<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Bick, Alexander G</style></author><author><style face="normal" font="default" size="100%">Weinstock, Joshua S</style></author><author><style face="normal" font="default" size="100%">Nandakumar, Satish K</style></author><author><style face="normal" font="default" size="100%">Fulco, Charles P</style></author><author><style face="normal" font="default" size="100%">Bao, Erik L</style></author><author><style face="normal" font="default" size="100%">Zekavat, Seyedeh M</style></author><author><style face="normal" font="default" size="100%">Szeto, Mindy D</style></author><author><style face="normal" font="default" size="100%">Liao, Xiaotian</style></author><author><style face="normal" font="default" size="100%">Leventhal, Matthew J</style></author><author><style face="normal" font="default" size="100%">Nasser, Joseph</style></author><author><style face="normal" font="default" size="100%">Chang, Kyle</style></author><author><style face="normal" font="default" size="100%">Laurie, Cecelia</style></author><author><style face="normal" font="default" size="100%">Burugula, Bala Bharathi</style></author><author><style face="normal" font="default" size="100%">Gibson, Christopher J</style></author><author><style face="normal" font="default" size="100%">Lin, Amy E</style></author><author><style face="normal" font="default" size="100%">Taub, Margaret A</style></author><author><style face="normal" font="default" size="100%">Aguet, François</style></author><author><style face="normal" font="default" size="100%">Ardlie, Kristin</style></author><author><style face="normal" font="default" size="100%">Mitchell, Braxton D</style></author><author><style face="normal" font="default" size="100%">Barnes, Kathleen C</style></author><author><style face="normal" font="default" size="100%">Moscati, Arden</style></author><author><style face="normal" font="default" size="100%">Fornage, Myriam</style></author><author><style face="normal" font="default" size="100%">Redline, Susan</style></author><author><style face="normal" font="default" size="100%">Psaty, Bruce M</style></author><author><style face="normal" font="default" size="100%">Silverman, Edwin K</style></author><author><style face="normal" font="default" size="100%">Weiss, Scott T</style></author><author><style face="normal" font="default" size="100%">Palmer, Nicholette D</style></author><author><style face="normal" font="default" size="100%">Vasan, Ramachandran S</style></author><author><style face="normal" font="default" size="100%">Burchard, Esteban G</style></author><author><style face="normal" font="default" size="100%">Kardia, Sharon L R</style></author><author><style face="normal" font="default" size="100%">He, Jiang</style></author><author><style face="normal" font="default" size="100%">Kaplan, Robert C</style></author><author><style face="normal" font="default" size="100%">Smith, Nicholas L</style></author><author><style face="normal" font="default" size="100%">Arnett, Donna K</style></author><author><style face="normal" font="default" size="100%">Schwartz, David A</style></author><author><style face="normal" font="default" size="100%">Correa, Adolfo</style></author><author><style face="normal" font="default" size="100%">de Andrade, Mariza</style></author><author><style face="normal" font="default" size="100%">Guo, Xiuqing</style></author><author><style face="normal" font="default" size="100%">Konkle, Barbara A</style></author><author><style face="normal" font="default" size="100%">Custer, Brian</style></author><author><style face="normal" font="default" size="100%">Peralta, Juan M</style></author><author><style face="normal" font="default" size="100%">Gui, Hongsheng</style></author><author><style face="normal" font="default" size="100%">Meyers, Deborah A</style></author><author><style face="normal" font="default" size="100%">McGarvey, Stephen T</style></author><author><style face="normal" font="default" size="100%">Chen, Ida Yii-Der</style></author><author><style face="normal" font="default" size="100%">Shoemaker, M Benjamin</style></author><author><style face="normal" font="default" size="100%">Peyser, Patricia A</style></author><author><style face="normal" font="default" size="100%">Broome, Jai G</style></author><author><style face="normal" font="default" size="100%">Gogarten, Stephanie M</style></author><author><style face="normal" font="default" size="100%">Wang, Fei Fei</style></author><author><style face="normal" font="default" size="100%">Wong, Quenna</style></author><author><style face="normal" font="default" size="100%">Montasser, May E</style></author><author><style face="normal" font="default" size="100%">Daya, Michelle</style></author><author><style face="normal" font="default" size="100%">Kenny, Eimear E</style></author><author><style face="normal" font="default" size="100%">North, Kari E</style></author><author><style face="normal" font="default" size="100%">Launer, Lenore J</style></author><author><style