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Browsing by Author "de Andrade, Mariza"
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Item An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs(Elsevier, 2021) Cordell, Heather J.; Fryett, James J.; Ueno, Kazuko; Darlay, Rebecca; Aiba, Yoshihiro; Hitomi, Yuki; Kawashima, Minae; Nishida, Nao; Khor, Seik-Soon; Gervais, Olivier; Kawai, Yosuke; Nagasaki, Masao; Tokunaga, Katsushi; Tang, Ruqi; Shi, Yongyong; Li, Zhiqiang; Juran, Brian D.; Atkinson, Elizabeth J.; Gerussi, Alessio; Carbone, Marco; Asselta, Rosanna; Cheung, Angela; de Andrade, Mariza; Baras, Aris; Horowitz, Julie; Ferreira, Manuel A. R.; Sun, Dylan; Jones, David E.; Flack, Steven; Spicer, Ann; Mulcahy, Victoria L.; Byan, Jinyoung; Han, Younghun; Sandford, Richard N.; Lazaridis, Konstantinos N.; Amos, Christopher I.; Hirschfield, Gideon M.; Seldin, Michael F.; Invernizzi, Pietro; Siminovitch, Katherine A.; Ma, Xiong; Nakamura, Minoru; Mells, George F.; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium; Medicine, School of MedicineBackgrounds & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.Item Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program(Springer Nature, 2021) Taliun, Daniel; Harris, Daniel N.; Kessler, Michael D.; Carlson, Jedidiah; Szpiech, Zachary A.; Torres, Raul; Gagliano Taliun, Sarah A.; 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 L. R.; 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; Loos, Ruth J. F.; Garman, Lori; Gerszten, Robert; Lubitz, Steven A.; Lunetta, Kathryn L.; Mak, Angel C. Y.; Manichaikul, Ani; Manning, Alisa K.; Mathias, Rasika A.; McManus, David D.; McGarvey, Stephen T.; Meigs, James B.; Meyers, Deborah A.; Mikulla, Julie L.; Minear, Mollie A.; Mitchell, Braxton D.; Mohanty, Sanghamitra; Montasser, May E.; Montgomery, Courtney; Morrison, Alanna C.; Murabito, Joanne M.; Natale, Andrea; Natarajan, Pradeep; Nelson, Sarah C.; North, Kari E.; O'Connell, Jeffrey R.; Palmer, Nicholette D.; Pankratz, Nathan; Peloso, Gina M.; Peyser, Patricia A.; Pleiness, Jacob; Post, Wendy S.; Psaty, Bruce M.; Rao, D. C.; Redline, Susan; Reiner, Alexander P.; Roden, Dan; Rotter, Jerome I.; Ruczinski, Ingo; Sarnowski, Chloé; Schoenherr, Sebastian; Schwartz, David A.; Seo, Jeong-Sun; Seshadri, Sudha; Sheehan, Vivien A.; Sheu, Wayne H.; Shoemaker, M. Benjamin; Smith, Nicholas L.; Smith, Jennifer A.; Sotoodehnia, Nona; Stilp, Adrienne M.; Tang, Weihong; Taylor, Kent D.; Telen, Marilyn; Thornton, Timothy A.; Tracy, Russell P.; Van Den Berg, David J.; Vasan, Ramachandran S.; Viaud-Martinez, Karine A.; Vrieze, Scott; Weeks, Daniel E.; Weir, Bruce S.; Weiss, Scott T.; Weng, Lu-Chen; Willer, Cristen J.; Zhang, Yingze; Zhao, Xutong; Arnett, Donna K.; Ashley-Koch, Allison E.; Barnes, Kathleen C.; Boerwinkle, Eric; Gabriel, Stacey; Gibbs, Richard; Rice, Kenneth M.; Rich, Stephen S.; Silverman, Edwin K.; Qasba, Pankaj; Gan, Weiniu; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Papanicolaou, George J.; Nickerson, Deborah A.; Browning, Sharon R.; Zody, Michael C.; Zöllner, Sebastian; Wilson, James G.; Cupples, L. Adrienne; Laurie, Cathy C.; Jaquish, Cashell E.; Hernandez, Ryan D.; O'Connor, Timothy D.; Abecasis, Gonçalo R.; Epidemiology, Richard M. Fairbanks School of Public HealthThe 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%.