Genetics Commons^™

Harnessing Microrna-Enriched Extracellular Vesicles For Liquid Biopsy, Song Yi Ko, Wonjae Lee, Honami Naora

Faculty, Staff and Student Publications

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given …

Failure To Mate Enhances Investment In Behaviors That May Promote Mating Reward And Impairs The Ability To Cope With Stressors Via A Subpopulation Of Neuropeptide F Receptor Neurons, Julia Ryvkin, Liora Omesi, Yong-Kyu Kim, Mali Levi, Hadar Pozeilov, Lital Barak-Buchris, Bella Agranovich, Ifat Abramovich, Eyal Gottlieb, Avi Jacob, Dick R Nässel, Ulrike Heberlein, Galit Shohat-Ophir

Faculty, Staff and Student Publications

Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward …

Single-Cell Multiomics Of The Human Retina Reveals Hierarchical Transcription Factor Collaboration In Mediating Cell Type-Specific Effects Of Genetic Variants On Gene Regulation, Jun Wang, Xuesen Cheng, Qingnan Liang, Leah A Owen, Jiaxiong Lu, Yiqiao Zheng, Meng Wang, Shiming Chen, Margaret M Deangelis, Yumei Li, Rui Chen

Faculty, Staff and Students Publications

BACKGROUND: Systematic characterization of how genetic variation modulates gene regulation in a cell type-specific context is essential for understanding complex traits. To address this question, we profile gene expression and chromatin accessibility in cells from healthy retinae of 20 human donors through single-cell multiomics and genomic sequencing.

RESULTS: We map eQTL, caQTL, allelic-specific expression, and allelic-specific chromatin accessibility in major retinal cell types. By integrating these results, we identify and characterize regulatory elements and genetic variants effective on gene regulation in individual cell types. The majority of identified sc-eQTLs and sc-caQTLs display cell type-specific effects, while the cis-elements containing genetic …

Health-Related Quality Of Life In A Systematically Assessed Cohort Of Children And Adults With Urea Cycle Disorders, Chaya N Murali, John R Barber, Robert Mccarter, Anqing Zhang, Natalie Gallant, Kara Simpson, Naghmeh Dorrani, Greta N Wilkening, Ron D Hays, Uta Lichter-Konecki, Members Of The Urea Cycle Disorders Consortium, Lindsay C Burrage, Sandesh C S Nagamani

Faculty, Staff and Students Publications

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs.

METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect …

Rare Variants Found In Clinical Gene Panels Illuminate The Genetic And Allelic Architecture Of Orofacial Clefting, Kimberly K Diaz Perez, Sarah W Curtis, Alba Sanchis-Juan, Xuefang Zhao, Taylor Head, Samantha Ho, Bridget Carter, Toby Mchenry, Madison R Bishop, Luz C Valencia-Ramirez, Claudia Restrepo, Jacqueline T Hecht, Lina M Uribe, George Wehby, Seth M Weinberg, Terri H Beaty, Jeffrey C Murray, Eleanor Feingold, Mary L Marazita, David J Cutler, Michael P Epstein, Harrison Brand, Elizabeth J Leslie

Faculty, Staff and Student Publications

PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.

METHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria.

RESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance.

CONCLUSION: …

Multi-Ancestry Genome-Wide Study Identifies Effector Genes And Druggable Pathways For Coronary Artery Calcification, Maryam Kavousi, Maxime M Bos, Hanna J Barnes, Christian L Lino Cardenas, Doris Wong, Haojie Lu, Chani J Hodonsky, Lennart P L Landsmeer, Adam W Turner, Minjung Kho, Natalie R Hasbani, Paul S De Vries, Donald W Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M Lutz, Leo-Pekka Lyytikäinen, Lotte Slenders, Albert V Smith, Maggie A Stanislawski, Jessica Van Setten, Quenna Wong, Lisa R Yanek, Diane M Becker, Marian Beekman, Matthew J Budoff, Mary F Feitosa, Chris Finan, Austin T Hilliard, Sharon L R Kardia, Jason C Kovacic, Brian G Kral, Carl D Langefeld, Lenore J Launer, Shaista Malik, Firdaus A A Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A Smith, Kent D Taylor, James G Terry, Jeroen Van Der Grond, Joyce Van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A Young, Nuno R Zilhão, Robert Zweiker, Themistocles L Assimes, Lewis C Becker, Daniel Bos, J Jeffrey Carr, L Adrienne Cupples, Dominique P V De Kleijn, Menno De Winther, Hester M Den Ruijter, Myriam Fornage, Barry I Freedman, Vilmundur Gudnason, Aroon D Hingorani, John E Hokanson, M Arfan Ikram, Ivana Išgum, David R Jacobs, Mika Kähönen, Leslie A Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T Raitakari, Helena Schmidt, P Eline Slagboom, André G Uitterlinden, Meike W Vernooij, Joshua C Bis, Nora Franceschini, Bruce M Psaty, Wendy S Post, Jerome I Rotter, Johan L M Björkegren, Christopher J O'Donnell, Lawrence F Bielak, Patricia A Peyser, Rajeev Malhotra, Sander W Van Der Laan, Clint L Miller