face="normal" font="default" size="100%">Cade, Brian E</style></author><author><style face="normal" font="default" size="100%">Bis, Joshua C</style></author><author><style face="normal" font="default" size="100%">Cho, Michael H</style></author><author><style face="normal" font="default" size="100%">Lasky-Su, Jessica</style></author><author><style face="normal" font="default" size="100%">Bowden, Donald W</style></author><author><style face="normal" font="default" size="100%">Cupples, L Adrienne</style></author><author><style face="normal" font="default" size="100%">Mak, Angel C Y</style></author><author><style face="normal" font="default" size="100%">Becker, Lewis C</style></author><author><style face="normal" font="default" size="100%">Smith, Jennifer A</style></author><author><style face="normal" font="default" size="100%">Kelly, Tanika N</style></author><author><style face="normal" font="default" size="100%">Aslibekyan, Stella</style></author><author><style face="normal" font="default" size="100%">Heckbert, Susan R</style></author><author><style face="normal" font="default" size="100%">Tiwari, Hemant K</style></author><author><style face="normal" font="default" size="100%">Yang, Ivana V</style></author><author><style face="normal" font="default" size="100%">Heit, John A</style></author><author><style face="normal" font="default" size="100%">Lubitz, Steven A</style></author><author><style face="normal" font="default" size="100%">Johnsen, Jill M</style></author><author><style face="normal" font="default" size="100%">Curran, Joanne E</style></author><author><style face="normal" font="default" size="100%">Wenzel, Sally E</style></author><author><style face="normal" font="default" size="100%">Weeks, Daniel E</style></author><author><style face="normal" font="default" size="100%">Rao, Dabeeru C</style></author><author><style face="normal" font="default" size="100%">Darbar, Dawood</style></author><author><style face="normal" font="default" size="100%">Moon, Jee-Young</style></author><author><style face="normal" font="default" size="100%">Tracy, Russell P</style></author><author><style face="normal" font="default" size="100%">Buth, Erin J</style></author><author><style face="normal" font="default" size="100%">Rafaels, Nicholas</style></author><author><style face="normal" font="default" size="100%">Loos, Ruth J F</style></author><author><style face="normal" font="default" size="100%">Durda, Peter</style></author><author><style face="normal" font="default" size="100%">Liu, Yongmei</style></author><author><style face="normal" font="default" size="100%">Hou, Lifang</style></author><author><style face="normal" font="default" size="100%">Lee, Jiwon</style></author><author><style face="normal" font="default" size="100%">Kachroo, Priyadarshini</style></author><author><style face="normal" font="default" size="100%">Freedman, Barry I</style></author><author><style face="normal" font="default" size="100%">Levy, Daniel</style></author><author><style face="normal" font="default" size="100%">Bielak, Lawrence F</style></author><author><style face="normal" font="default" size="100%">Hixson, James E</style></author><author><style face="normal" font="default" size="100%">Floyd, James S</style></author><author><style face="normal" font="default" size="100%">Whitsel, Eric A</style></author><author><style face="normal" font="default" size="100%">Ellinor, Patrick T</style></author><author><style face="normal" font="default" size="100%">Irvin, Marguerite R</style></author><author><style face="normal" font="default" size="100%">Fingerlin, Tasha E</style></author><author><style face="normal" font="default" size="100%">Raffield, Laura M</style></author><author><style face="normal" font="default" size="100%">Armasu, Sebastian M</style></author><author><style face="normal" font="default" size="100%">Wheeler, Marsha M</style></author><author><style face="normal" font="default" size="100%">Sabino, Ester C</style></author><author><style face="normal" font="default" size="100%">Blangero, John</style></author><author><style face="normal" font="default" size="100%">Williams, L Keoki</style></author><author><style face="normal" font="default" size="100%">Levy, Bruce D</style></author><author><style face="normal" font="default" size="100%">Sheu, Wayne Huey-Herng</style></author><author><style face="normal" font="default" size="100%">Roden, Dan M</style></author><author><style face="normal" font="default" size="100%">Boerwinkle, Eric</style></author><author><style face="normal" font="default" size="100%">Manson, JoAnn E</style></author><author><style face="normal" font="default" size="100%">Mathias, Rasika A</style></author><author><style face="normal" font="default" size="100%">Desai, Pinkal</style></author><author><style face="normal" font="default" size="100%">Taylor, Kent D</style></author><author><style face="normal" font="default" size="100%">Johnson, Andrew D</style></author><author><style