@article {142, title = {Transethnic Transferability of a Genome-Wide Polygenic Score for Coronary Artery Disease.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Feb}, pages = {e003092}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003092}, author = {Fahed, Akl C and Aragam, Krishna G and Hindy, George and Chen, Yii-Der Ida and Chaudhary, Kumardeep and Dobbyn, Amanda and Krumholz, Harlan M and Sheu, Wayne H H and Rich, Stephen S and Rotter, Jerome I and Chowdhury, Rajiv and Cho, Judy and Do, Ron and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {117, title = {Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 05 07}, pages = {2254}, abstract = {

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.

}, keywords = {Cardiomyopathy, Dilated, Genome-Wide Association Study, Heart, Humans, Magnetic Resonance Imaging, Myocardium, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/s41467-020-15823-7}, author = {Pirruccello, James P and Bick, Alexander and Wang, Minxian and Chaffin, Mark and Friedman, Samuel and Yao, Jie and Guo, Xiuqing and Venkatesh, Bharath Ambale and Taylor, Kent D and Post, Wendy S and Rich, Stephen and Lima, Joao A C and Rotter, Jerome I and Philippakis, Anthony and Lubitz, Steven A and Ellinor, Patrick T and Khera, Amit V and Kathiresan, Sekar and Aragam, Krishna G} } @article {144, title = {Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 04 01}, pages = {e203959}, abstract = {

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening.

Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.

Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.

Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.

Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.

Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55\%]), 441 (0.9\%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3\%) for familial hypercholesterolemia, 235 (0.5\%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2\%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4\%) vs 4663 of 49 607 noncarriers (9.4\%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6\%) vs 2080 of 27 028 female noncarriers (7.7\%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4\%) vs 929 of 49 662 noncarriers (1.9\%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3\% for carriers of familial hypercholesterolemia, 41.1\% for hereditary breast and ovarian cancer syndrome, and 38.3\% for Lynch syndrome. Across the 3 conditions, 39.7\% (175 of 441) of the carriers reported a family history of disease vs 23.2\% (34 517 of 148 772) of noncarriers.

Conclusions and Relevance: The findings suggest that approximately 1\% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

}, keywords = {Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome, Heterozygote, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Pedigree, Proportional Hazards Models, United Kingdom, Whole Exome Sequencing}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.3959}, author = {Patel, Aniruddh P and Wang, Minxian and Fahed, Akl C and Mason-Suares, Heather and Brockman, Deanna and Pelletier, Renee and Amr, Sami and Machini, Kalotina and Hawley, Megan and Witkowski, Leora and Koch, Christopher and Philippakis, Anthony and Cassa, Christopher A and Ellinor, Patrick T and Kathiresan, Sekar and Ng, Kenney and Lebo, Matthew and Khera, Amit V} } @article {120, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

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.

}, keywords = {Adult, Africa, African Continental Ancestry Group, Aged, Aged, 80 and over, alpha Karyopherins, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Fran{\c c}ois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Gon{\c c}alo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {105, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

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.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {136, title = {Titin Truncating Variants in Adults Without Known Congestive Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {75}, year = {2020}, month = {2020 03 17}, pages = {1239-1241}, keywords = {Adult, Aged, Asymptomatic Diseases, Connectin, Female, Genetic Variation, Heart Failure, Humans, Male, Middle Aged}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.01.013}, author = {Pirruccello, James P and Bick, Alexander and Chaffin, Mark and Aragam, Krishna G and Choi, Seung Hoan and Lubitz, Steven A and Ho, Carolyn Y and Ng, Kenney and Philippakis, Anthony and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {43, title = {Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1219-1224}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0183-z}, author = {Khera, Amit V and Chaffin, Mark and Aragam, Krishna G and Haas, Mary E and Roselli, Carolina and Choi, Seung Hoan and Natarajan, Pradeep and Lander, Eric S and Lubitz, Steven A and Ellinor, Patrick T and Kathiresan, Sekar} }