Faculty, Staff and Student Publications

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci …

A Multicenter Analysis Of Abnormal Chromosomal Microarray Findings In Congenital Heart Disease, Benjamin J Landis, Lindsey R Helvaty, Gabrielle C Geddes, Jiuann-Huey Ivy Lin, Svetlana A Yatsenko, Cecilia W Lo, William L Border, Stephanie Burns Wechsler, Chaya N Murali, Mahshid S Azamian, Seema R Lalani, Robert B Hinton, Vidu Garg, Kim L Mcbride, Jennelle C Hodge, Stephanie M Ware

Faculty, Staff and Students Publications

Background

Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships.

Methods and Results

Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

Genetic Control Of Mrna Splicing As A Potential Mechanism For Incomplete Penetrance Of Rare Coding Variants, Jonah Einson, Dafni Glinos, Eric Boerwinkle, Peter Castaldi, Dawood Darbar, Mariza De Andrade, Patrick Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Craig P Hersh, Jill Johnsen, Robert Kaplan, Barbara A Konkle, Charles Kooperberg, Rami Nassir, Ruth J F Loos, Deborah A Meyers, Braxton D Mitchell, Bruce Psaty, Ramachandran S Vasan, Stephen S Rich, Michael Rienstra, Jerome I Rotter, Aabida Saferali, Moore Benjamin Shoemaker, Edwin Silverman, Albert Vernon Smith, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium; Pejman Mohammadi, Pejman Mohammadi, Stephane E Castel, Ivan Iossifov, Tuuli Lappalainen

Faculty, Staff and Student Publications

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce …

Genotype Error Due To Low-Coverage Sequencing Induces Uncertainty In Polygenic Scoring, Ella Petter, Yi Ding, Kangcheng Hou, Arjun Bhattacharya, Alexander Gusev, Noah Zaitlen, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Polygenic scores (PGSs) have emerged as a standard approach to predict phenotypes from genotype data in a wide array of applications from socio-genomics to personalized medicine. Traditional PGSs assume genotype data to be error-free, ignoring possible errors and uncertainties introduced from genotyping, sequencing, and/or imputation. In this work, we investigate the effects of genotyping error due to low coverage sequencing on PGS estimation. We leverage SNP array and low-coverage whole-genome sequencing data (lcWGS, median coverage 0.04×) of 802 individuals from the Dana-Farber PROFILE cohort to show that PGS error correlates with sequencing depth (p = 1.2 × 10