face="normal" font="default" size="100%">Auer, Paul L</style></author><author><style face="normal" font="default" size="100%">Kooperberg, Charles</style></author><author><style face="normal" font="default" size="100%">Laurie, Cathy C</style></author><author><style face="normal" font="default" size="100%">Blackwell, Thomas W</style></author><author><style face="normal" font="default" size="100%">Smith, Albert V</style></author><author><style face="normal" font="default" size="100%">Zhao, Hongyu</style></author><author><style face="normal" font="default" size="100%">Lange, Ethan</style></author><author><style face="normal" font="default" size="100%">Lange, Leslie</style></author><author><style face="normal" font="default" size="100%">Rich, Stephen S</style></author><author><style face="normal" font="default" size="100%">Rotter, Jerome I</style></author><author><style face="normal" font="default" size="100%">Wilson, James G</style></author><author><style face="normal" font="default" size="100%">Scheet, Paul</style></author><author><style face="normal" font="default" size="100%">Kitzman, Jacob O</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Engreitz, Jesse M</style></author><author><style face="normal" font="default" size="100%">Ebert, Benjamin L</style></author><author><style face="normal" font="default" size="100%">Reiner, Alexander P</style></author><author><style face="normal" font="default" size="100%">Jaiswal, Siddhartha</style></author><author><style face="normal" font="default" size="100%">Abecasis, Gonçalo</style></author><author><style face="normal" font="default" size="100%">Sankaran, Vijay G</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author><author><style face="normal" font="default" size="100%">Natarajan, Pradeep</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">NHLBI Trans-Omics for Precision Medicine Consortium</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Inherited causes of clonal haematopoiesis in 97,691 whole genomes.</style></title><secondary-title><style face="normal" font="default" size="100%">Nature</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Nature</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Africa</style></keyword><keyword><style  face="normal" font="default" size="100%">African Continental Ancestry Group</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged, 80 and over</style></keyword><keyword><style  face="normal" font="default" size="100%">alpha Karyopherins</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Self Renewal</style></keyword><keyword><style  face="normal" font="default" size="100%">Clonal Hematopoiesis</style></keyword><keyword><style  face="normal" font="default" size="100%">DNA-Binding Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome, Human</style></keyword><keyword><style  face="normal" font="default" size="100%">Germ-Line Mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Hematopoietic Stem Cells</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Intracellular Signaling Peptides and Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">National Heart, Lung, and Blood Institute (U.S.)</style></keyword><keyword><style  face="normal" font="default" size="100%">Phenotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Precision Medicine</style></keyword><keyword><style  face="normal" font="default" size="100%">Proto-Oncogene Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Tripartite Motif Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">United States</style></keyword><keyword><style  face="normal" font="default" size="100%">Whole Genome Sequencing</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2020</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2020 10</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">586</style></volume><pages><style face="normal" font="default" size="100%">763-768</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">7831</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Abel, Haley J</style></author><author><style face="normal" font="default" size="100%">Larson, David E</style></author><author><style face="normal" font="default" size="100%">Regier, Allison A</style></author><author><style face="normal" font="default" size="100%">Chiang, Colby</style></author><author><style face="normal" font="default" size="100%">Das, Indraniel</style></author><author><style face="normal" font="default" size="100%">Kanchi, Krishna L</style></author><author><style face="normal" font="default" size="100%">Layer, Ryan M</style></author><author><style face="normal" font="default" size="100%">Neale, Benjamin M</style></author><author><style face="normal" font="default" size="100%">Salerno, William J</style></author><author><style face="normal" font="default" size="100%">Reeves, Catherine</style></author><author><style face="normal" font="default" size="100%">Buyske, Steven</style></author><author><style face="normal" font="default" size="100%">Matise, Tara C</style></author><author><style face="normal" font="default" size="100%">Muzny, Donna M</style></author><author><style face="normal" font="default" size="100%">Zody, Michael C</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Dutcher, Susan K</style></author><author><style face="normal" font="default" size="100%">Stitziel, Nathan O</style></author><author><style face="normal" font="default" size="100%">Hall, Ira M</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">NHGRI Centers for Common Disease Genomics</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Mapping and characterization of structural variation in 17,795 human genomes.