Genetics and Genomics Commons^™

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 …

Braf V600e-Mutant Cancers Treated With Vemurafenib Alone Or In Combination With Everolimus, Sorafenib, Or Crizotinib Or With Paclitaxel And Carboplatin (Vem-Plus) Study, Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David S Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Lamki Busaidy, Milind Javle, Lauren Averett Byers, John V Heymach, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or …

Genetic Effect On Body Mass Index And Cardiovascular Disease Across Generations, Chloé Sarnowski, Matthew P Conomos, Ramachandran S Vasan, James B Meigs, Josée Dupuis, Ching-Ti Liu, Aaron Leong

Faculty, Staff and Student Publications

BACKGROUND: Whether genetics contribute to the rising prevalence of obesity or its cardiovascular consequences in today's obesogenic environment remains unclear. We sought to determine whether the effects of a higher aggregate genetic burden of obesity risk on body mass index (BMI) or cardiovascular disease (CVD) differed by birth year.

METHODS: We split the FHS (Framingham Heart Study) into 4 equally sized birth cohorts (birth year before 1932, 1932 to 1946, 1947 to 1959, and after 1960). We modeled a genetic predisposition to obesity using an additive genetic risk score (GRS) of 941 BMI-associated variants and tested for GRS-birth year interaction …

Systemic Interindividual Epigenetic Variation In Humans Is Associated With Transposable Elements And Under Strong Genetic Control, Chathura J Gunasekara, Harry Mackay, C Anthony Scott, Shaobo Li, Eleonora Laritsky, Maria S Baker, Sandra L Grimm, Goo Jun, Yumei Li, Rui Chen, Joseph L Wiemels, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Student Publications

BACKGROUND: Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition.

RESULTS: We use target-capture bisulfite sequencing to assess DNA methylation at 4086 CoRSIVs in multiple tissues from each of 188 donors in the NIH Gene-Tissue Expression (GTEx) program. At CoRSIVs, DNA methylation in peripheral blood correlates with …

Genome-Wide Mendelian Randomization Identifies Putatively Causal Gut Microbiota For Multiple Peptic Ulcer Diseases, Jingwei Zhao, Yucheng Hou, Tianyi Xie, Yizhang Zhu, Xinyi Feng, Yong Zhang, Ziyi Yang, Wei Gong

Faculty, Staff and Student Publications

OBJECTIVE: The pathogenesis of peptic ulcer diseases (PUDs) involves multiple factors, and the contribution of gut microbiota to this process remains unclear. While previous studies have associated gut microbiota with peptic ulcers, the precise nature of the relationship, whether causal or influenced by biases, requires further elucidation.

DESIGN: The largest meta-analysis of genome-wide association studies was conducted by the MiBioGen consortium, which provided the summary statistics of gut microbiota for implementation in the Mendelian randomization (MR) analysis. Summary statistics for five types of PUDs were compiled using the FinnGen Consortium R8 release data. Various statistical techniques, including inverse variance weighting …

Whole Genome Sequence Analysis Of Apparent Treatment Resistant Hypertension Status In Participants From The Trans-Omics For Precision Medicine Program, Nicole D Armstrong, Vinodh Srinivasasainagendra, Farah Ammous, Themistocles L Assimes, Amber L Beitelshees, Jennifer Brody, Brian E Cade, Yii-Der Ida Chen, Han Chen, Paul S De Vries, James S Floyd, Nora Franceschini, Xiuqing Guo, Jacklyn N Hellwege, John S House, Chii-Min Hwu, Sharon L R Kardia, Ethan M Lange, Leslie A Lange, Caitrin W Mcdonough, May E Montasser, Jeffrey R O'Connell, Megan M Shuey, Xiao Sun, Rikki M Tanner, Zhe Wang, Wei Zhao, April P Carson, Todd L Edwards, Tanika N Kelly, Eimear E Kenny, Charles Kooperberg, Ruth J F Loos, Alanna C Morrison, Alison Motsinger-Reif, Bruce M Psaty, Dabeeru C Rao, Susan Redline, Stephen S Rich, Jerome I Rotter, Jennifer A Smith, Albert V Smith, Marguerite R Irvin, Donna K Arnett

Faculty, Staff and Student Publications

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data.

Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American).

Results: One variant in …

The Assembled Genome Of The Stroke-Prone Spontaneously Hypertensive Rat, Theodore S Kalbfleisch, Nahla A Hussien Abouel Ela, Kai Li, Wesley A Brashear, Kelli J Kochan, Andrew E Hillhouse, Yaming Zhu, Isha S Dhande, Eric J Kline, Elizabeth A Hudson, Terence D Murphy, Françoise Thibaud-Nissen, Melissa L Smith, Peter A Doris

Faculty, Staff and Student Publications

BACKGROUND: We report the creation and evaluation of a de novo assembly of the genome of the spontaneously hypertensive rat, the most widely used model of human cardiovascular disease.

METHODS: The genome is assembled from long read sequencing (PacBio HiFi and continuous long read data [CLR]) and scaffolded with long-range structural information obtained from Bionano optical maps and proximity ligation sequencing proximity analysis of the genome. The genome assembly was polished with Illumina short reads. Completeness of the assembly was investigated using Benchmarking Universal Single Copy Orthologs analysis. The genome assembly was also evaluated with the rat reference gene set, …

Artificial Intelligence-Driven Meta-Analysis Of Brain Gene Expression Identifies Novel Gene Candidates And A Role For Mitochondria In Alzheimer’S Disease, Caitlin A Finney, Fabien Delerue, Wendy A Gold, David A Brown, Artur Shvetcov

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional …

Gene-Educational Attainment Interactions In A Multi-Population Genome-Wide Meta-Analysis Identify Novel Lipid Loci, Lisa De Las Fuentes, Karen L Schwander, Michael R Brown, Amy R Bentley, Thomas W Winkler, Yun Ju Sung, Patricia B Munroe, Clint L Miller, Hugo Aschard, Stella Aslibekyan, Traci M Bartz, Lawrence F Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F Feitosa, Xiuqing Guo, Fernando P Hartwig, Andrea Horimoto, Ivana Kolčić, Elise Lim, Yongmei Liu, Alisa K Manning, Jonathan Marten, Solomon K Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A Richard, Paul M Ridker, Albert V Smith, Dina Vojinovic, Alan B Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I Freedman, Chuan Gao, Franco Giulianini, Sarah E Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O Tayo, Peter J Van Der Most, Niek Verweij, Erin B Ware, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Yiqiang Zhan, Najaf Amin, Dan E Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf De Faire, Renée De Mutsert, H Janaka De Silva, Paul S De Vries, Ahn Do, Jessica D Faul, Virginia Fisher, James S Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C Charles Gu, Göran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M Arfan Ikram, David R Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W Manichaikul, Colin A Mckenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P Nelson, Jeffrey R O'Connell, Nicholette D Palmer, Alexandre C Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T Raitakari, Kenneth Rice, Treva K Rice, Stephen S Rich, Charumathi Sabanayagam, Pamela J Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A Smith, John M Starr, Konstantin Strauch, E Shyong Tai, Kent D Taylor, Michael Y Tsai, André G Uitterlinden, Diana Van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M Becker, Amélie Bonnefond, Donald W Bowden, Richard S Cooper, Ian J Deary, Jasmin Divers, Tõnu Esko, Paul W Franks, Philippe Froguel, Christian Gieger, Jost B Jonas, Norihiro Kato, Timo A Lakka, Karin Leander, Terho Lehtimäki, Patrik K E Magnusson, Kari E North, Ioanna Ntalla, Brenda Penninx, Nilesh J Samani, Harold Snieder, Beatrice Spedicati, Pim Van Der Harst, Henry Völzke, Lynne E Wagenknecht, David R Weir, Mary K Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I Chasman, Michele K Evans, Ervin R Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L Horta, Sharon L R Kardia, Jose Eduardo Krieger, Dennis O Mook-Kanamori, Patricia A Peyser, Michael M Province, Bruce M Psaty, Igor Rudan, Xueling Sim, Blair H Smith, Rob M Van Dam, Cornelia M Van Duijn, Tien Yin Wong, Donna K Arnett, Dabeeru C Rao, James Gauderman, Ching-Ti Liu, Alanna C Morrison, Jerome I Rotter, Myriam Fornage

Faculty, Staff and Student Publications

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.

Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).

Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine …

Development Of Competency-Based Online Genomic Medicine Training (Cogent), Susanne B Haga, Wendy K Chung, Luis A Cubano, Timothy B Curry, Philip E Empey, Geoffrey S Ginsburg, Kara Mangold, Christina Y Miyake, Siddharth K Prakash, Laura B Ramsey, Robb Rowley, Carolyn R Rohrer Vitek, Todd C Skaar, Julia Wynn, Teri A Manolio

Faculty, Staff and Student Publications

The fields of genetics and genomics have greatly expanded across medicine through the development of new technologies that have revealed genetic contributions to a wide array of traits and diseases. Thus, the development of widely available educational resources for all healthcare providers is essential to ensure the timely and appropriate utilization of genetics and genomics patient care. In 2020, the National Human Genome Research Institute released a call for new proposals to develop accessible, sustainable online education for health providers. This paper describes the efforts of the six teams awarded to reach the goal of providing genetic and genomic training …

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 …

Whole Genome Sequencing Identifies Structural Variants Contributing To Hematologic Traits In The Nhlbi Topmed Program, Marsha M Wheeler, Adrienne M Stilp, Shuquan Rao, Bjarni V Halldórsson, Doruk Beyter, Jia Wen, Anna V Mihkaylova, Caitlin P Mchugh, John Lane, Min-Zhi Jiang, Laura M Raffield, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B Bis, Nathalie Chami, Paul S De Vries, Pinkal Desai, James S Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R Yanek, Laura Almasy, Lewis C Becker, John Blangero, Michael H Cho, Joanne E Curran, Myriam Fornage, Robert C Kaplan, Joshua P Lewis, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Michael Preuss, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Hua Tang, Russell P Tracy, Eric Boerwinkle, Goncalo R Abecasis, Thomas W Blackwell, Albert V Smith, Andrew D Johnson, Rasika A Mathias, Deborah A Nickerson, Matthew P Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K Magnússon, Kari Stefansson, Nathan D Pankratz, Daniel E Bauer, Paul L Auer, Alex P Reiner

Faculty, Staff and Student Publications

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits …

Leveraging Pleiotropy To Discover And Interpret Gwas Results For Sleep-Associated Traits, Sung Chun, Sebastian Akle, Athanasios Teodosiadis, Brian E Cade, Heming Wang, Tamar Sofer, Daniel S Evans, Katie L Stone, Sina A Gharib, Sutapa Mukherjee, Lyle J Palmer, David Hillman, Jerome I Rotter, Craig L Hanis, John A Stamatoyannopoulos, Susan Redline, Chris Cotsapas, Shamil R Sunyaev

Faculty, Staff and Student Publications

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations …

Further Evidence That Arih1 Rare Variants Predispose To Thoracic Aortic Disease, Maura L Boerio, Nicole M Engelhardt, Sanmati Cuddapah, Jessica I Gold, Isabella C Marin, Amélie Pinard, Dongchuan Guo, Siddharth K Prakash, Dianna M Milewicz

Faculty, Staff and Student Publications

No abstract provided.

