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1. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Author

Weinstock, Joshua S, Laurie, Cecelia A, Broome, Jai G, Taylor, Kent D, Guo, Xiuqing, Shuldiner, Alan R, O'Connell, Jeffrey R, Lewis, Joshua P, Boerwinkle, Eric, Barnes, Kathleen C, Chami, Nathalie, Kenny, Eimear E, Loos, Ruth JF, Fornage, Myriam, Redline, Susan, Cade, Brian E, Gilliland, Frank D, Chen, Zhanghua, Gauderman, W James, Kumar, Rajesh, Grammer, Leslie, Schleimer, Robert P, Psaty, Bruce M, Bis, Joshua C, Brody, Jennifer A, Silverman, Edwin K, Yun, Jeong H, Qiao, Dandi, Weiss, Scott T, Lasky-Su, Jessica, DeMeo, Dawn L, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Cho, Michael H, Vasan, Ramachandran S, Johnson, Andrew D, Yanek, Lisa R, Becker, Lewis C, Kardia, Sharon, He, Jiang, Kaplan, Robert, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Arnett, Donna K, Irvin, Marguerite R, Tiwari, Hemant, Correa, Adolfo, Raffield, Laura M, Gao, Yan, de Andrade, Mariza, Rotter, Jerome I, Rich, Stephen S, Manichaikul, Ani W, Konkle, Barbara A, Johnsen, Jill M, Wheeler, Marsha M, Custer, Brian S, Duggirala, Ravindranath, Curran, Joanne E, Blangero, John, Gui, Hongsheng, Xiao, Shujie, Williams, L Keoki, Meyers, Deborah A, Li, Xingnan, Ortega, Victor, McGarvey, Stephen, Gu, C Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Shoemaker, M Benjamin, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Desai, Pinkal, Blackwell, Thomas W, Abecasis, Goncalo R, Smith, Albert V, Kang, Hyun M, Mathias, Rasika, Natarajan, Pradeep, Jaiswal, Siddhartha, Reiner, Alexander P, Bick, Alexander G, and NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Subjects
Human Genome, Middle Aged, Hematopoiesis, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Phenotype, Good Health and Well Being, Clinical Research, Mutation, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Testing, Missense, Aetiology, Lung, Germ-Line Mutation, Biotechnology
Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Published
2023

2. Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Author

Einson, Jonah, Glinos, Dafni, Boerwinkle, Eric, Castaldi, Peter, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick, Fornage, Myriam, Gabriel, Stacey, Germer, Soren, Gibbs, Richard, Hersh, Craig P., Johnsen, Jill, Kaplan, Robert, Konkle, Barbara A., Kooperberg, Charles, Nassir, Rami, Loos, Ruth J.F., Meyers, Deborah A, Mitchell, Braxton D., Psaty, Bruce, Vasan, Ramachandran S., Rich, Stephen S., Rienstra, Michael, Rotter, Jerome I., Saferali, Aabida, Shoemaker, M. Benjamin, Silverman, Edwin, Smith, Albert Vernon, Mohammadi, Pejman, Castel, Stephane E., Iossifov, Ivan, and Lappalainen, Tuuli