</style></title><secondary-title><style face="normal" font="default" size="100%">Nature</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Nature</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Alleles</style></keyword><keyword><style  face="normal" font="default" size="100%">Case-Control Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">Continental Population Groups</style></keyword><keyword><style  face="normal" font="default" size="100%">Epigenesis, Genetic</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Dosage</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Variation</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetics, Population</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome, Human</style></keyword><keyword><style  face="normal" font="default" size="100%">High-Throughput Nucleotide Sequencing</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Molecular Sequence Annotation</style></keyword><keyword><style  face="normal" font="default" size="100%">Quantitative Trait Loci</style></keyword><keyword><style  face="normal" font="default" size="100%">Software</style></keyword><keyword><style  face="normal" font="default" size="100%">Whole Genome Sequencing</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2020</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2020 07</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">583</style></volume><pages><style face="normal" font="default" size="100%">83-89</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">7814</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/32460305?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Fahed, Akl C</style></author><author><style face="normal" font="default" size="100%">Wang, Minxian</style></author><author><style face="normal" font="default" size="100%">Homburger, Julian R</style></author><author><style face="normal" font="default" size="100%">Patel, Aniruddh P</style></author><author><style face="normal" font="default" size="100%">Bick, Alexander G</style></author><author><style face="normal" font="default" size="100%">Neben, Cynthia L</style></author><author><style face="normal" font="default" size="100%">Lai, Carmen</style></author><author><style face="normal" font="default" size="100%">Brockman, Deanna</style></author><author><style face="normal" font="default" size="100%">Philippakis, Anthony</style></author><author><style face="normal" font="default" size="100%">Ellinor, Patrick T</style></author><author><style face="normal" font="default" size="100%">Cassa, Christopher A</style></author><author><style face="normal" font="default" size="100%">Lebo, Matthew</style></author><author><style face="normal" font="default" size="100%">Ng, Kenney</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Zhou, Alicia Y</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author><author><style face="normal" font="default" size="100%">Khera, Amit V</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.</style></title><secondary-title><style face="normal" font="default" size="100%">Nat Commun</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Nat Commun</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Breast Neoplasms</style></keyword><keyword><style  face="normal" font="default" size="100%">Case-Control Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">Colorectal Neoplasms</style></keyword><keyword><style  face="normal" font="default" size="100%">Coronary Artery Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome, Human</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Multifactorial Inheritance</style></keyword><keyword><style  face="normal" font="default" size="100%">Odds Ratio</style></keyword><keyword><style  face="normal" font="default" size="100%">Penetrance</style></keyword><keyword><style  face="normal" font="default" size="100%">Risk Factors</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2020</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2020 08 20</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">11</style></volume><pages><style face="normal" font="default" size="100%">3635</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/32820175?