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

Faculty, Staff and Student 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 Framework For Detecting Noncoding Rare-Variant Associations Of Large-Scale Whole-Genome Sequencing Studies, Zilin Li, Xihao Li, Hufeng Zhou, Sheila M Gaynor, Margaret Sunitha Selvaraj, Theodore Arapoglou, Corbin Quick, Yaowu Liu, Han Chen, Ryan Sun, Rounak Dey, Donna K Arnett, Paul L Auer, Lawrence F Bielak, Joshua C Bis, Thomas W Blackwell, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, Matthew P Conomos, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Paul S De Vries, Ravindranath Duggirala, Nora Franceschini, Barry I Freedman, Harald H H Göring, Xiuqing Guo, Rita R Kalyani, Charles Kooperberg, Brian G Kral, Leslie A Lange, Bridget M Lin, Ani Manichaikul, Alisa K Manning, Lisa W Martin, Rasika A Mathias, James B Meigs, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Laura M Raffield, Susan Redline, Alexander P Reiner, Muagututi'a Sefuiva Reupena, Kenneth M Rice, Stephen S Rich, Jennifer A Smith, Kent D Taylor, Margaret A Taub, Ramachandran S Vasan, Daniel E Weeks, James G Wilson, Lisa R Yanek, Wei Zhao, Jerome I Rotter, Cristen J Willer, Pradeep Natarajan, Gina M Peloso, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate …

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

Faculty, Staff and Student 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

Faculty, Staff and Student 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 …

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

Faculty, Staff and Student 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 …

Scgwas: Landscape Of Trait-Cell Type Associations By Integrating Single-Cell Transcriptomics-Wide And Genome-Wide Association Studies, Peilin Jia, Ruifeng Hu, Fangfang Yan, Yulin Dai, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: The rapid accumulation of single-cell RNA sequencing (scRNA-seq) data presents unique opportunities to decode the genetically mediated cell-type specificity in complex diseases. Here, we develop a new method, scGWAS, which effectively leverages scRNA-seq data to achieve two goals: (1) to infer the cell types in which the disease-associated genes manifest and (2) to construct cellular modules which imply disease-specific activation of different processes.

RESULTS: scGWAS only utilizes the average gene expression for each cell type followed by virtual search processes to construct the null distributions of module scores, making it scalable to large scRNA-seq datasets. We demonstrated scGWAS in …

Metarnn: Differentiating Rare Pathogenic And Rare Benign Missense Snvs And Indels Using Deep Learning, Chang Li, Degui Zhi, Kai Wang, Xiaoming Liu

Faculty, Staff and Student Publications

Multiple computational approaches have been developed to improve our understanding of genetic variants. However, their ability to identify rare pathogenic variants from rare benign ones is still lacking. Using context annotations and deep learning methods, we present pathogenicity prediction models, MetaRNN and MetaRNN-indel, to help identify and prioritize rare nonsynonymous single nucleotide variants (nsSNVs) and non-frameshift insertion/deletions (nfINDELs). We use independent test sets to demonstrate that these new models outperform state-of-the-art competitors and achieve a more interpretable score distribution. Importantly, prediction scores from both models are comparable, enabling easy adoption of integrated genotype-phenotype association analysis methods. All pre-computed nsSNV scores …

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

Faculty, Staff and Student 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 …

Machine Learning Modeling Of Protein-Intrinsic Features Predicts Tractability Of Targeted Protein Degradation, Wubing Zhang, Shourya S Roy Burman, Jiaye Chen, Katherine A Donovan, Yang Cao, Chelsea Shu, Boning Zhang, Zexian Zeng, Shengqing Gu, Yi Zhang, Dian Li, Eric S Fischer, Collin Tokheim, X Shirley Liu

Faculty, Staff and Student Publications

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed “degradability”, is largely unknown. Here, we developed a machine learning model, model-free analysis of protein degradability (MAPD), to predict degradability from features intrinsic to protein targets. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds [with an area under the precision–recall curve (AUPRC) of 0.759 and an area under the receiver operating characteristic curve (AUROC) of 0.775] and is …

Leveraging Family History In Genetic Association Analyses Of Binary Traits, Yixin Zhang, James B Meigs, Ching-Ti Liu, Josée Dupuis, Chloé Sarnowski

Faculty, Staff and Student Publications

BACKGROUND: Considering relatives' health history in logistic regression for case-control genome-wide association studies (CC-GWAS) may provide new information that increases accuracy and power to detect disease associated genetic variants. We conducted simulations and analyzed type 2 diabetes (T2D) data from the Framingham Heart Study (FHS) to compare two methods, liability threshold model conditional on both case-control status and family history (LT-FH) and Fam-meta, which incorporate family history into CC-GWAS.

