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1. 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
Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Cytochrome P-450 CYP2D6, Genetic Variation, Genome, Human, Genomics, Haplotypes, Heterozygote, Humans, INDEL Mutation, Loss of Function Mutation, Mutagenesis, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Population Density, Precision Medicine, Quality Control, Sample Size, United States, Whole Genome Sequencing, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, General Science & Technology
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 400 million 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 400 million 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

2. Genome-wide association study identifies 74 loci associated with educational attainment

Author

Okbay, Aysu, Beauchamp, Jonathan P, Fontana, Mark Alan, Lee, James J, Pers, Tune H, Rietveld, Cornelius A, Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Meddens, S Fleur W, Oskarsson, Sven, Pickrell, Joseph K, Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Abdellaoui, Abdel, Ahluwalia, Tarunveer S, Bacelis, Jonas, Baumbach, Clemens, Bjornsdottir, Gyda, Brandsma, Johannes H, Pina Concas, Maria, Derringer, Jaime, Furlotte, Nicholas A, Galesloot, Tessel E, Girotto, Giorgia, Gupta, Richa, Hall, Leanne M, Harris, Sarah E, Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E, Kaasik, Kadri, Kalafati, Ioanna P, Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J van der, deLeeuw, Christiaan, Lind, Penelope A, Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B, van der Most, Peter J, Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J, Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E, Shi, Jianxin, Smith, Albert V, Poot, Raymond A, St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm-Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z, Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E, Biino, Ginevra, Bønnelykke, Klaus, Boyle, Patricia A, Campbell, Harry, Cappuccio, Francesco P, Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Panos, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M, Faul, Jessica D, Feitosa, Mary F, Forstner, Andreas J, Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V, Harris, Tamara B, Heath, Andrew C, Hocking, Lynne J, Holliday, Elizabeth G, Homuth, Georg, and Horan, Michael A

Subjects
Biological Sciences, Genetics, Epidemiology, Health Sciences, Statistics, Mathematical Sciences, Human Genome, Clinical Research, Alzheimer Disease, Bipolar Disorder, Brain, Cognition, Computational Biology, Educational Status, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, United Kingdom, LifeLines Cohort Study, General Science & Technology
Abstract

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Published
2016

3. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, Peter K, Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U, Schurmann, Claudia, Smith, Albert V, Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D, Zhao, Wei, Bartz, Traci M, Concas, Maria Pina, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I, O'Connel, Jeffrey R, Corre, Tanguy, Nongmaithem, Suraj S, Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki-Eleni, Kacprowski, Tim, Bjonnes, Andrew, van der Spek, Ashley, Wu, Ying, Giri, Anil K, Yanek, Lisa R, Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A, McLeod, Olga, Cornelis, Marilyn C, Pattaro, Cristian, Verweij, Niek, Baumbach, Clemens, Abdellaoui, Abdel, Warren, Helen R, Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John RB, Cappellani, Stefania, Mirza, Saira S, Benton, Miles C, Broeckel, Ulrich, Medland, Sarah E, Lind, Penelope A, Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F, Zhi, Degui, van der Most, Peter J, Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaros, van der Laan, Sander W, Bradfield, Jonathan P, Wood, Andrew R, Bonnefond, Amelie, Ahluwalia, Tarunveer S, Hall, Leanne M, Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, de Haan, Hugoline G, Abney, Mark, Afzal, Uzma, Allison, Matthew A, Amin, Najaf, Asselbergs, Folkert W, Bakker, Stephan JL, Barr, R Graham, Baumeister, Sebastian E, Benjamin, Daniel J, Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P, Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J, Chen, Constance, and Chen, Y-D Ida

Subjects
Biological Sciences, Genetics, Clinical Research, Human Genome, Biological Evolution, Blood Pressure, Body Height, Cholesterol, LDL, Cognition, Cohort Studies, Educational Status, Female, Forced Expiratory Volume, Genome, Human, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype, General Science & Technology
Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Published
2015

4. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John RB, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, de Geus, Eco EJ, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, and Kiel, Douglas P

Subjects
Paediatrics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Pediatric, Biotechnology, Human Genome, Clinical Research, Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Calcium-Binding Proteins, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins, Ubiquitin-Protein Ligases, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P

Published
2014

5. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, Tanya M, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Ripatti, Samuli, Chasman, Daniel I, Willer, Cristen J, Johansen, Christopher T, Fouchier, Sigrid W, Isaacs, Aaron, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Aulchenko, Yurii S, Thorleifsson, Gudmar, Feitosa, Mary F, Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Shin Cho, Yoon, Jin Go, Min, Jin Kim, Young, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Twee-Hee Ong, Rick, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Song, Kijoung, Hua Zhao, Jing, Yuan, Xin, Luan, Jian’an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Wright, Alan F, Witteman, Jacqueline CM, Wilson, James F, Willemsen, Gonneke, Wichmann, H-Erich, Whitfield, John B, Waterworth, Dawn M, Wareham, Nicholas J, Waeber, Gérard, Vollenweider, Peter, Voight, Benjamin F, Vitart, Veronique, Uitterlinden, Andre G, Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R, Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M, Spector, Tim D, Soranzo, Nicole, Smit, Johannes H, Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric JG, Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Psaty, Bruce M, Pramstaller, Peter P, Pichler, Irene, Perola, Markus, Penninx, Brenda WJH, Pedersen, Nancy L, Pattaro, Cristian, Parker, Alex N, Pare, Guillaume, Oostra, Ben A, O’Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, Meitinger, Thomas, McPherson, Ruth, and McCarthy, Mark I

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Human Genome, Cardiovascular, Prevention, Atherosclerosis, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Animals, Asian People, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipids, Liver, Male, Mice, N-Acetylgalactosaminyltransferases, Phenotype, Polymorphism, Single Nucleotide, Protein Phosphatase 1, Reproducibility of Results, Triglycerides, White People, Polypeptide N-acetylgalactosaminyltransferase, General Science & Technology
Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

6. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Author

Weinstock, Joshua S., Gopakumar, Jayakrishnan, Burugula, Bala Bharathi, Uddin, Md Mesbah, Jahn, Nikolaus, Belk, Julia A., Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn M., Luna, Sofia E., Prothro, Katherine P., Mitchell, Shaneice R., Laurie, Cecelia A., Broome, Jai G., Taylor, Kent D., Guo, Xiuqing, Sinner, Moritz F., von Falkenhausen, Aenne S., Kääb, Stefan, Shuldiner, Alan R., O’Connell, Jeffrey R., Lewis, Joshua P., Boerwinkle, Eric, Barnes, Kathleen C., Chami, Nathalie, Kenny, Eimear E., Loos, Ruth J. F., Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald M., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Qiao, Dandi, Palmer, Nicholette D., Freedman, Barry I., Bowden, Donald W., Cho, Michael H., DeMeo, Dawn L., Vasan, Ramachandran S., Yanek, Lisa R., Becker, Lewis C., Kardia, Sharon L. R., Peyser, Patricia A., He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Arnett, Donna K., Irvin, Marguerite R., Tiwari, Hemant, Cutler, Michael J., Knight, Stacey, Muhlestein, J. Brent, Correa, Adolfo, Raffield, Laura M., Gao, Yan, de Andrade, Mariza, Rotter, Jerome I., Rich, Stephen S., Tracy, Russell P., Konkle, Barbara A., Johnsen, Jill M., Wheeler, Marsha M., Smith, J. Gustav, Melander, Olle, Nilsson, Peter M., Custer, Brian S., Duggirala, Ravindranath, Curran, Joanne E., Blangero, John, McGarvey, Stephen, Williams, L. Keoki, Xiao, Shujie, Yang, Mao, Gu, C. Charles, Chen, Yii-Der Ida, Lee, Wen-Jane, Marcus, Gregory M., Kane, John P., Pullinger, Clive R., Shoemaker, M. Benjamin, Darbar, Dawood, Roden, Dan M., Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn E., Desai, Pinkal, Johnson, Andrew D., Mathias, Rasika A., Blackwell, Thomas W., Abecasis, Goncalo R., Smith, Albert V., Kang, Hyun M., Satpathy, Ansuman T., Natarajan, Pradeep, Kitzman, Jacob O., Whitsel, Eric A., Reiner, Alexander P., Bick, Alexander G., and Jaiswal, Siddhartha