Evaluating Approaches For Constructing Polygenic Risk Scores For Prostate Cancer In Men Of African And European Ancestry, Burcu F Darst, Jiayi Shen, Ravi K Madduri, Alexis A Rodriguez, Yukai Xiao, Xin Sheng, Edward J Saunders, Tokhir Dadaev, Mark N Brook, Thomas J Hoffmann, Kenneth Muir, Peggy Wan, Loic Le Marchand, Lynne Wilkens, Ying Wang, Johanna Schleutker, Robert J Macinnis, Cezary Cybulski, David E Neal, Børge G Nordestgaard, Sune F Nielsen, Jyotsna Batra, Judith A Clements, Australian Prostate Cancer Bioresource, Henrik Grönberg, Nora Pashayan, Ruth C Travis, Jong Y Park, Demetrius Albanes, Stephanie Weinstein, Lorelei A Mucci, David J Hunter, Kathryn L Penney, Catherine M Tangen, Robert J Hamilton, Marie-Élise Parent, Janet L Stanford, Stella Koutros, Alicja Wolk, Karina D Sørensen, William J Blot, Edward D Yeboah, James E Mensah, Yong-Jie Lu, Daniel J Schaid, Stephen N Thibodeau, Catharine M West, Christiane Maier, Adam S Kibel, Géraldine Cancel-Tassin, Florence Menegaux, Esther M John, Eli Marie Grindedal, Kay-Tee Khaw, Sue A Ingles, Ana Vega, Barry S Rosenstein, Manuel R Teixeira, Nc-La Pcap Investigators, Manolis Kogevinas, Lisa Cannon-Albright, Chad Huff, Luc Multigner, Radka Kaneva, Robin J Leach, Hermann Brenner, Ann W Hsing, Rick A Kittles, Adam B Murphy, Christopher J Logothetis, Susan L Neuhausen, William B Isaacs, Barbara Nemesure, Anselm J Hennis, John Carpten, Hardev Pandha, Kim De Ruyck, Jianfeng Xu, Azad Razack, Soo-Hwang Teo, Canary Pass Investigators, Lisa F Newcomb, Jay H Fowke, Christine Neslund-Dudas, Benjamin A Rybicki, Marija Gamulin, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Jose Esteban Castelao, Paul A Townsend, Dana C Crawford, Gyorgy Petrovics, Graham Casey, Monique J Roobol, Jennifer F Hu, Sonja I Berndt, Stephen K Van Den Eeden, Douglas F Easton, Stephen J Chanock, Michael B Cook, Fredrik Wiklund, John S Witte, Rosalind A Eeles, Zsofia Kote-Jarai, Stephen Watya, John M Gaziano, Amy C Justice, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and …

Genome-Wide Association Study Of Thoracic Aortic Aneurysm And Dissection In The Million Veteran Program, Derek Klarin, Poornima Devineni, Anoop K Sendamarai, Anthony R Angueira, Sarah E Graham, Ying H Shen, Michael G Levin, James P Pirruccello, Ida Surakka, Purushotham R Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E Shakt, Noah L Tsao, Renae L Judy, Ha My T Vy, Shefali S Verma, Daniel J Rader, Ron Do, Joseph E Bavaria, Girish N Nadkarni, Marylyn D Ritchie, Stephen Burgess, Dong-Chuan Guo, Patrick T Ellinor, Scott A Lemaire, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Philip S Tsao, Saiju Pyarajan, Scott M Damrauer

Faculty, Staff and Student Publications

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and …

Germline Genetic Variants And Pediatric Rhabdomyosarcoma Outcomes: A Report From The Children’S Oncology Group, Bailey A Martin-Giacalone, Melissa A Richard, Michael E Scheurer, Javed Khan, Pagna Sok, Priya B Shetty, Stephen J Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T Mcevoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J Lupo

Faculty, Staff and Student Publications

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.

METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical …

Declining Autozygosity Over Time: An Exploration In Over 1 Million Individuals From Three Diverse Cohorts, Sarah M C Colbert, Frank R Wendt, Gita A Pathak, Drew A Helmer, Elizabeth R Hauser, Matthew C Keller, Renato Polimanti, Emma C Johnson

Faculty, Staff and Students Publications

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict F

Comprehensive Ecg Reference Intervals In C57bl/6n Substrains Provide A Generalizable Guide For Cardiac Electrophysiology Studies In Mice, Manuela A Oestereicher, Janine M Wotton, Shinya Ayabe, Ghina Bou About, Tsz Kwan Cheng, Jae-Hoon Choi, Dave Clary, Emily M Dew, Lahcen Elfertak, Alain Guimond, Hamed Haseli Mashhadi, Jason D Heaney, Lois Kelsey, Piia Keskivali-Bond, Federico Lopez Gomez, Susan Marschall, Michael Mcfarland, Hamid Meziane, Violeta Munoz Fuentes, Ki-Hoan Nam, Zuzana Nichtová, Dale Pimm, Lynette Bower, Jan Prochazka, Jan Rozman, Luis Santos, Michelle Stewart, Nobuhiko Tanaka, Christopher S Ward, Amelia M E Willett, Robert Wilson, Robert E Braun, Mary E Dickinson, Ann M Flenniken, Yann Herault, K C Kent Lloyd, Ann-Marie Mallon, Colin Mckerlie, Stephen A Murray, Lauryl M J Nutter, Radislav Sedlacek, Je Kyung Seong, Tania Sorg, Masaru Tamura, Sara Wells, Elida Schneltzer, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe De Angelis, Jacqueline K White, Nadine Spielmann

Faculty, Staff and Students Publications

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key …

Impact Of Cross-Ancestry Genetic Architecture On Gwass In Admixed Populations, Rachel Mester, Kangcheng Hou, Yi Ding, Gillian Meeks, Kathryn S Burch, Arjun Bhattacharya, Brenna M Henn, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWASs in admixed populations, such as the need to correctly adjust …

