.

RESULTS: Here, we present SIGFRIED, which makes …

The Evolving Privacy And Security Concerns For Genomic Data Analysis And Sharing As Observed From The Idash Competition, Tsung-Ting Kuo, Xiaoqian Jiang, Haixu Tang, Xiaofeng Wang, Arif Harmanci, Miran Kim, Kai Post, Diyue Bu, Tyler Bath, Jihoon Kim, Weijie Liu, Hongbo Chen, Lucila Ohno-Machado

Student and Faculty Publications

Concerns regarding inappropriate leakage of sensitive personal information as well as unauthorized data use are increasing with the growth of genomic data repositories. Therefore, privacy and security of genomic data have become increasingly important and need to be studied. With many proposed protection techniques, their applicability in support of biomedical research should be well understood. For this purpose, we have organized a community effort in the past 8 years through the integrating data for analysis, anonymization and sharing consortium to address this practical challenge. In this article, we summarize our experience from these competitions, report lessons learned from the events …

Editorial: Epigenetics And Molecular Genetics Of Rare Tumors, Mauro Tognon, George A. Calin, Luis Del Valle

School of Medicine Faculty Publications

No abstract provided.

A Multi-Omics Framework Reveals Strawberry Flavor Genes And Their Regulatory Elements, Zhen Fan, Denise M Tieman, Steven J Knapp, Philipp Zerbe, Randi Famula, Christopher R Barbey, Kevin M Folta, Rodrigo R Amadeu, Manbo Lee, Youngjae Oh, Seonghee Lee, Vance M Whitaker

Student and Faculty Publications

Flavor is essential to consumer preference of foods and is an increasing focus of plant breeding programs. In fruit crops, identifying genes underlying volatile organic compounds has great promise to accelerate flavor improvement, but polyploidy and heterozygosity in many species have slowed progress. Here we use octoploid cultivated strawberry to demonstrate how genomic heterozygosity, transcriptomic intricacy and fruit metabolomic diversity can be treated as strengths and leveraged to uncover fruit flavor genes and their regulatory elements. Multi-omics datasets were generated including an expression quantitative trait loci map with 196 diverse breeding lines, haplotype-phased genomes of a highly-flavored breeding selection, a …

Yap And Taz Promote Osteogenesis And Prevent Chondrogenesis In Neural Crest Cells In Vitro And In Vivo, Xiaolei Zhao, Li Tang, Tram P Le, Bao H Nguyen, Wen Chen, Mingjie Zheng, Hiroyuki Yamaguchi, Brian Dawson, Shuangjie You, Idaliz M Martinez-Traverso, Shannon Erhardt, Jianxin Wang, Min Li, James F Martin, Brendan H Lee, Yoshihiro Komatsu, Jun Wang

Student and Faculty Publications

Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute the majority of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in Yap and Taz switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for Yap and Taz resulted in bone loss and ectopic cartilage in mice. Yap bound to the regulatory elements of key …

Should Health Systems Share Genetic Findings With At-Risk Relatives When The Proband Is Deceased? Interviews With Individuals Diagnosed With Lynch Syndrome, Jessica Ezzell Hunter, Jennifer L. Schneider, Alison J. Firemark, James V. Davis, Sara Gille, Pamala A. Pawloski, Su-Ying Liang, Victoria Schlieder, Alanna Kulchak Rahm

Journal of Patient-Centered Research and Reviews

Purpose: Genetic information has health implications for patients and their biological relatives. Death of a patient before sharing a genetic diagnosis with at-risk relatives is a missed opportunity to provide important information that could guide interventions to minimize cancer-related morbidity and mortality in relatives.

