Genetics and Genomics Commons^™

Genetic Variants For Head Size Share Genes And Pathways With Cancer, Maria J Knol, Raymond A Poot, Tavia E Evans, Claudia L Satizabal, Aniket Mishra, Muralidharan Sargurupremraj, Sandra Van Der Auwera, Marie-Gabrielle Duperron, Xueqiu Jian, Isabel C Hostettler, Dianne H K Van Dam-Nolen, Sander Lamballais, Mikolaj A Pawlak, Cora E Lewis, Amaia Carrion-Castillo, Theo G M Van Erp, Céline S Reinbold, Jean Shin, Markus Scholz, Asta K Håberg, Anders Kämpe, Gloria H Y Li, Reut Avinun, Joshua R Atkins, Fang-Chi Hsu, Alyssa R Amod, Max Lam, Ami Tsuchida, Mariël W A Teunissen, Nil Aygün, Yash Patel, Dan Liang, Alexa S Beiser, Frauke Beyer, Joshua C Bis, Daniel Bos, R Nick Bryan, Robin Bülow, Svenja Caspers, Gwenaëlle Catheline, Charlotte A M Cecil, Shareefa Dalvie, Jean-François Dartigues, Charles Decarli, Maria Enlund-Cerullo, Judith M Ford, Barbara Franke, Barry I Freedman, Nele Friedrich, Melissa J Green, Simon Haworth, Catherine Helmer, Per Hoffmann, Georg Homuth, M Kamran Ikram, Clifford R Jack, Neda Jahanshad, Christiane Jockwitz, Yoichiro Kamatani, Annchen R Knodt, Shuo Li, Keane Lim, W T Longstreth, Fabio Macciardi, Outi Mäkitie, Bernard Mazoyer, Sarah E Medland, Susumu Miyamoto, Susanne Moebus, Thomas H Mosley, Ryan Muetzel, Thomas W Mühleisen, Manabu Nagata, Soichiro Nakahara, Nicholette D Palmer, Zdenka Pausova, Adrian Preda, Yann Quidé, William R Reay, Gennady V Roshchupkin, Reinhold Schmidt, Pamela J Schreiner, Kazuya Setoh, Chin Yang Shapland, Stephen Sidney, Beate St Pourcain, Jason L Stein, Yasuharu Tabara, Alexander Teumer, Anne Uhlmann, Aad Van Der Lugt, Meike W Vernooij, David J Werring, B Gwen Windham, A Veronica Witte, Katharina Wittfeld, Qiong Yang, Kazumichi Yoshida, Han G Brunner, Quentin Le Grand, Kang Sim, Dan J Stein, Donald W Bowden, Murray J Cairns, Ahmad R Hariri, Ching-Lung Cheung, Sture Andersson, Arno Villringer, Tomas Paus, Sven Cichon, Vince D Calhoun, Fabrice Crivello, Lenore J Launer, Tonya White, Peter J Koudstaal, Henry Houlden, Myriam Fornage, Fumihiko Matsuda, Hans J Grabe, M Arfan Ikram, Stéphanie Debette, Paul M Thompson, Sudha Seshadri, Hieab H H Adams

Journal Articles

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size …

Unsupervised Deep Representation Learning Enables Phenotype Discovery For Genetic Association Studies Of Brain Imaging, Khush Patel, Ziqian Xie, Hao Yuan, Sheikh Muhammad Saiful Islam, Yaochen Xie, Wei He, Wanheng Zhang, Assaf Gottlieb, Han Chen, Luca Giancardo, Alexander Knaack, Evan Fletcher, Myriam Fornage, Shuiwang Ji, Degui Zhi

Journal Articles

Understanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants' T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning …

Association Between Regulatory T Cells And Ischemic Heart Disease: A Mendelian Randomization Study, Yucheng Hou, Ke Si, Jingyue Yang, Tan Liu, Basel Abdelazeem, Nonthikorn Theerasuwipakorn, Jingwei Zhao, Zhenya Shen

Journal Articles

BACKGROUND: An imbalance of innate and acquired immune responses is significantly involved in the pathophysiology of coronary atherosclerosis and the occurrence of ischemic heart disease (IHD). Regulatory T cells (Tregs) play an essential regulatory role in atherosclerotic plaque formation and maintenance; therefore, dysfunction of Tregs triggers the formation of atherosclerotic plaques and accelerates their progression. However, due to the inherent limitations of observational research, clinical evidence is limited concerning the relationship between the variation in peripheral Tregs and the risk of IHD, and the cause-and-effect relationship between these factors is unclear. Mendelian randomization (MR) uses genetic variation as a proxy …

