Browsing by Author "Fuchsberger, Christian"

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    A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
    (Springer Nature, 2021) Luo, Yang; Kanai, Masahiro; Choi, Wanson; Li, Xinyi; Sakaue, Saori; Yamamoto, Kenichi; Ogawa, Kotaro; Gutierrez-Arcelus, Maria; Gregersen, Peter K.; Stuart, Philip E.; Elder, James T.; Forer, Lukas; Schönherr, Sebastian; Fuchsberger, Christian; Smith, Albert V.; Fellay, Jacques; Carrington, Mary; Haas, David W.; Guo, Xiuqing; Palmer, Nicholette D.; Chen, Yii-Der Ida; Rotter, Jerome I.; Taylor, Kent D.; Rich, Stephen S.; Correa, Adolfo; Wilson, James G.; Kathiresan, Sekar; Cho, Michael H.; Metspalu, Andres; Esko, Tonu; Okada, Yukinori; Han, Buhm; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; McLaren, Paul J.; Raychaudhuri, Soumya; Obstetrics and Gynecology, School of Medicine
    Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.
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    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 Health
    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%.