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Khera, Amit V</style></author><author><style face="normal" font="default" size="100%">Chaffin, Mark</style></author><author><style face="normal" font="default" size="100%">Aragam, Krishna G</style></author><author><style face="normal" font="default" size="100%">Haas, Mary E</style></author><author><style face="normal" font="default" size="100%">Roselli, Carolina</style></author><author><style face="normal" font="default" size="100%">Choi, Seung Hoan</style></author><author><style face="normal" font="default" size="100%">Natarajan, Pradeep</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Lubitz, Steven A</style></author><author><style face="normal" font="default" size="100%">Ellinor, Patrick T</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.</style></title><secondary-title><style face="normal" font="default" size="100%">Nat Genet</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Nat. Genet.</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2018</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2018 Sep</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">50</style></volume><pages><style face="normal" font="default" size="100%">1219-1224</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">9</style></issue><custom1><style face="normal" font="default" size="100%">http://www.ncbi.nlm.nih.gov/pubmed/30104762?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Stitziel, Nathan O</style></author><author><style face="normal" font="default" size="100%">Khera, Amit V</style></author><author><style face="normal" font="default" size="100%">Wang, Xiao</style></author><author><style face="normal" font="default" size="100%">Bierhals, Andrew J</style></author><author><style face="normal" font="default" size="100%">Vourakis, A Christina</style></author><author><style face="normal" font="default" size="100%">Sperry, Alexandra E</style></author><author><style face="normal" font="default" size="100%">Natarajan, Pradeep</style></author><author><style face="normal" font="default" size="100%">Klarin, Derek</style></author><author><style face="normal" font="default" size="100%">Emdin, Connor A</style></author><author><style face="normal" font="default" size="100%">Zekavat, Seyedeh M</style></author><author><style face="normal" font="default" size="100%">Nomura, Akihiro</style></author><author><style face="normal" font="default" size="100%">Erdmann, Jeanette</style></author><author><style face="normal" font="default" size="100%">Schunkert, Heribert</style></author><author><style face="normal" font="default" size="100%">Samani, Nilesh J</style></author><author><style face="normal" font="default" size="100%">Kraus, William E</style></author><author><style face="normal" font="default" size="100%">Shah, Svati H</style></author><author><style face="normal" font="default" size="100%">Yu, Bing</style></author><author><style face="normal" font="default" size="100%">Boerwinkle, Eric</style></author><author><style face="normal" font="default" size="100%">Rader, Daniel J</style></author><author><style face="normal" font="default" size="100%">Gupta, Namrata</style></author><author><style face="normal" font="default" size="100%">Frossard, Philippe M</style></author><author><style face="normal" font="default" size="100%">Rasheed, Asif</style></author><author><style face="normal" font="default" size="100%">Danesh, John</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author><author><style face="normal" font="default" size="100%">Gabriel, Stacey</style></author><author><style face="normal" font="default" size="100%">Saleheen, Danish</style></author><author><style face="normal" font="default" size="100%">Musunuru, Kiran</style></author><author><style face="normal" font="default" size="100%">Kathiresan, Sekar</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">PROMIS and Myocardial Infarction Genetics Consortium Investigators</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.</style></title><secondary-title><style face="normal" font="default" size="100%">J Am Coll Cardiol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">J Am Coll Cardiol</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Angiopoietin-Like Protein 3</style></keyword><keyword><style  face="normal" font="default" size="100%">Angiopoietin-like Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Angiopoietins</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Atherosclerosis</style></keyword><keyword><style  face="normal" font="default" size="100%">Case-Control Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">Coronary Artery Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Lipids</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Mice, Inbred C57BL</style></keyword><keyword><style  face="normal" font="default" size="100%">Mice, Knockout</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Mutation, Missense</style></keyword><keyword><style  face="normal" font="default" size="100%">Myocardial Infarction</style></keyword><keyword><style  face="normal" font="default" size="100%">Risk Factors</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2017</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2017 Apr 25</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">69</style></volume><pages><style face="normal" font="default" size="100%">2054-2063</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.