Subjects
Article
Abstract

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Published
2023

3. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author

Nakao, Tetsushi, Bick, Alexander G, Taub, Margaret A, Zekavat, Seyedeh M, Uddin, Md M, Niroula, Abhishek, Carty, Cara L, Lane, John, Honigberg, Michael C, Weinstock, Joshua S, Pampana, Akhil, Gibson, Christopher J, Griffin, Gabriel K, Clarke, Shoa L, Bhattacharya, Romit, Assimes, Themistocles L, Emery, Leslie S, Stilp, Adrienne M, Wong, Quenna, Broome, Jai, Laurie, Cecelia A, Khan, Alyna T, Smith, Albert V, Blackwell, Thomas W, Codd, Veryan, Nelson, Christopher P, Yoneda, Zachary T, Peralta, Juan M, Bowden, Donald W, Irvin, Marguerite R, Boorgula, Meher, Zhao, Wei, Yanek, Lisa R, Wiggins, Kerri L, Hixson, James E, Gu, C Charles, Peloso, Gina M, Roden, Dan M, Reupena, Muagututi'a S, Hwu, Chii-Min, DeMeo, Dawn L, North, Kari E, Kelly, Shannon, Musani, Solomon K, Bis, Joshua C, Lloyd-Jones, Donald M, Johnsen, Jill M, Preuss, Michael, Tracy, Russell P, Peyser, Patricia A, Qiao, Dandi, Desai, Pinkal, Curran, Joanne E, Freedman, Barry I, Tiwari, Hemant K, Chavan, Sameer, Smith, Jennifer A, Smith, Nicholas L, Kelly, Tanika N, Hidalgo, Bertha, Cupples, L Adrienne, Weeks, Daniel E, Hawley, Nicola L, Minster, Ryan L, Samoan Obesity, Lifestyle And Genetic Adaptations Study (OLaGA) Group, Deka, Ranjan, Naseri, Take T, De Las Fuentes, Lisa, Raffield, Laura M, Morrison, Alanna C, Vries, Paul S, Ballantyne, Christie M, Kenny, Eimear E, Rich, Stephen S, Whitsel, Eric A, Cho, Michael H, Shoemaker, M Benjamin, Pace, Betty S, Blangero, John, Palmer, Nicholette D, Mitchell, Braxton D, Shuldiner, Alan R, Barnes, Kathleen C, Redline, Susan, Kardia, Sharon LR, Abecasis, Gonçalo R, Becker, Lewis C, Heckbert, Susan R, He, Jiang, Post, Wendy, Arnett, Donna K, Vasan, Ramachandran S, Darbar, Dawood, Weiss, Scott T, McGarvey, Stephen T, De Andrade, Mariza, Chen, Yii-Der Ida, Kaplan, Robert C, Meyers, Deborah A, Custer, Brian S, Correa, Adolfo, Psaty, Bruce M, Fornage, Myriam, Manson, JoAnn E, Boerwinkle, Eric, Konkle, Barbara A, Loos, Ruth JF, Rotter, Jerome I, Silverman, Edwin K, Kooperberg, Charles, Danesh, John, Samani, Nilesh J, Jaiswal, Siddhartha, Libby, Peter, Ellinor, Patrick T, Pankratz, Nathan, Ebert, Benjamin L, Reiner, Alexander P, Mathias, Rasika A, Do, Ron, NHLBI Trans-Omics For Precision Medicine (TOPMed) Consortium, Natarajan, Pradeep, Nakao, Tetsushi [0000-0001-9979-2682], Bick, Alexander G [0000-0001-5824-9595], Zekavat, Seyedeh M [0000-0003-4026-8944], Uddin, Md M [0000-0003-1846-0411], Niroula, Abhishek [0000-0002-5904-0635], Carty, Cara L [0000-0002-6378-8195], Lane, John [0000-0002-3582-5825], Honigberg, Michael C [0000-0001-8630-5021], Weinstock, Joshua S [0000-0001-7013-1899], Pampana, Akhil [0000-0002-4167-0540], Griffin, Gabriel K [0000-0002-4042-6757], Clarke, Shoa L [0000-0002-6592-1172], Bhattacharya, Romit [0000-0002-0782-4753], Assimes, Themistocles L [0000-0003-2349-0009], Emery, Leslie S [0000-0002-9070-9886], Stilp, Adrienne M [0000-0002-3910-0776], Wong, Quenna [0000-0002-9027-2100], Broome, Jai [0000-0001-7638-0749], Khan, Alyna T [0000-0002-2240-7931], Smith, Albert V [0000-0003-1942-5845], Codd, Veryan [0000-0002-9430-8254], Nelson, Christopher P [0000-0001-8025-2897], Yoneda, Zachary T [0000-0002-2055-732X], Peralta, Juan M [0000-0002-8811-5579], Yanek, Lisa R [0000-0001-7117-1075], Wiggins, Kerri L [0000-0003-2749-1279], Gu, C Charles [0000-0002-8527-8145], Peloso, Gina M [0000-0002-5355-8636], Roden, Dan M [0000-0002-6302-0389], Hwu, Chii-Min [0000-0002-8209-9627], North, Kari E [0000-0002-8903-0366], Bis, Joshua C [0000-0002-3409-1110], Lloyd-Jones, Donald M [0000-0003-0847-6110], Johnsen, Jill M [0000-0002-2279-2550], Preuss, Michael [0000-0001-5266-8465], Tracy, Russell P [0000-0002-0080-2420], Peyser, Patricia A [0000-0002-9717-8459], Qiao, Dandi [0000-0001-9450-205X], Curran, Joanne E [0000-0002-6898-155X], Freedman, Barry I [0000-0003-0275-5530], Chavan, Sameer [0000-0002-0220-0845], Smith, Jennifer A [0000-0002-3575-5468], Kelly, Tanika N [0000-0002-7348-4451], Hidalgo, Bertha [0000-0002-2556-1969], Weeks, Daniel E [0000-0001-9410-7228], Hawley, Nicola L [0000-0002-2601-3454], Minster, Ryan L [0000-0001-7382-6717], de Las Fuentes, Lisa [0000-0002-4689-325X], Raffield, Laura M [0000-0002-7892-193X], Ballantyne, Christie M [0000-0002-6432-1730], Kenny, Eimear E [0000-0001-9198-759X], Rich, Stephen S [0000-0003-3872-7793], Whitsel, Eric A [0000-0003-4843-3641], Cho, Michael H [0000-0002-4907-1657], Palmer, Nicholette D [0000-0001-8883-2511], Mitchell, Braxton D [0000-0003-4920-4744], Shuldiner, Alan R [0000-0001-9921-4305], Redline, Susan [0000-0002-6585-1610], Heckbert, Susan R [0000-0002-7100-512X], He, Jiang [0000-0002-8286-9652], Post, Wendy [0000-0002-8655-5204], Arnett, Donna K [0000-0003-2219-657X], Vasan, Ramachandran S [0000-0001-7357-5970], Weiss, Scott T [0000-0001-7196-303X], McGarvey, Stephen T [0000-0003-1233-6970], Custer, Brian S [0000-0001-6251-366X], Correa, Adolfo [0000-0002-9501-600X], Manson, JoAnn E [0000-0002-9426-7595], Konkle, Barbara A [0000-0002-3959-8797], Loos, Ruth JF [0000-0002-8532-5087], Rotter, Jerome I [0000-0001-7191-1723], Silverman, Edwin K [0000-0002-3641-3822], Kooperberg, Charles [0000-0002-7986-8560], Samani, Nilesh J [0000-0002-3286-8133], Jaiswal, Siddhartha [0000-0002-9597-0477], Libby, Peter [0000-0002-1502-502X], Ellinor, Patrick T [0000-0002-2067-0533], Pankratz, Nathan [0000-0001-5958-693X], Ebert, Benjamin L [0000-0003-0197-5451], Mathias, Rasika A [0000-0002-2282-9042], Do, Ron [0000-0002-3144-3627], Natarajan, Pradeep [0000-0001-8402-7435], Apollo - University of Cambridge Repository, and Danesh, John [0000-0003-1158-6791]