Abstract

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2–6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1Apromoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1Awas not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2or ASXL1led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1Aexpression. Forced expression of TCL1Apromoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1Aactivation.

Published
2023
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7. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J., Dahia, Chitra L., Park-Min, Kyung Hyun, Tobias, Jonathan H., Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S., Nielson, Carrie M., Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E., Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A., Gregson, Celia L., Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J., Marshall, Mhairi, Gardiner, Brooke B., Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y., Thorleifsson, Gudmar, Enneman, Anke W., van Schoor, Natasja M., de Groot, Lisette C. P. G. M., van der Velde, Nathalie, Melin, Beatrice, Kemp, John P., Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G., Williams, Stephen R., Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z., Haessler, Jeff, Chasman, Daniel I., Giulianini, Franco, Rose, Lynda M., Ridker, Paul M., Eisman, John A., Nguyen, Tuan V., Center, Jacqueline R., Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L., Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P., Koromani, Fjorda, Prince, Richard L., Lewis, Joshua R., Langdahl, Bente L., Hermann, Pernille A., Jensen, Jens-Erik B., Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M., Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E., Garg, Gaurav, Olmos, Jose M., Zarrabeitia, Maria T., Riancho, Jose A., Ralston, Stuart H., Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S., Karasik, David, Davey-Smith, George, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, Carola M., van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, Scott G., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, Adrienne L., Ohlsson, Claes, Greenwood, Celia M. T., Jackson, Rebecca D., Rowe, David W., Loomis, Cynthia A., Evans, David M., Ackert-Bicknell, Cheryl L., Joyner, Alexandra L., Duncan, Emma L., Kiel, Douglas P., Rivadeneira, Fernando, and Richards, Brent J.

Published
2015
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8. PLD3 variants in population studies

Author

van der Lee, Sven J., Holstege, Henne, Wong, Tsz Hang, Jakobsdottir, Johanna, Bis, Joshua C., Chouraki, Vincent, van Rooij, Jeroen G. J., Grove, Megan L., Smith, Albert V., Amin, Najaf, Choi, Seung-Hoan, Beiser, Alexa S., Garcia, Melissa E., van IJcken, Wilfred F. J., Pijnenburg, Yolande A. L., Louwersheimer, Eva, Brouwer, Rutger W. W., van den Hout, Mirjam C. G. N., Oole, Edwin, Eirkisdottir, Gudny, Levy, Daniel, Rotter, Jerome I., Emilsson, Valur, OʼDonnell, Christopher J., Aspelund, Thor, Uitterlinden, Andre G., Launer, Lenore J., Hofman, Albert, Boerwinkle, Eric, Psaty, Bruce M., DeStefano, Anita L., Scheltens, Philip, Seshadri, Sudha, van Swieten, John C., Gudnason, Vilmundur, van der Flier, Wiesje M., Ikram, Arfan M., and van Duijn, Cornelia M.