RESULTS: In our simulation scenario of trait with modest T2D heritability (h

CONCLUSIONS: Overall, LT-FH and Fam-meta had higher power than CC-GWAS in simulations, especially using phenotypes that were more prevalent …

Cost-Effectiveness Frameworks For Comparing Genome And Exome Sequencing Versus Conventional Diagnostic Pathways: A Scoping Review And Recommended Methods, Bart S Ferket, Zach Baldwin, Priyanka Murali, Akila Pai, Kathleen F Mittendorf, Heidi V Russell, Flavia Chen, Frances L Lynch, Kristen Hassmiller Lich, Lucia A Hindorff, Renate Savich, Anne Slavotinek, Hadley Stevens Smith, Bruce D Gelb, David L Veenstra

Faculty, Staff and Student Publications

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES.

METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening.

RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses …

Genetic Variations Mir-10aa>T, Mir-30ca>G, Mir-181at>C, And Mir-499ba>G And The Risk Of Recurrent Pregnancy Loss In Korean Women, Hui-Jeong An, Sung-Hwan Cho, Han-Sung Park, Ji-Hyang Kim, Young-Ran Kim, Woo-Sik Lee, Jung-Ryeol Lee, Seong-Soo Joo, Eun-Hee Ahn, Nam-Keun Kim

Faculty, Staff and Student Publications

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = …

Temporal Lobe White Matter Asymmetry And Language Laterality In Epilepsy Patients, Nikolaos Soldatos, Huy Pham, Walid D Fakhouri, Binh Ngo, Panagiotis Lampropoulos, Tiffany Tran, Robin Weltman

Faculty, Staff and Student 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, …

Invasive Group A Streptococcal Penicillin Binding Protein 2× Variants Associated With Reduced Susceptibility To Β-Lactam Antibiotics In The United States, 2015-2021, Sopio Chochua, Benjamin Metcalf, Zhongya Li, Saundra Mathis, Theresa Tran, Joy Rivers, Katherine E Fleming-Dutra, Yuan Li, Lesley Mcgee, Bernard Beall

Faculty, Staff and Student Publications

All known group A streptococci [GAS] are susceptible to β-lactam antibiotics. We recently identified an invasive GAS (iGAS) variant (emm43.4/PBP2x-T553K) with unusually high minimum inhibitory concentrations (MICs) for ampicillin and amoxicillin, although clinically susceptible to β-lactams. We aimed to quantitate PBP2x variants, small changes in β-lactam MICs, and lineages within contemporary population-based iGAS. PBP2x substitutions were comprehensively identified among 13,727 iGAS recovered during 2015-2021, in the USA. Isolates were subjected to antimicrobial susceptibility testing employing low range agar diffusion and PBP2x variants were subjected to phylogenetic analyses. Fifty-five variants were defined based upon substitutions within an assigned PBP2x …

“Stripe” Transcription Factors Provide Accessibility To Co-Binding Partners In Mammalian Genomes, Yongbing Zhao, Supriya V Vartak, Andrea Conte, Xiang Wang, David A Garcia, Evan Stevens, Seol Kyoung Jung, Kyong-Rim Kieffer-Kwon, Laura Vian, Timothy Stodola, Francisco Moris, Laura Chopp, Silvia Preite, Pamela L Schwartzberg, Joseph M Kulinski, Ana Olivera, Christelle Harly, Avinash Bhandoola, Elisabeth F Heuston, David M Bodine, Raul Urrutia, Arpita Upadhyaya, Matthew T Weirauch, Gordon Hager, Rafael Casellas

Faculty, Staff and Student Publications

Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, …

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 …