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2022
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4. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author

Nakao, Tetsushi, Bick, Alexander G, Taub, Margaret A, Zekavat, Seyedeh M, Uddin, Md M, Niroula, Abhishek, Carty, Cara L, Lane, John, Honigberg, Michael C, Weinstock, Joshua S, Pampana, Akhil, Gibson, Christopher J, Griffin, Gabriel K, Clarke, Shoa L, Bhattacharya, Romit, Assimes, Themistocles L, Emery, Leslie S, Stilp, Adrienne M, Wong, Quenna, Broome, Jai, Laurie, Cecelia A, Khan, Alyna T, Smith, Albert V, Blackwell, Thomas W, Codd, Veryan, Nelson, Christopher P, Yoneda, Zachary T, Peralta, Juan M, Bowden, Donald W, Irvin, Marguerite R, Boorgula, Meher, Zhao, Wei, Yanek, Lisa R, Wiggins, Kerri L, Hixson, James E, Gu, C Charles, Peloso, Gina M, Roden, Dan M, Reupena, Muagututi'a S, Hwu, Chii-Min, DeMeo, Dawn L, North, Kari E, Kelly, Shannon, Musani, Solomon K, Bis, Joshua C, Lloyd-Jones, Donald M, Johnsen, Jill M, Preuss, Michael, Tracy, Russell P, Peyser, Patricia A, Qiao, Dandi, Desai, Pinkal, Curran, Joanne E, Freedman, Barry I, Tiwari, Hemant K, Chavan, Sameer, Smith, Jennifer A, Smith, Nicholas L, Kelly, Tanika N, Hidalgo, Bertha, Cupples, L Adrienne, Weeks, Daniel E, Hawley, Nicola L, Minster, Ryan L, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, Deka, Ranjan, Naseri, Take T, de Las Fuentes, Lisa, Raffield, Laura M, Morrison, Alanna C, Vries, Paul S, Ballantyne, Christie M, Kenny, Eimear E, Rich, Stephen S, Whitsel, Eric A, Cho, Michael H, Shoemaker, M Benjamin, Pace, Betty S, Blangero, John, Palmer, Nicholette D, Mitchell, Braxton D, Shuldiner, Alan R, Barnes, Kathleen C, Redline, Susan, Kardia, Sharon LR, Abecasis, Gonçalo R, Becker, Lewis C, Heckbert, Susan R, He, Jiang, Post, Wendy, Arnett, Donna K, Vasan, Ramachandran S, Darbar, Dawood, Weiss, Scott T, McGarvey, Stephen T, de Andrade, Mariza, Chen, Yii-Der Ida, Kaplan, Robert C, Meyers, Deborah A, and Custer, Brian S

Subjects
Lifestyle and Genetic Adaptations Study (OLaGA) Group, Aging, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Heart Disease, Human Genome, Genetics, 2.1 Biological and endogenous factors, Samoan Obesity, Atherosclerosis, Cardiovascular, Heart Disease - Coronary Heart Disease
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2022

5. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author

Taliun, Daniel, Harris, Daniel N, Kessler, Michael D, Carlson, Jedidiah, Szpiech, Zachary A, Torres, Raul, Taliun, Sarah A Gagliano, Corvelo, André, Gogarten, Stephanie M, Kang, Hyun Min, Pitsillides, Achilleas N, LeFaive, Jonathon, Lee, Seung-Been, Tian, Xiaowen, Browning, Brian L, Das, Sayantan, Emde, Anne-Katrin, Clarke, Wayne E, Loesch, Douglas P, Shetty, Amol C, Blackwell, Thomas W, Smith, Albert V, Wong, Quenna, Liu, Xiaoming, Conomos, Matthew P, Bobo, Dean M, Aguet, François, Albert, Christine, Alonso, Alvaro, Ardlie, Kristin G, Arking, Dan E, Aslibekyan, Stella, Auer, Paul L, Barnard, John, Barr, R Graham, Barwick, Lucas, Becker, Lewis C, Beer, Rebecca L, Benjamin, Emelia J, Bielak, Lawrence F, Blangero, John, Boehnke, Michael, Bowden, Donald W, Brody, Jennifer A, Burchard, Esteban G, Cade, Brian E, Casella, James F, Chalazan, Brandon, Chasman, Daniel I, Chen, Yii-Der Ida, Cho, Michael H, Choi, Seung Hoan, Chung, Mina K, Clish, Clary B, Correa, Adolfo, Curran, Joanne E, Custer, Brian, Darbar, Dawood, Daya, Michelle, de Andrade, Mariza, DeMeo, Dawn L, Dutcher, Susan K, Ellinor, Patrick T, Emery, Leslie S, Eng, Celeste, Fatkin, Diane, Fingerlin, Tasha, Forer, Lukas, Fornage, Myriam, Franceschini, Nora, Fuchsberger, Christian, Fullerton, Stephanie M, Germer, Soren, Gladwin, Mark T, Gottlieb, Daniel J, Guo, Xiuqing, Hall, Michael E, He, Jiang, Heard-Costa, Nancy L, Heckbert, Susan R, Irvin, Marguerite R, Johnsen, Jill M, Johnson, Andrew D, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika, Kelly, Shannon, Kenny, Eimear E, Kiel, Douglas P, Klemmer, Robert, Konkle, Barbara A, Kooperberg, Charles, Köttgen, Anna, Lange, Leslie A, Lasky-Su, Jessica, Levy, Daniel, Lin, Xihong, Lin, Keng-Han, Liu, Chunyu, and Loos, Ruth JF