Published
2015
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9. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author

Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O’Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sõber, Siim, Parsa, Afshin, Luan, Jian’an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F, Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Onland-Moret, Charlotte N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O’Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N.M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Young, Hunter J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A. Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, Erich H., Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O’Donnell, Christopher J., Schwartz, Stephen M., Ikram, Arfan M., Longstreth, W. T., Jr, Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R.G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Mani, Radha K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Ong, Rick Twee-Hee, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kumar, Kranthi M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, Gerald F.R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Tai, Shyong E, Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M, Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., and Johnson, Toby

Published
2011
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10. Variability in the analysis of a single neuroimaging dataset by many teams

Author

Botvinik-Nezer, Rotem, primary, Holzmeister, Felix, additional, Camerer, Colin F., additional, Dreber, Anna, additional, Huber, Juergen, additional, Johannesson, Magnus, additional, Kirchler, Michael, additional, Iwanir, Roni, additional, Mumford, Jeanette A., additional, Adcock, R. Alison, additional, Avesani, Paolo, additional, Baczkowski, Blazej M., additional, Bajracharya, Aahana, additional, Bakst, Leah, additional, Ball, Sheryl, additional, Barilari, Marco, additional, Bault, Nadège, additional, Beaton, Derek, additional, Beitner, Julia, additional, Benoit, Roland G., additional, Berkers, Ruud M. W. J., additional, Bhanji, Jamil P., additional, Biswal, Bharat B., additional, Bobadilla-Suarez, Sebastian, additional, Bortolini, Tiago, additional, Bottenhorn, Katherine L., additional, Bowring, Alexander, additional, Braem, Senne, additional, Brooks, Hayley R., additional, Brudner, Emily G., additional, Calderon, Cristian B., additional, Camilleri, Julia A., additional, Castrellon, Jaime J., additional, Cecchetti, Luca, additional, Cieslik, Edna C., additional, Cole, Zachary J., additional, Collignon, Olivier, additional, Cox, Robert W., additional, Cunningham, William A., additional, Czoschke, Stefan, additional, Dadi, Kamalaker, additional, Davis, Charles P., additional, Luca, Alberto De, additional, Delgado, Mauricio R., additional, Demetriou, Lysia, additional, Dennison, Jeffrey B., additional, Di, Xin, additional, Dickie, Erin W., additional, Dobryakova, Ekaterina, additional, Donnat, Claire L., additional, Dukart, Juergen, additional, Duncan, Niall W., additional, Durnez, Joke, additional, Eed, Amr, additional, Eickhoff, Simon B., additional, Erhart, Andrew, additional, Fontanesi, Laura, additional, Fricke, G. Matthew, additional, Fu, Shiguang, additional, Galván, Adriana, additional, Gau, Remi, additional, Genon, Sarah, additional, Glatard, Tristan, additional, Glerean, Enrico, additional, Goeman, Jelle J., additional, Golowin, Sergej A. E., additional, González-García, Carlos, additional, Gorgolewski, Krzysztof J., additional, Grady, Cheryl L., additional, Green, Mikella A., additional, Guassi Moreira, João