Contextualizing The Revised Patient Perception Of Patient-Centeredness (Pppc-R) Scale In Primary Healthcare Settings: A Validity And Reliability Evaluation Study, Yiyuan Cai, Pengfei Guo, Jiong Tu, Mengyao Hu, Lingrui Liu, Bridget L Ryan, Jing Liao, Rubee Dev, Yiran Li, Tianyu Huang, Ruilin Wang, Li Kuang, Ruonan Huang, Xinfang Li, Edmundo Roberto Melipillán, Shuaixiang Zhao, Wenjun He, Xiaohui Wang, Nan Zhang, Dong Roman Xu

Journal Articles

BACKGROUND: An English version of the Patient Perception of Patient-Centeredness (PPPC) scale was recently revised, and it is necessary to test this instrument in different primary care populations.

AIM: This study aimed to assess the validity and reliability of a Chinese version of the PPPC scale.

DESIGN: A mixed method was used in this study. The Delphi method was used to collect qualitative and quantitative data to address the content validity of the PPPC scale by calculating the Content Validity Index, Content Validity Ratio, the adjusted Kappa, and the Item Impact Score. Confirmatory factor analysis (CFA) and exploratory factor analysis …

The Use Of Cardiac Magnetic Resonance In Hypertrophic Cardiomyopathy Over The Past 10 Years [2013-2023]: A Citespace-Based Bibliometric Analysis, Mengyao Hu, Yu Shen, Yipei Song, Shuhao Li, Pei Yang, Ao Kan, Qiming Fang, Yun Peng, Haibo Ren, Yajing Zhang, Lianggeng Gong

Journal Articles

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder characterized by the hypertrophy of a segment of the myocardium. Cardiac magnetic resonance (CMR) has been widely used in the assessment of HCM. However, no bibliometric assessment has been conducted on the progress of research in this field. This study thus aimed to examine the current state of research into the application of CMR in HCM and the hotspots and trends that have emerged in this field over the past decade.

METHODS: A systematic search was conducted on the Web of Science regarding CMR in the assessment of HCM. The …

Chromosome 10q2432 Variants Associate With Brain Arterial Diameters In Diverse Populations: A Genome-Wide Association Study, Minghua Liu, Farid Khasiyev, Sanjeev Sariya, Antonio Spagnolo-Allende, Danurys L Sanchez, Howard Andrews, Qiong Yang, Alexa Beiser, Ye Qiao, Emy A Thomas, Jose Rafael Romero, Tatjana Rundek, Adam M Brickman, Jennifer J Manly, Mitchell Sv Elkind, Sudha Seshadri, Christopher Chen, Saima Hilal, Bruce A Wasserman, Giuseppe Tosto, Myriam Fornage, Jose Gutierrez

Journal Articles

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown.

METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide …

Type 2 Diabetes Modifies The Association Of Cad Genomic Risk Variants With Subclinical Atherosclerosis, Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S De Vries

Journal Articles

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 …

Estimating Heritability Explained By Local Ancestry And Evaluating Stratification Bias In Admixture Mapping From Summary Statistics, Tsz Fung Chan, Xinyue Rui, David V Conti, Myriam Fornage, Mariaelisa Graff, Jeffrey Haessler, Christopher Haiman, Heather M Highland, Su Yon Jung, Eimear E Kenny, Charles Kooperberg, Loic Le Marchand, Kari E North, Ran Tao, Genevieve Wojcik, Christopher R Gignoux, Charleston W K Chiang, Nicholas Mancuso

Journal Articles

The heritability explained by local ancestry markers in an admixed population (h

Mosaic Chromosomal Alterations In Blood Across Ancestries Using Whole-Genome Sequencing, Yasminka A Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin W Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Joshua C Bis, Eric Boerwinkle, Jennifer A Brody, April P Carson, Daniel I Chasman, Jiawen Chen, Michael Cho, Matthew P Conomos, Nancy Cox, Margaret F Doyle, Myriam Fornage, Xiuqing Guo, Sharon L R Kardia, Joshua P Lewis, Ruth J F Loos, Xiaolong Ma, Mitchell J Machiela, Taralynn M Mack, Rasika A Mathias, Braxton D Mitchell, Josyf C Mychaleckyj, Kari North, Nathan Pankratz, Patricia A Peyser, Michael H Preuss, Bruce Psaty, Laura M Raffield, Ramachandran S Vasan, Susan Redline, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Jennifer A Smith, Aaron P Smith, Margaret Taub, Kent D Taylor, Jeong Yun, Yun Li, Pinkal Desai, Alexander G Bick, Alexander P Reiner, Paul Scheet, Paul L Auer