Subjects
Quality Control, Heterozygote, General Science & Technology, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, INDEL Mutation, Loss of Function Mutation, and Blood Institute (U.S.), Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Precision Medicine, Aetiology, Lung, Population Density, Genome, Whole Genome Sequencing, Human Genome, Genetic Variation, Genomics, Single Nucleotide, National Heart, United States, Phenotype, Good Health and Well Being, Cytochrome P-450 CYP2D6, Haplotypes, Mutagenesis, Sample Size, Generic health relevance, Human, Biotechnology
Abstract

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Published
2021

6. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Author

Nielsen, Jonas B, Rom, Oren, Surakka, Ida, Graham, Sarah E, Zhou, Wei, Roychowdhury, Tanmoy, Fritsche, Lars G, Gagliano Taliun, Sarah A, Sidore, Carlo, Liu, Yuhao, Gabrielsen, Maiken E, Skogholt, Anne Heidi, Wolford, Brooke, Overton, William, Zhao, Ying, Chen, Jin, Zhang, He, Hornsby, Whitney E, Acheampong, Akua, Grooms, Austen, Schaefer, Amanda, Zajac, Gregory JM, Villacorta, Luis, Zhang, Jifeng, Brumpton, Ben, Løset, Mari, Rai, Vivek, Lundegaard, Pia R, Olesen, Morten S, Taylor, Kent D, Palmer, Nicholette D, Chen, Yii-Der, Choi, Seung H, Lubitz, Steven A, Ellinor, Patrick T, Barnes, Kathleen C, Daya, Michelle, Rafaels, Nicholas, Weiss, Scott T, Lasky-Su, Jessica, Tracy, Russell P, Vasan, Ramachandran S, Cupples, L Adrienne, Mathias, Rasika A, Yanek, Lisa R, Becker, Lewis C, Peyser, Patricia A, Bielak, Lawrence F, Smith, Jennifer A, Aslibekyan, Stella, Hidalgo, Bertha A, Arnett, Donna K, Irvin, Marguerite R, Wilson, James G, Musani, Solomon K, Correa, Adolfo, Rich, Stephen S, Guo, Xiuqing, Rotter, Jerome I, Konkle, Barbara A, Johnsen, Jill M, Ashley-Koch, Allison E, Telen, Marilyn J, Sheehan, Vivien A, Blangero, John, Curran, Joanne E, Peralta, Juan M, Montgomery, Courtney, Sheu, Wayne H-H, Chung, Ren-Hua, Schwander, Karen, Nouraie, Seyed M, Gordeuk, Victor R, Zhang, Yingze, Kooperberg, Charles, Reiner, Alexander P, Jackson, Rebecca D, Bleecker, Eugene R, Meyers, Deborah A, Li, Xingnan, Das, Sayantan, Yu, Ketian, LeFaive, Jonathon, Smith, Albert, Blackwell, Tom, Taliun, Daniel, Zollner, Sebastian, Forer, Lukas, Schoenherr, Sebastian, Fuchsberger, Christian, Pandit, Anita, Zawistowski, Matthew, Kheterpal, Sachin, Brummett, Chad M, Natarajan, Pradeep, Schlessinger, David, Lee, Seunggeun, Kang, Hyun Min, Cucca, Francesco, and Holmen, Oddgeir L

Subjects
Aging, Cardiovascular, LDL, Loss of Function Mutation, Receptors, Genetics, Humans, 2.1 Biological and endogenous factors, Gene Silencing, Molecular Targeted Therapy, Phenomics, Aetiology, Biological Specimen Banks, Genome, Liver Disease, Prevention, Human Genome, Atherosclerosis, Lipids, United Kingdom, Heart Disease, Good Health and Well Being, Liver, Cardiovascular Diseases, 5.1 Pharmaceuticals, Gene Targeting, Development of treatments and therapeutic interventions, Digestive Diseases, Human, Genome-Wide Association Study, Biotechnology
Abstract