F., additional, Guest, Olivia, additional, Hakimi, Shabnam, additional, Hamilton, J. Paul, additional, Hancock, Roeland, additional, Handjaras, Giacomo, additional, Harry, Bronson B., additional, Hawco, Colin, additional, Herholz, Peer, additional, Herman, Gabrielle, additional, Heunis, Stephan, additional, Hoffstaedter, Felix, additional, Hogeveen, Jeremy, additional, Holmes, Susan, additional, Hu, Chuan-Peng, additional, Huettel, Scott A., additional, Hughes, Matthew E., additional, Iacovella, Vittorio, additional, Iordan, Alexandru D., additional, Isager, Peder M., additional, Isik, Ayse I., additional, Jahn, Andrew, additional, Johnson, Matthew R., additional, Johnstone, Tom, additional, Joseph, Michael J. E., additional, Juliano, Anthony C., additional, Kable, Joseph W., additional, Kassinopoulos, Michalis, additional, Koba, Cemal, additional, Kong, Xiang-Zhen, additional, Koscik, Timothy R., additional, Kucukboyaci, Nuri Erkut, additional, Kuhl, Brice A., additional, Kupek, Sebastian, additional, Laird, Angela R., additional, Lamm, Claus, additional, Langner, Robert, additional, Lauharatanahirun, Nina, additional, Lee, Hongmi, additional, Lee, Sangil, additional, Leemans, Alexander, additional, Leo, Andrea, additional, Lesage, Elise, additional, Li, Flora, additional, Li, Monica Y. C., additional, Lim, Phui Cheng, additional, Lintz, Evan N., additional, Liphardt, Schuyler W., additional, Losecaat Vermeer, Annabel B., additional, Love, Bradley C., additional, Mack, Michael L., additional, Malpica, Norberto, additional, Marins, Theo, additional, Maumet, Camille, additional, McDonald, Kelsey, additional, McGuire, Joseph T., additional, Melero, Helena, additional, Méndez Leal, Adriana S., additional, Meyer, Benjamin, additional, Meyer, Kristin N., additional, Mihai, Glad, additional, Mitsis, Georgios D., additional, Moll, Jorge, additional, Nielson, Dylan M., additional, Nilsonne, Gustav, additional, Notter, Michael P., additional, Olivetti, Emanuele, additional, Onicas, Adrian I., additional, Papale, Paolo, additional, Patil, Kaustubh R., additional, Peelle, Jonathan E., additional, Pérez, Alexandre, additional, Pischedda, Doris, additional, Poline, Jean-Baptiste, additional, Prystauka, Yanina, additional, Ray, Shruti, additional, Reuter-Lorenz, Patricia A., additional, Reynolds, Richard C., additional, Ricciardi, Emiliano, additional, Rieck, Jenny R., additional, Rodriguez-Thompson, Anais M., additional, Romyn, Anthony, additional, Salo, Taylor, additional, Samanez-Larkin, Gregory R., additional, Sanz-Morales, Emilio, additional, Schlichting, Margaret L., additional, Schultz, Douglas H., additional, Shen, Qiang, additional, Sheridan, Margaret A., additional, Silvers, Jennifer A., additional, Skagerlund, Kenny, additional, Smith, Alec, additional, Smith, David V., additional, Sokol-Hessner, Peter, additional, Steinkamp, Simon R., additional, Tashjian, Sarah M., additional, Thirion, Bertrand, additional, Thorp, John N., additional, Tinghög, Gustav, additional, Tisdall, Loreen, additional, Tompson, Steven H., additional, Toro-Serey, Claudio, additional, Torre Tresols, Juan Jesus, additional, Tozzi, Leonardo, additional, Truong, Vuong, additional, Turella, Luca, additional, van ‘t Veer, Anna E., additional, Verguts, Tom, additional, Vettel, Jean M., additional, Vijayarajah, Sagana, additional, Vo, Khoi, additional, Wall, Matthew B., additional, Weeda, Wouter D., additional, Weis, Susanne, additional, White, David J., additional, Wisniewski, David, additional, Xifra-Porxas, Alba, additional, Yearling, Emily A., additional, Yoon, Sangsuk, additional, Yuan, Rui, additional, Yuen, Kenneth S. L., additional, Zhang, Lei, additional, Zhang, Xu, additional, Zosky, Joshua E., additional, Nichols, Thomas E., additional, Poldrack, Russell A., additional, and Schonberg, Tom, additional