&lt;/p&gt;&lt;p&gt;&lt;b&gt;OBJECTIVES: &lt;/b&gt;The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in &lt;25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p &lt; 0.001).&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSIONS: &lt;/b&gt;ANGPTL3 deficiency is associated with protection from CAD.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">16</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/28385496?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Rusu, Victor</style></author><author><style face="normal" font="default" size="100%">Hoch, Eitan</style></author><author><style face="normal" font="default" size="100%">Mercader, Josep M</style></author><author><style face="normal" font="default" size="100%">Tenen, Danielle E</style></author><author><style face="normal" font="default" size="100%">Gymrek, Melissa</style></author><author><style face="normal" font="default" size="100%">Hartigan, Christina R</style></author><author><style face="normal" font="default" size="100%">DeRan, Michael</style></author><author><style face="normal" font="default" size="100%">von Grotthuss, Marcin</style></author><author><style face="normal" font="default" size="100%">Fontanillas, Pierre</style></author><author><style face="normal" font="default" size="100%">Spooner, Alexandra</style></author><author><style face="normal" font="default" size="100%">Guzman, Gaelen</style></author><author><style face="normal" font="default" size="100%">Deik, Amy A</style></author><author><style face="normal" font="default" size="100%">Pierce, Kerry A</style></author><author><style face="normal" font="default" size="100%">Dennis, Courtney</style></author><author><style face="normal" font="default" size="100%">Clish, Clary B</style></author><author><style face="normal" font="default" size="100%">Carr, Steven A</style></author><author><style face="normal" font="default" size="100%">Wagner, Bridget K</style></author><author><style face="normal" font="default" size="100%">Schenone, Monica</style></author><author><style face="normal" font="default" size="100%">Ng, Maggie C Y</style></author><author><style face="normal" font="default" size="100%">Chen, Brian H</style></author><author><style face="normal" font="default" size="100%">Centeno-Cruz, Federico</style></author><author><style face="normal" font="default" size="100%">Zerrweck, Carlos</style></author><author><style face="normal" font="default" size="100%">Orozco, Lorena</style></author><author><style face="normal" font="default" size="100%">Altshuler, David M</style></author><author><style face="normal" font="default" size="100%">Schreiber, Stuart L</style></author><author><style face="normal" font="default" size="100%">Florez, Jose C</style></author><author><style face="normal" font="default" size="100%">Jacobs, Suzanne B R</style></author><author><style face="normal" font="default" size="100%">Lander, Eric S</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">MEDIA Consortium</style></author><author><style face="normal" font="default" size="100%">SIGMA T2D Consortium</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.</style></title><secondary-title><style face="normal" font="default" size="100%">Cell</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Cell</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Basigin</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Membrane</style></keyword><keyword><style  face="normal" font="default" size="100%">Chromosomes, Human, Pair 17</style></keyword><keyword><style  face="normal" font="default" size="100%">Diabetes Mellitus, Type 2</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Knockdown Techniques</style></keyword><keyword><style  face="normal" font="default" size="100%">Haplotypes</style></keyword><keyword><style  face="normal" font="default" size="100%">Hepatocytes</style></keyword><keyword><style  face="normal" font="default" size="100%">Heterozygote</style></keyword><keyword><style  face="normal" font="default" size="100%">Histone Code</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Liver</style></keyword><keyword><style  face="normal" font="default" size="100%">Models, Molecular</style></keyword><keyword><style  face="normal" font="default" size="100%">Monocarboxylic Acid Transporters</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2017</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2017 Jun 29</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">170</style></volume><pages><style face="normal" font="default" size="100%">199-212.e20</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/28666119?dopt=Abstract</style></custom1></record></records></xml>