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Published
2020

7. Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Bick, Alexander G, Weinstock, Joshua S, Nandakumar, Satish K, Fulco, Charles P, Bao, Erik L, Zekavat, Seyedeh M, Szeto, Mindy D, Liao, Xiaotian, Leventhal, Matthew J, Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J, Lin, Amy E, Taub, Margaret A, Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D, Barnes, Kathleen C, Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M, Silverman, Edwin K, Weiss, Scott T, Palmer, Nicholette D, Vasan, Ramachandran S, Burchard, Esteban G, Kardia, Sharon LR, He, Jiang, Kaplan, Robert C, Smith, Nicholas L, Arnett, Donna K, Schwartz, David A, Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A, Custer, Brian, Peralta, Juan M, Gui, Hongsheng, Meyers, Deborah A, McGarvey, Stephen T, Chen, Ida Yii-Der, Shoemaker, M Benjamin, Peyser, Patricia A, Broome, Jai G, Gogarten, Stephanie M, Wang, Fei Fei, Wong, Quenna, Montasser, May E, Daya, Michelle, Kenny, Eimear E, North, Kari E, Launer, Lenore J, Cade, Brian E, Bis, Joshua C, Cho, Michael H, Lasky-Su, Jessica, Bowden, Donald W, Cupples, L Adrienne, Mak, Angel CY, Becker, Lewis C, Smith, Jennifer A, Kelly, Tanika N, Aslibekyan, Stella, Heckbert, Susan R, Tiwari, Hemant K, Yang, Ivana V, Heit, John A, Lubitz, Steven A, Johnsen, Jill M, Curran, Joanne E, Wenzel, Sally E, Weeks, Daniel E, Rao, Dabeeru C, Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P, Buth, Erin J, Rafaels, Nicholas, Loos, Ruth JF, Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I, Levy, Daniel, Bielak, Lawrence F, Hixson, James E, Floyd, James S, Whitsel, Eric A, Ellinor, Patrick T, Irvin, Marguerite R, Fingerlin, Tasha E, Raffield, Laura M, Armasu, Sebastian M, and Wheeler, Marsha M

Subjects
alpha Karyopherins, Adult, Male, General Science & Technology, 1.1 Normal biological development and functioning, Black People, and over, NHLBI Trans-Omics for Precision Medicine Consortium, Regenerative Medicine, Cardiovascular, Dioxygenases, Tripartite Motif Proteins, Underpinning research, Proto-Oncogene Proteins, and Blood Institute (U.S.), 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Precision Medicine, Cell Self Renewal, Aetiology, Lung, Germ-Line Mutation, African Continental Ancestry Group, Aged, Genome, Whole Genome Sequencing, Inflammatory and immune system, Human Genome, Intracellular Signaling Peptides and Proteins, National Heart, Middle Aged, Hematopoietic Stem Cells, Stem Cell Research, and Blood Institute, United States, DNA-Binding Proteins, Phenotype, Good Health and Well Being, Africa, Female, Generic health relevance, Clonal Hematopoiesis, Human, Biotechnology
Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. 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 cancer2-4 and coronary heart disease5-this phenomenon istermed clonal haematopoiesis of indeterminate potential (CHIP)6. 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 CHIPdriver 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.