Published
2020
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11. Crystal structure of the breakage-reunion domain of DNA gyrase

Author

Cabral, Joao H. Morais, Jackson, Andrew P., Smith, Clare V., Shikotra, Nita, Maxwell, Anthony, and Liddington, Robert C.

Subjects
DNA topoisomerase II -- Research, DNA repair -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Researchers have been able to determine the crystal structure of the 'breakage-reunion' domain of the DNA gyrase at 2.8 angstrom resolution. The structure of this 59K (relative molecular mass, 59,000) domain was compared with that of a 92K fragment of yeast topoisomerase II. The structures indicate how it may be possible for the T segment to exit from the bottom of the molecule through the 'primary' dimer interface after passing through the G segment.

Published
1997

12. Quantum-well states in copper thin films

Author

Kawakami, R. K., Rotenberg, E., Choi, Hyuk J., Escorcia-Aparicio, Ernesto J., Bowen, M. O., Wolfe, J. H., Arenholz, E., Zhang, Z. D., Smith, N. V., and Qiu, Z. Q.

Published
1999

13. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., and Hirschhorn, Joel N.

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022
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16. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B., Sulem, Patrick, Walters, Robin G., Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N. Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N., Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W., Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Alizadeh, Behrooz Z., Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Becher, Heiko, Beckmann, Matthias W., Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J. C. N., de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K., Hopper, John L., Hottenga, Jouke J., Hu, Frank, Hunter, David, Ikram, Mohammad A., Jackson, Rebecca D., Joaquim, Micaella D. R., John, Esther M., Joshi, Peter K., Karasik, David, Kardia, Sharon L. R., Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M., Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R., Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Ridker, Paul M., Ring, Susan M., Robino, Antonietta, Rose, Lynda M., Rosendaal, Frits R., Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Saloustros, Emmanouil, Sandler, Dale P., Sanna, Serena, Sawyer, Elinor J., Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K., Schoemaker, Minouk J., Schraut, Katharina E., Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B. J., Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Troester, Melissa A., Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Weinberg, Clarice R., Weir, David R., Wilcox, Amber N., van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H., Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Lopez-Contreras, Andres J., Daniel, Jeremy A., Stefansson, Kari, Chang-Claude, Jenny, van der Schouw, Yvonne T., Lunetta, Kathryn L., Chasman, Daniel I., Easton, Douglas F., Visser, Jenny A., Ozanne, Susan E., Namekawa, Satoshi H., Solc, Petr, Murabito, Joanne M., Ong, Ken K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, and Perry, John R. B.

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021
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17. 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 L. R., 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 C. Y., 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 J. F., 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., Wheeler, Marsha M., Sabino, Ester C., Blangero, John, Williams, L. Keoki, Levy, Bruce D., Sheu, Wayne Huey-Herng, Roden, Dan M., Boerwinkle, Eric, Manson, JoAnn E., Mathias, Rasika A., Desai, Pinkal, Taylor, Kent D., Johnson, Andrew D., Auer, Paul L., Kooperberg, Charles, Laurie, Cathy C., Blackwell, Thomas W., Smith, Albert V., Zhao, Hongyu, Lange, Ethan, Lange, Leslie, Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Scheet, Paul, Kitzman, Jacob O., Lander, Eric S., Engreitz, Jesse M., Ebert, Benjamin L., Reiner, Alexander P., Jaiswal, Siddhartha, Abecasis, Gonçalo, Sankaran, Vijay G., Kathiresan, Sekar, and Natarajan, Pradeep

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 cancer2–4and coronary heart disease5—this phenomenon is termed 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 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 TET2that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2germline locus enabled the identification of a causal variant that disrupts a TET2distal 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
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18. Minor-element signature of relic olivine grains in deep-sea particles - A match with forsterites from C2 meteorites

Author

Steele, I. M, Smith, J. V, and Brownlee, D. E

Subjects
Lunar And Planetary Exploration
Abstract

The results of high-precision electron microprobe analyses on relic forsterites in 13 different deep sea particles (DSP) are described, comparing their 'minor' element (Mn, Cr, Ca, Ti, Al) signatures with those of olivines found in several types of meteorites. The results show that the DSP olivines do not match those from terrestrial and lunar rocks and achondritic meteoroties, match poorly those of the carbonaceous Allende (CV3) and Orgeuil (CI) meteorites, but are well matched with olivines from C2 meteorites, including the unusual Belgica 7904 meteorite.