Methods: We performed semi-structured interviews with individuals diagnosed with Lynch syndrome at 1 of 4 health systems to explore their perspectives on whether health systems should share genetic risk information with relatives following a patient’s death. An inductive, open-coding approach was used to analyze audio-recorded content, with software-generated code reports undergoing iterative comparative analysis by a …

In-Depth Analysis Of Next-Generation Sequencing (Ngs) And Bioinformatics Results In Pediatric Adgrv1 Compound Heterozygotes, Sloane Clay, Adele Evans, Chindo Hicks, David Otohinoyi

Medical Student Research Poster Symposium

Genetic diagnosis of sensorineural hearing loss (SNHL) using NGS proves challenging when encountering multigenic, multiallelic variants of uncertain significance (VUS). These VUS make it difficult to provide anticipatory guidance regarding progressive disorders such as Type II Usher syndrome (SNHL at birth and retinitis pigmentosa in the second decade of life). With genetic testing companies are identifying, reporting, and reclassifying VUS at a rapid pace; there is a need for in depth-analysis and interpretation. For example, VUS in ADGRV1, a gene implicated in Type II Usher Syndrome, may be inherited in a compound heterozygous manner and misinterpreted as benign, when in …

The Fecal Position: Tracking Progressive Dna Repeat Expansion Via Stool Dna Extraction, Margaret Conrad, Hayley Ulloa, Ed Grabczyk

Medical Student Research Poster Symposium

Friedreich Ataxia is a progressive DNA repeat expansion disease. Examining DNA repeat expansion in mouse models require sacrificing the mouse and taking samples of organs. The obvious non-lethal targets, such as ears, tails, and blood do not have levels of repeat expansion comparable to internal organs. However, recent publications suggest that stool may be a suitable non-lethal candidate for tracking repeat expansion over time. Stool DNA may allow researchers to monitor the effect of interventions aimed at slowing DNA repeat expansion over time without harming the mouse. A commercial kit was first used to extract DNA from feces without success. …

Development Of Genetic Strategies To Treat Vision Loss In Usher Syndrome Type 1c (Ush1c), Dongjoon (Jason) Kim, Inga Kristaponyte, Bhagwat Alapure, Katelyn Robillard, Wadih Zein, Robert Koenekoop, Maria Reinoso, Jennifer J. Lentz

Medical Student Research Poster Symposium

Background: Usher Syndrome (Usher) is the most common genetic cause of deaf-blindness, characterized by the loss of hearing, vestibular function, and vision. Three clinical types (USH1- 3) and 10 genes are associated with the disease. USH1 is the most severe with congenital severeprofound sensorineural hearing loss and vestibular areflexia, and childhood onset of retinitis pigmentosa. Mutations in the USH1C gene account for 6-15% USH1, however USH1C c.216G>A (216A) accounts for nearly all USH1 cases in the Acadian populations in U.S. and Canada. The 216A splicing mutation results in a truncated harmonin protein, and photoreceptor and cochlear hair cell dysfunction. …

Mismatch In Mice And Men, Ryan Schroeder, Hayley Ulloa, Alan Williams, Ed Grabczyk

Medical Student Research Poster Symposium

Friedreich ataxia is a progressive degenerative neuromuscular disease that is caused by the expansion of a repetitive region of DNA, composed of three nucleotide repeats (GAA•TTC). Expansion of the DNA occurs throughout the lifespan of the patient and has been linked to the activity of specific DNA mismatch repair proteins. Disease onset occurs when the expansion increases in size beyond a certain threshold, silencing the gene and causing progressive ataxia, diabetes mellitus, and cardiomyopathy. These symptoms are linked to an increased repeat number observed within the heart, pancreas, and brain relative to other tissues within an individual. Friedreich ataxia is …

Risk Factors For Thoracic Aortic Dissection, Zhen Zhou, Alana C Cecchi, Siddharth K Prakash, Dianna M Milewicz

Faculty and Staff Publications

Thoracic aortic aneurysms involving the root and/or the ascending aorta enlarge over time until an acute tear in the intimal layer leads to a highly fatal condition, an acute aortic dissection (AAD). These Stanford type A AADs, in which the tear occurs above the sinotubular junction, leading to the formation of a false lumen in the aortic wall that may extend to the arch and thoracoabdominal aorta. Type B AADs originate in the descending thoracic aorta just distal to the left subclavian artery. Genetic variants and various environmental conditions that disrupt the aortic wall integrity have been identified that increase …