Published
2020

8. Novel genetic determinants of telomere length from a multi-ethnic analysis of 75,000 whole genome sequences in TOPMed

Author

Taub, Margaret A, Weinstock, Joshua S, Iyer, Kruthika R, Yanek, Lisa R, Conomos, Matthew P, Brody, Jennifer A, Keramati, Ali, Laurie, Cecelia A, Arvanitis, Marios, Smith, Albert V, Lane, John, Becker, Lewis C, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Burchard, Esteban G, Celedon, Juan C, Chang, Yen Pei C, Custer, Brian, Darbar, Dawood, de las Fuentes, Lisa, DeMeo, Dawn L, Freedman, Barry I, Garrett, Melanie E, Gladwin, Mark T, Heckbert, Susan R, Hidalgo, Bertha A, Ingram, Christie, Irvin, Marguerite R, Craig Johnson, W, Kaab, Stefan, Launer, Lenore, Lee, Jiwon, Liu, Simin, Moscati, Arden, North, Kari E, Peyser, Patricia A, Rafaels, Nicholas, Raffield, Laura M, Weeks, Daniel E, Wheeler, Marsha M, Keoki Williams, L., Zhao, Wei, Armanios, Mary, Aslibekyan, Stella, Auer, Paul L, Bowden, Donald W, Cade, Brian E, Yii-Der Chen, Ida, Cho, Michael H, Cupples, L Adrienne, Curran, Joanne E, Daya, Michelle, Deka, Ranjan, Guo, Xiuqing, Hou, Lifang, Hwang, Shih-Jen, Johnsen, Jill M, Kenny, Eimear E, Levin, Albert M, Liu, Chunyu, Minster, Ryan L, Nouraie, Mehdi, Sabino, Ester C, Smith, Jennifer A, Smith, Nicholas L, Lasky Su, Jessica, Telen, Marilyn J, Tiwari, Hemant K, Tracy, Russell P, White, Marquitta J, Zhang, Yingze, Wiggins, Kerri L, Weiss, Scott T, Vasan, Ramachandran S, Taylor, Kent D, Sinner, Moritz F, Silverman, Edwin K, Benjamin Shoemaker, M., Sheu, Wayne H-H, Rotter, Jerome I, Redline, Susan, Psaty, Bruce M, Peralta, Juan M, Palmer, Nicholette D, Loos, Ruth JF, Montgomery, Courtney G, Mitchell, Braxton D, Meyers, Deborah A, McGarvey, Stephen T, Mak, Angel CY, Kumar, Rajesh, Kooperberg, Charles, Konkle, Barbara A, Kelly, Shannon, Kardia, Sharon LR, Kaplan, Robert, He, Jiang, Gui, Hongsheng, Fornage, Myriam, Ellinor, Patrick T, de Andrade, Mariza, Correa, Adolfo, Boerwinkle, Eric, Barnes, Kathleen C, Ashley-Koch, Allison E, Arnett, Donna K, Albert, Christine, Laurie, Cathy C, Abecasis, Goncalo, Aviv, Abraham, Nickerson, Deborah A, Wilson, James G, Rich, Stephen S, Levy, Daniel, Battle, Alexis, Blackwell, Thomas W, Ruczinski, Ingo, Thornton, Timothy, O’Connell, Jeff, Perry, James A, Pankratz, Nathan, Reiner, Alexander P, and Mathias, Rasika A

Abstract

Telomeres shorten in replicating somatic cells and with age; in human leukocytes, telomere length (TL) is associated with a host of aging-related diseases 1,2 . To date, 16 genome-wide association studies (GWAS) have identified twenty-three loci associated with leukocyte TL 3–18 , but prior studies were primarily in individuals of European and Asian ancestry and relied on laboratory assays including Southern Blot and qPCR to quantify TL. Here, we estimated TL bioinformatically, leveraging whole genome sequencing (WGS) of whole blood from n=75,176 subjects in the Trans-Omics for Precision Medicine (TOPMed) Program. We performed the largest multi-ethnic and only WGS-based genome-wide association analysis of TL to date. We identified 22 associated loci (p-value

Published
2019
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9. Illustrated State-of-the-Art Capsules of the ISTH 2019 Congress in Melbourne, Australia : Plasminogen in wound healing

Author

Andrews, Robert K., Wolberg, Alisa, Lip, Gregory Y. H., Eikelboom, John, De Meyer, Simon F., Mast, Alan, Flick, Matthew, Urano, Tetsumei, Ny, Tor, Cutler, Daniel, Ju, Lining A., Zhu, Cheng, Randi, Anna M., O'Donnell, James S., O'Brien, Sarah H., Fijnvandraat, Karin, Shima, Midori, Nathwani, Amit, Luyendyk, Jim, Vanhoorelbeke, Karen, Barco, Stefano, Chuansumrit, Ampaiwan, Stanworth, Simon J., Curry, Nicola, Del Rio, J. Mauricio, Battinelli, Elisabeth M., Bos, Mettine H. A., Reinhardt, Christoph, Peter, Karlheinz, Gomez, Keith, Danese, Elisa, Rak, Janusz, Flaumenhaft, Robert, Di Paola, Jorge, Nilsson, Susie, Severin, Sonia, Eto, Koji, Hitchcock, Ian S., Ni, Heyu, Despotovic, Jenny, Boilard, Eric, Rondina, Matthew, Mangin, Pierre, Hamilton, Justin R., Suzuki-Inoue, Katsue, Tsukiji, Nagaharu, Conway, Edward M., Maas, Coen, Emsley, Jonas, Jenne, Craig N., Fuchs, Tobias A., Weitz, Jeffrey, Johnsen, Jill M., Rauova, Lubica, Spyropoulos, Alex, Goto, Shinya, Verhamme, Peter, Miranda, Sebastien, Rodger, Marc, Ni Ainle, Fionnuala, Schreiber, Karen, Thomas, Moumneh, Le Gal, Gregoire, Zentner, Dominica, McLintock, Claire, and Magnusson, Maria