Published
1985
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19. Cathodoluminescence zoning and minor elements in forsterites from the Murchison (C2) and Allende (C3V) carbonaceous chondrites

Author

Steele, I. M, Smith, J. V, and Skirius, C

Subjects
Lunar And Planetary Exploration
Abstract

Cathodoluminescence has been applied to look for textural features of olivine in carbonaceous meteorites relevant to the unresolved dispute over the origin of the olivine, whether from a vapor or a liquid. Cathodoluminescence photographs of forsterite grains in Murchison (C2) and Allende (C3) meteorites presented here reveal a blue core with planar boundaries to a red or dark rim. High-precision electron microprobe analyses have been performed which reveal unusually large amounts of the 'minor' elements Al, Ti, and Ca in the blue cores of these forsterites, suggesting formation by crystallization at high temperatures from a source rich in these metals. Following conclusions drawn from previous analyses of olivine in meteorites, it is argued that the minor element signature should be able to characterize olivines in micrometeorites and in deep-sea particles.

Published
1985
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20. Mechanical aggregation of enstatite chondrites from an inhomogeneous debris cloud

Author

Leitch, C. A and Smith, J. V

Subjects
Lunar And Planetary Exploration
Abstract

Enstatite chondrites have oxygen isotope ratios closer to those of the earth and moon than other meteorites. Their minerals are chemically reduced; metal contains Si, and some Ca, Ti, Mg and Mn are incorporated in sulphides rather than silicates. Clinoenstatite and olivine are virtually Fe-free. Two types of clinoenstatite in the Indarch enstatite chondrite have been reported, one luminescing blue and one red. Similar clinoenstatites in the Kota-Kota enstatite chondrite are associated with two distinct types of forsteritic olivine, one luminescing orange and the other blue. The textural relations and differences in chemical composition cannot be explained by progressive condensation from the solar nebula and require the mechanical mixing of material from at least two sources. It is suggested here that enstatite chondrites result from mechanical and chemical processes during aerodynamic sorting and gravitational settling of debris from a hot cloud of dust, liquid and gas produced during collision of planetesimals.

Published
1981
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21. Halogen and phosphorus storage in the earth

Author

Smith, J. V

Subjects
Geophysics
Abstract

Chemical analyses of surface reservoirs, coupled with compositions for interior zones inferred from geophysical and geochemical data have been used to obtain a range of estimates of the bulk composition of the earth. It is suggested that (1) apatite with 3 wt% Fe, up to 1 wt% Cl, and 0.003 wt% Br is the principal mineral reservoir for halogens, and mica is a subsidiary reservoir; (2) apatite with 18 wt% P is the principal store of P in the upper mantle and perhaps lower mantle, but accounts for only one-twentieth of P in the earth; and (3) the remaining P is in a reservoir inaccessible to magmatism, and may amount to a maximum of 0.7 wt% in the core.

Published
1981
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22. Carbonic metamorphism, granulites and crustal growth

Author

Newton, R. C, Smith, J. V, and Windley, B. F

Subjects
Geophysics
Abstract

Stabilization of early crust against melting by high radioactivity and against resorption into the mantle by fast convective overturn requires that water and heat producers were flushed upwards within 50 Myr of accretion. Creation of a refractory base of granulite by metamorphism associated with CO2 vapour explains CO2-rich fluid inclusions in ancient high-grade rocks, minor-element depletions and local phenomena of arrested development of charnockite in Precambrian terrains. The hot-spot and plate-tectonic models of Precambrian crustal evolution lead to different schemes for CO2 delivery to continental roots. New tectonic concepts may be needed to explain carbonic metamorphism and other features of early crustal evolution.

Published
1980
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24. Mineralogy of Apollo 15415 ?genesis rock' - Source of anorthosite on moon.