Complement Component C4 Structural Variation And Quantitative Traits Contribute To Sex-Biased Vulnerability In Systemic Sclerosis, Martin Kerick, Marialbert Acosta-Herrera, Carmen Pilar Simeón-Aznar, José Luis Callejas, Shervin Assassi, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Gisela Orozco, Anne Barton, Ariane L Herrick, Chikashi Terao, Yannick Allanore, Carmen Fonseca, Marta Eugenia Alarcón-Riquelme, Timothy R D J Radstake, Lorenzo Beretta, Christopher P Denton, Maureen D Mayes, Javier Martin

Student and Faculty Publications

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its …

Shared Brain And Genetic Architectures Between Mental Health And Physical Activity, Wei Zhang, Sarah E. Paul, Anderson M. Winkler, Ryan Bogdan, Janine D. Bijsterbosch

School of Medicine Publications and Presentations

Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N = 6389), we applied canonical correlation analysis to estimate associations between the amplitude and connectivity strength of subnetworks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health measures (primarily of depression, anxiety …

Svat: Secure Outsourcing Of Variant Annotation And Genotype Aggregation, Miran Kim, Su Wang, Xiaoqian Jiang, Arif Harmanci

Student and Faculty Publications

BACKGROUND: Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

RESULTS: We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at …

Genetics And Epigenetics Of Self-Injurious Thoughts And Behaviors: Systematic Review Of The Suicide Literature And Methodological Considerations, Salahudeen Mirza, Anna R Docherty, Amanda Bakian, Hilary Coon, Jair C Soares, Consuelo Walss-Bass, Gabriel R Fries

Student and Faculty Publications

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based …

Heterozygous Variants In Myh10 Associated With Neurodevelopmental Disorders And Congenital Anomalies With Evidence For Primary Cilia-Dependent Defects In Hedgehog Signaling, Alexander M Holtz, Rachel Vancoillie, Elizabeth A Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J Guillen Sacoto, Yue Si, Ingrid M Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H Sherr, Kimberly A Aldinger, William B Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A Donald, Emily O'Heir, Shade Moody, Katherine H Kim, Barbara K Burton, Grace Yoon, Miguel Del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L Sell, Patricia L Gordon, Jeremy W Prokop, Amel Karaa, Caleb Bupp, Benjamin A Raby

Student and Faculty Publications

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.

METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.

RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a …

Nasal Nitric Oxide Levels: Improving The Diagnosis Of Primary Ciliary Dyskinesia In Puerto Rico, Wilfredo De Jesús-Rojas, Francisco Alvarado-Huerta, Jesús M Meléndez-Montañez, José Muñiz-Hernández, Arnaldo Santos-López, Ricardo A Mosquera

Student and Faculty Publications

Primary Ciliary Dyskinesia (PCD) is a rare genetic disease characterized by motile cilia dysfunction with a prevalence of 1 in 16,309 individuals in Hispanic populations. In Puerto Rico, the prevalence of PCD is unknown. Diagnosis of PCD in Puerto Rico is challenging due to the lack of diagnostic technology. Algorithms for PCD diagnosis include clinical history, genetic testing, ciliary biopsy, and nasal Nitric Oxide (nNO) levels. For the first time, this study successfully implemented and measured the nNO levels in subjects with the RSPH4A (c.921+3_921+6del (intronic)) as a diagnostic tool to complement the current algorithm for PCD diagnosis on the …

Temperature Changes During Implant Osteotomy Preparations In Human Cadaver Tibiae Comparing Mis® Straight Drills With Densah® Burs, Nikolaos Soldatos, Huy Pham, Walid D Fakhouri, Binh Ngo, Panagiotis Lampropoulos, Tiffany Tran, Robin Weltman

Student and Faculty Publications

(1) Background: Several studies showed a sustained temperature of 47 °C or 50 °C for one minute resulted in vascular stasis and bone resorption with only limited bone regrowth over a 3–4-week healing period. The purpose of the present study was to evaluate the temperature changes (ΔΤ) that occur during the preparation of dental implant osteotomies using MIS® straight drills versus Densah® burs in a clockwise (cutting) drilling protocol. (2) Methods: Two hundred forty (240) osteotomies of two different systems’ drills were prepared at 6 mm depth at 800, 1000, and 1200 revolutions per minute (RPM), in fresh, unembalmed tibiae, …