Subjects
education, Hematology, Hematologi
Abstract

The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

Published
2019

10. Von Willebrand Factor Propeptide to Antigen Ratio Identifies Platelet Activation and Reduced VWF Survival Phenotype in Mice

Author

Jacobi, Paula M., Kanaji, Sachiko, Jakab, David, Gehrand, Ashley L., Johnsen, Jill M., and Haberichter, Sandra L.

Subjects
Blood Platelets, congenital, hereditary, and neonatal diseases and abnormalities, Hemorrhage, Article, Mice, Phlebotomy, hemic and lymphatic diseases, von Willebrand Factor, Animals, Humans, Saphenous Vein, Antigens, Protein Precursors, Blood Coagulation, Alleles, Bone Marrow Transplantation, Reproducibility of Results, Platelet Activation, Mice, Inbred C57BL, Disease Models, Animal, von Willebrand Diseases, HEK293 Cells, Phenotype, cardiovascular system, Peptides, circulatory and respiratory physiology
Abstract

Essentials Reduced survival of von Willebrand factor (VWF) in plasma causes type 1C von Willebrand disease. Blood was collected from mouse strains by various methods and VWF propeptide and antigen assayed. VWF propeptide to antigen ratio identifies a reduced VWF survival phenotype in mice. This ratio validates the acceptability of murine blood samples for coagulation studies.Background Reduced plasma survival of von Willebrand factor (VWF) is characteristic of patients with type 1C von Willebrand disease (VWD). These subjects can be identified by an increased steady-state ratio of plasma VWF propeptide (VWFpp) to VWF antigen (VWF:Ag). A similar phenotype occurs in mice with the Mvwf1 allele. Objectives To (i) determine if the VWFpp/VWF:Ag ratio can be used to identify a 'type 1C' phenotype in mice, (ii) determine the most reliable method for murine blood sampling, and (iii) identify the source of VWF released during problematic blood collection. Methods 'Platelet-VWF' and 'endothelial-VWF' mice were generated by bone marrow transplantation between C57BL/6J and VWF-/- mice. Several blood sampling methods were used and murine VWFpp and VWF:Ag levels determined. Plasma and platelet VWF:Ag and VWFpp, VWF multimers and VWF half-life were examined in mouse strains with and without Mvwf1. Results A single retro-orbital bleed and vena cava collection were found to be the optimal methods of blood collection. Problematic collection resulted in release of VWF from platelets and endothelium. The VWFpp/VWF:Ag ratio identified strains of mice with reduced VWF survival. Conclusion Assay of murine VWFpp and VWF:Ag has utility in determining the acceptability of murine blood samples for coagulation testing and in identification of a reduced VWF survival phenotype in mice.

Published
2018

11. A Variational Bayes Discrete Mixture Test for Rare Variant Association

Author

O'Donnell, Christopher J., Lettre, Guillaume, Rich, Stephen S., Wilson, James G., Lange, Leslie A., Tracy, Russell P., Wurfel, Mark M., Ganesh, Santhi K., Tang, Hua, Jiao, Shuo, Smith, Nicholas L., Dai, James Y., Kooperberg, Charles, Jackson, Rebecca D., Nickerson, Deborah A., Auer, Paul L., Carlson, Christopher S., Johnsen, Jill M., Reiner, Alexander P., and Logsdon, Benjamin A.

Abstract

Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that “aggregate” tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute’s Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.

Published
2014
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