Journal Articles

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. …

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, And Cardiovascular Disease Risk, Xue Liu, Xianbang Sun, Yuankai Zhang, Wenqing Jiang, Meng Lai, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Wei Zhao, Achilleas Pitsillides, Jeffrey Haessler, Yinan Zheng, Thomas W Blackwell, Jie Yao, Xiuqing Guo, Yong Qian, Bharat Thyagarajan, Nathan Pankratz, Stephen S Rich, Kent D Taylor, Patricia A Peyser, Susan R Heckbert, Sudha Seshadri, Eric Boerwinkle, Megan L Grove, Nicholas B Larson, Jennifer A Smith, Ramachandran S Vasan, Annette L Fitzpatrick, Myriam Fornage, Jun Ding, April P Carson, Goncalo Abecasis, Josée Dupuis, Alexander Reiner, Charles Kooperberg, Lifang Hou, Bruce M Psaty, James G Wilson, Daniel Levy, Jerome I Rotter, Joshua C Bis, Claudia L Satizabal, Dan E Arking, Chunyu Liu

Journal Articles

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia).

Next-Generation Crispr Gene-Drive Systems Using Cas12a Nuclease, Sara Sanz Juste, Emily M Okamoto, Christina Nguyen, Xuechun Feng, Víctor López Del Amo

Journal Articles

One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. to address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated …

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

Journal Articles

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 …

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

Journal Articles

No abstract provided.

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

Journal Articles

No abstract provided.

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

Journal Articles

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

Journal Articles

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 …

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

Journal Articles

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 …

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

Journal Articles

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] = …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Journal Articles

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Top-Ld: A Tool To Explore Linkage Disequilibrium With Topmed Whole-Genome Sequence Data, Le Huang, Jonathan D Rosen, Quan Sun, Jiawen Chen, Marsha M Wheeler, Ying Zhou, Yuan-I Min, Charles Kooperberg, Matthew P Conomos, Adrienne M Stilp, Stephen S Rich, Jerome I Rotter, Ani Manichaikul, Ruth J F Loos, Eimear E Kenny, Thomas W Blackwell, Albert V Smith, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Eric Boerwinkle, Laura M Raffield, Alex P Reiner, Paul L Auer, Yun Li

Journal Articles

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Here, we present toP-LD, an online tool to explore LD inferred with high-coverage (∼30×) WGS data from 15,578 individuals in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. toP-LD provides a significant upgrade compared to current LD tools, as the toPMed WGS data provide a more comprehensive representation of genetic variation than the 1000 Genomes data, particularly for rare variants and in the specific populations that we …

Association Study Between Mucin 4 (Muc4) Polymorphisms And Idiopathic Recurrent Pregnancy Loss In A Korean Population, Ji-Hyang Kim, Han-Sung Park, Jeong-Yong Lee, Eun-Ju Ko, Young-Ran Kim, Hee-Young Cho, Woo-Sik Lee, Eun-Hee Ahn, Nam-Keun Kim

Journal Articles

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were …

Meta-Analyses Identify Dna Methylation Associated With Kidney Function And Damage, Pascal Schlosser, Adrienne Tin, Pamela R Matias-Garcia, Chris H L Thio, Roby Joehanes, Hongbo Liu, Antoine Weihs, Zhi Yu, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L Min, Adebowale A Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Monique M B Breteler, Cristian Carmeli, Layal Chaker, John C Chambers, Shelley A Cole, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R Cox, Niek De Klein, Graciela E Delgado, Arce Domingo-Relloso, Kai-Uwe Eckardt, Arif B Ekici, Karlhans Endlich, Kathryn L Evans, James S Floyd, Myriam Fornage, Lude Franke, Eliza Fraszczyk, Xu Gao, Xīn Gào, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L Grove, Sarah E Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A Hurme, Shih-Jen Hwang, Marjo-Riitta Jarvelin, Sharon L R Kardia, Silva Kasela, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Holly Kramer, Florian Kronenberg, Brigitte Kühnel, Terho Lehtimäki, Lars Lind, Dan Liu, Yongmei Liu, Donald M Lloyd-Jones, Kurt Lohman, Stefan Lorkowski, Ake T Lu, Riccardo E Marioni, Winfried März, Daniel L Mccartney, Karlijn A C Meeks, Lili Milani, Pashupati P Mishra, Matthias Nauck, Ana Navas-Acien, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M Psaty, Olli T Raitakari, Scott M Ratliff, Alex P Reiner, Sylvia E Rosas, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A Smith, Nona Sotoodehnia, Hannah R Stocker, Silvia Stringhini, Johan Sundström, Brenton R Swenson, Maria Tellez-Plaza, Joyce B J Van Meurs, Jana V Van Vliet-Ostaptchouk, Andrea Venema, Niek Verweij, Rosie M Walker, Matthias Wielscher, Juliane Winkelmann, Bruce H R Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Daniel Levy, Melanie Waldenberger, Katalin Susztak, Anna Köttgen, Alexander Teumer