Author

Steele, I. M and Smith, J. V

Subjects
Space Sciences
Abstract

Results of electron microprobe analyses of plagioclase points and pyroxene grains of Apollo 15415 ?genesis rock.' It is pointed out that no evidence of cumulate textures has yet appeared to support suggestions of extensive crystal-liquid differentiation producing an anorthositic crust or a lunar crust composed of a mixture of plagioclase-rich rock, basalts and minor ultramafic material, which require that plagioclase crystals float in a basaltic liquid. The plagioclase in 15415 does not show cumulate texture either. It is noted that it remains to be seen whether rock 15415 is correctly named the ?genesis rock.'

Published
1971
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28. Ancient crustal metamorphism at low pH2O:charnockite formation at Kabbaldurga, south India

Author

Janardhan, A. S., Newton, R. C., and Smith, J. V.

Abstract

Arrested charnockitic conversion of amphibolitic gneiss at Kabbaldurga, Karnataka State, south India, was studied mineralogically. Iron-rich pyroxenes were generated from amphibole in patches and stringers without melting. The dark colour of charnockite arises from numerous tiny veins of chlorite and manganese-bearing calcite, particularly in feldspars. The metamorphism was effected by very local, mainly grain-boundary, migration of volatiles low in H2O, and probably dominantly CO2. This was followed by vein alteration at lower temperatures from volatiles richer in H2O. The volatiles are ascribed to massive liberation from the mantle in upwelling areas, and this may have been an important process in the evolution of the deep continental crust.

Published
1979
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29. Archaean high grade complexes and modern continental margins

Author

Windley, B. F. and Smith, J. V.

Abstract

Two kinds of geological terrain formed before 2,500 Myr ago. First, the greenstone belts, which are linear basins full of sediments and volcanics, possibly comparable with the marginal basins that occur behind modern island arcs. Second, and the subject of this paper, are high grade complexes containing rocks that have been deformed and recrystallised at high temperatures and pressures—granitic gneisses derived from granitic rocks are particularly common. Examples occur in north-western Scotland, Greenland, the Labrador coast, the Limpopo Belt in southern Africa, southern India, and probably the Aldan and Kola shields in the USSR. These complexes are so similar lithologically that broad generalisations about their tectonic evolution are justifiable. No major attempt has been made to see if they share any similarities with modern geological environments whose origins are better understood. We suggest that they are ancient analogues of the modern deep seated granitic batholiths located along the main arc axis of active plate margins of North and South America, for example in California and the Andes; accordingly, they are complementary to the greenstone belts in their back-arc setting.

Published
1976
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30. Dehydrated Lanthanum-exchanged Type Y Zeolite

Author

SMITH, J. V., BENNETT, J. M., and FLANIGEN, E. M.

Abstract

Lanthanum atoms occupy different sites in the crystal structure of dehydrated type Y zeolite as the temperature changes, probably because of the absence of residual molecules for bonding at 725° C compared with their presence at lower temperatures.

Published
1967
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31. Author Correction: 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., Niroula, Abhishek, 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 L. R., 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 C. Y., 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 J. F., 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., Wheeler, Marsha M., Sabino, Ester C., Blangero, John, Williams, L. Keoki, Levy, Bruce D., Sheu, Wayne Huey-Herng, Roden, Dan M., Boerwinkle, Eric, Manson, JoAnn E., Mathias, Rasika A., Desai, Pinkal, Taylor, Kent D., Johnson, Andrew D., Auer, Paul L., Kooperberg, Charles, Laurie, Cathy C., Blackwell, Thomas W., Smith, Albert V., Zhao, Hongyu, Lange, Ethan, Lange, Leslie, Rich, Stephen S., Rotter, Jerome I., Wilson, James G., Scheet, Paul, Kitzman, Jacob O., Lander, Eric S., Engreitz, Jesse M., Ebert, Benjamin L., Reiner, Alexander P., Jaiswal, Siddhartha, Abecasis, Gonçalo, Sankaran, Vijay G., Kathiresan, Sekar, and Natarajan, Pradeep

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03280-1.

Published
2021
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