An Fbn1 Deep Intronic Variant Is Associated With Pseudoexon Formation And A Variable Marfan Phenotype In A Five Generation Family, Dong-Chuan Guo, Xueyan Duan, Kathleen Mimnagh, Alana C Cecchi, Isabella C Marin, Yang Yu, Walter V Velasco, Kwanghyuk Lee, Xue Zhu, David R Murdock, Suzanne M Leal, Marsha M Wheeler, Josh Smith, Michael J Bamshad, Dianna M Milewicz

Faculty, Staff and Student Publications

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to …

Delineating The Cellular Mechanisms Of Endoplasmic Reticulum-Retained Endoglin Mutants Causing Hereditary Hemorrhagic Telangiectasia Type 1, Nesrin Mohammed Gariballa

Dissertations

Endoglin, also known as cluster of differentiation 105 (CD105), is an auxiliary receptor in the TGFβ signaling pathway. It is predominantly expressed in endothelial cells as a component of the heterotetrameric receptor dimers comprising type I, type II receptors and the binding ligands. Mutations in ENG, the gene encoding endoglin, have been associated with Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), a rare autosomal dominant inherited disorder affecting about 1 in 5000-8000 individuals, which is generally characterized by vascular malformations. Secretory and many endomembrane proteins synthesized in the Endoplasmic Reticulum (ER) are subjected to a highly stringent protein folding and assembly …

Leukocyte Tyrosine Kinase (Ltk) Is The Mendelian Determinant Of The Axolotl Melanoid Color Variant, Mirindi Kabangu, Raissa Cecil, Lloyd Strohl Ii, Nataliya Y. Timoshevskaya, Jeramiah James Smith, Stephen Randal Voss

Markey Cancer Center Faculty Publications

The great diversity of color patterns observed among amphibians is largely explained by the differentiation of relatively few pigment cell types during development. Mexican axolotls present a variety of color phenotypes that span the continuum from leucistic to highly melanistic. The melanoid axolotl is a Mendelian variant characterized by large numbers of melanophores, proportionally fewer xanthophores, and no iridophores. Early studies of melanoid were influential in developing the single-origin hypothesis of pigment cell development, wherein it has been proposed that all three pigment cell types derive from a common progenitor cell, with pigment metabolites playing potential roles in directing the …

Rare Variant Enrichment Analysis Supports Greb1l As A Contributory Driver Gene In The Etiology Of Mayer-Rokitansky-Küster-Hauser Syndrome, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Faculty, Staff and Student Publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was …

A Biallelic Frameshift Indel In Ppp1r35 As A Cause Of Primary Microcephaly, Moez Dawood, Gulsen Akay, Tadahiro Mitani, Dana Marafi, Jawid M Fatih, Alper Gezdirici, Hossein Najmabadi, Kimia Kahrizi, Jaya Punetha, Christopher M Grochowski, Haowei Du, Angad Jolly, He Li, Zeynep Coban-Akdemir, Fritz J Sedlazeck, Jill V Hunter, Shalini N Jhangiani, Donna Muzny, Davut Pehlivan, Jennifer E Posey, Claudia M B Carvalho, Richard A Gibbs, James R Lupski

Faculty, Staff and Student Publications

Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule-binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family-based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (-4.3 SD at birth, -6.1 SD by …

Deepbend: An Interpretable Model Of Dna Bendability, Samin Rahman Khan, Sadman Sakib, M Sohel Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

The bendability of genomic DNA impacts chromatin packaging and protein-DNA binding. However, we do not have a comprehensive understanding of the motifs influencing DNA bendability. Recent high-throughput technologies such as Loop-Seq offer an opportunity to address this gap but the lack of accurate and interpretable machine learning models still remains. Here we introduce DeepBend, a convolutional neural network model with convolutions designed to directly capture the motifs underlying DNA bendability and their periodic occurrences or relative arrangements that modulate bendability. DeepBend consistently performs on par with alternative models while giving an extra edge through mechanistic interpretations. Besides confirming the known …

Biallelic Variants In Ogdh Encoding Oxoglutarate Dehydrogenase Lead To A Neurodevelopmental Disorder Characterized By Global Developmental Delay, Movement Disorder, And Metabolic Abnormalities, Ella F Whittle, Madison Chilian, Ehsan Ghayoor Karimiani, Helga Progri, Daniela Buhas, Melis Kose, Rebecca D Ganetzky, Mehran Beiraghi Toosi, Paria Najarzadeh Torbati, Reza Shervin Badv, Ivan Shelihan, Hui Yang, Houda Zghal Elloumi, Sukyeong Lee, Yalda Jamshidi, Alan M Pittman, Henry Houlden, Erika Ignatius, Shamima Rahman, Reza Maroofian, Wan Hee Yoon, Christopher J Carroll

Faculty, Staff and Students Publications

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.

RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme …

Exome Array Analysis Of 9721 Ischemic Stroke Cases From The Sign Consortium, Huichun Xu, Kevin Nguyen, Brady J Gaynor, Hua Ling, Wei Zhao, Patrick F Mcardle, Timothy D O'Connor, O Colin Stine, Kathleen A Ryan, Megan Lynch, Jennifer A Smith, Jessica D Faul, Yao Hu, Jeffrey W Haessler, Myriam Fornage, Charles Kooperberg, On Behalf Of The Trans-Omics For Precision Medicine Topmed Stroke Working Group, James A Perry, Charles C Hong, John W Cole, Elizabeth Pugh, Kimberly Doheny, Sharon L R Kardia, David R Weir, Steven J Kittner, Braxton D Mitchell, Sign Consortium

Faculty, Staff and Student Publications

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare …

Deciphering The Mechanism And Function Of Hsp100 Unfoldases From Protein Structure, Grace Lee, Rebecca S Kim, Sang Bum Lee, Sukyeong Lee, Francis T F Tsai

Faculty, Staff and Students Publications

Hsp100 chaperones, also known as Clp proteins, constitute a family of ring-forming ATPases that differ in 3D structure and cellular function from other stress-inducible molecular chaperones. While the vast majority of ATP-dependent molecular chaperones promote the folding of either the nascent chain or a newly imported polypeptide to reach its native conformation, Hsp100 chaperones harness metabolic energy to perform the reverse and facilitate the unfolding of a misfolded polypeptide or protein aggregate. It is now known that inside cells and organelles, different Hsp100 members are involved in rescuing stress-damaged proteins from a previously aggregated state or in recycling polypeptides marked …

Lpa Disruption With Aav-Crispr Potently Lowers Plasma Apo(A) In Transgenic Mouse Model: A Proof-Of-Concept Study, Alexandria M Doerfler, So Hyun Park, Julia M Assini, Amer Youssef, Lavanya Saxena, Adam B Yaseen, Marco De Giorgi, Marcel Chuecos, Ayrea E Hurley, Ang Li, Santica M Marcovina, Gang Bao, Michael B Boffa, Marlys L Koschinsky, William R Lagor

Faculty, Staff and Students Publications

Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Prenatal And Pregnancy Loss Evaluation By Noninvasive Screening And Diagnostic Genetic Testing, Abigail Haggerty

Theses & Dissertations

Noninvasive prenatal testing (NIPT) utilizing cell-free fetal DNA (cffDNA) in the maternal blood is the screening test of choice for physicians today. NIPT depends on the amount of cffDNA in the maternal blood, called the fetal fraction (FF). Researchers are investigating the implications of the FF value in reference to multiple variables in pregnancy outcome, including the risk for aneuploidy and maternal factors that influence the FF.

Diagnostic techniques utilized in patient care include cytogenetics, fluorescence in-situ hybridization (FISH), and microarray. Diagnostic testing is critical to confirm or rule out genetic abnormalities among women with abnormal screening results, …

A Large-Scale Genome-Wide Gene-Gene Interaction Study Of Lung Cancer Susceptibility In Europeans With A Trans-Ethnic Validation In Asians, Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J Hung, Christopher I Amos, Hongbing Shen, Feng Chen, David C Christiani

Faculty, Staff and Students Publications

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms …

Genetics And Genomics Education Among Physician Assistants, Wesley Patterson

All Dissertations

This dissertation comprises five chapters to describe genetics and genomics education among physician assistant/associate (PA) students and practicing PAs. Chapter I introduces the gap in supply and demand of genetic services, the need for non-genetics healthcare providers to fill the gap, and the PA profession as a solution.

Chapter II is a rapid literature review that summarizes the available literature regarding genetics and genomics education for PAs. A paucity of literature exists to describe the current state of PA genetics-genomics education. The few studies retrieved describe content being taught in PA programs, the number of genetics-genomics contact hours PA students …