Journal Articles

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. to extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. …

Genome-Wide Association Study Of Serum Metabolites In The African American Study Of Kidney Disease And Hypertension, Shengyuan Luo, Elena V Feofanova, Adrienne Tin, Sarah Tung, Eugene P Rhee, Josef Coresh, Dan E Arking, Aditya Surapaneni, Pascal Schlosser, Yong Li, Anna Köttgen, Bing Yu, Morgan E Grams

Journal Articles

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. to date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m

Genetic And Non-Genetic Factors Affecting The Expression Of Covid-19-Relevant Genes In The Large Airway Epithelium, Silva Kasela, Victor E Ortega, Molly Martorella, Suresh Garudadri, Jenna Nguyen, Elizabeth Ampleford, Anu Pasanen, Srilaxmi Nerella, Kristina L Buschur, Igor Z Barjaktarevic, R Graham Barr, Eugene R Bleecker, Russell P Bowler, Alejandro P Comellas, Christopher B Cooper, David J Couper, Gerard J Criner, Jeffrey L Curtis, Meilan K Han, Nadia N Hansel, Eric A Hoffman, Robert J Kaner, Jerry A Krishnan, Fernando J Martinez, Merry-Lynn N Mcdonald, Deborah A Meyers, Robert Paine, Stephen P Peters, Mario Castro, Loren C Denlinger, Serpil C Erzurum, John V Fahy, Elliot Israel, Nizar N Jarjour, Bruce D Levy, Xingnan Li, Wendy C Moore, Sally E Wenzel, Charles Langelier, Prescott G Woodruff, Tuuli Lappalainen, Stephanie A Christenson

Journal Articles

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with …

Genome-Wide Meta-Analysis Of Muscle Weakness Identifies 15 Susceptibility Loci In Older Men And Women, Garan Jones, Katerina Trajanoska, Adam J Santanasto, Najada Stringa, Chia-Ling Kuo, Janice L Atkins, Joshua R Lewis, Thuyvy Duong, Shengjun Hong, Mary L Biggs, Jian'an Luan, Chloe Sarnowski, Kathryn L Lunetta, Toshiko Tanaka, Mary K Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L Ackert-Bicknell, Dan E Arking, B Gwen Windham, Eric Boerwinkle, Megan L Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie Van Der Velde, Lisette C P G M De Groot, Bruce M Psaty, Michelle C Odden, Alison E Fohner, Claudia Langenberg, Nicholas J Wareham, Stefania Bandinelli, Natasja M Van Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellström, Magnus Karlsson, David A Bennett, Aron S Buchman, Philip L De Jager, Andre G Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguéz-Mañas, Francisco J García, José A Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M Murabito, David Melzer, George A Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P Kiel, Luke C Pilling

Journal Articles

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10

A Genome-Wide Association Study Discovers 46 Loci Of The Human Metabolome In The Hispanic Community Health Study/Study Of Latinos, Elena V Feofanova, Han Chen, Yulin Dai, Peilin Jia, Megan L Grove, Alanna C Morrison, Qibin Qi, Martha Daviglus, Jianwen Cai, Kari E North, Cathy C Laurie, Robert C Kaplan, Eric Boerwinkle, Bing Yu

Journal Articles

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10

Diet, Weight Management, Physical Activity And Ovarian & Breast Cancer Risk In Women With, Adriana M Coletta, Susan K Peterson, Leticia A Gatus, Kate J Krause, Susan M Schembre, Susan C Gilchrist, Banu Arun, Y Nancy You, Miguel A Rodriguez-Bigas, Larkin L Strong, Karen H Lu, Karen Basen-Engquist

Journal Articles

INTRODUCTION: Women with pathogenic germline gene variants in

METHODS: We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to October 3, 2019. We identified 2775 records and included 21.

RESULTS: There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk.

CONCLUSIONS: There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women …

Unraveling The Functional Role Of The Orphan Solute Carrier, Slc22a24 In The Transport Of Steroid Conjugates Through Metabolomic And Genome-Wide Association Studies, Sook Wah Yee, Adrian Stecula, Huan-Chieh Chien, Ling Zou, Elena V Feofanova, Marjolein Van Borselen, Kit Wun Kathy Cheung, Noha A Yousri, Karsten Suhre, Jason M Kinchen, Eric Boerwinkle, Roshanak Irannejad, Bing Yu, Kathleen M Giacomini

Journal Articles

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value