Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Autor: Li X; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Li Z; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Zhou H; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Gaynor SM; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Liu Y; School of Statistics, Southwestern University of Finance and Economics, Chengdu, China., Chen H; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA., Sun R; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dey R; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Arnett DK; College of Public Health, University of Kentucky, Lexington, KY, USA., Aslibekyan S; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA., Ballantyne CM; Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Bielak LF; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Blangero J; Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA., Boerwinkle E; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Bowden DW; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Broome JG; Division of Medical Genetics, University of Washington, Seattle, WA, USA., Conomos MP; Department of Biostatistics, University of Washington, Seattle, WA, USA., Correa A; Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA., Cupples LA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.; Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA, USA., Curran JE; Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA., Freedman BI; Department of Internal Medicine, Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA., Guo X; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA., Hindy G; Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar., Irvin MR; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA., Kardia SLR; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Kathiresan S; Verve Therapeutics, Cambridge, MA, USA.; Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Khan AT; Department of Biostatistics, University of Washington, Seattle, WA, USA., Kooperberg CL; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Laurie CC; Department of Biostatistics, University of Washington, Seattle, WA, USA., Liu XS; Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Statistics, Harvard University, Cambridge, MA, USA., Mahaney MC; Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA., Manichaikul AW; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Martin LW; Division of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC, USA., Mathias RA; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., McGarvey ST; Department of Epidemiology, International Health Institute, Department of Anthropology, Brown University, Providence, RI, USA., Mitchell BD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, MD, USA., Montasser ME; Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Moore JE; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA., Morrison AC; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA., O'Connell JR; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Palmer ND; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Pampana A; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Peralta JM; Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA., Peyser PA; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA., Redline S; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Rice KM; Department of Biostatistics, University of Washington, Seattle, WA, USA., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Smith JA; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.; Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA., Tiwari HK; Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA., Tsai MY; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Vasan RS; Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA, USA.; Department of Medicine, Boston University School of Medicine, Boston, MA, USA., Wang FF; Department of Biostatistics, University of Washington, Seattle, WA, USA., Weeks DE; Department of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA., Weng Z; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA., Wilson JG; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.; Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA., Yanek LR; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Neale BM; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Sunyaev SR; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Abecasis GR; Regeneron Pharmaceuticals, Tarrytown, NY, USA.; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA., Willer CJ; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Natarajan P; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Lin X; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. xlin@hsph.harvard.edu.; Department of Statistics, Harvard University, Cambridge, MA, USA. xlin@hsph.harvard.edu.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. xlin@hsph.harvard.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2020 Sep; Vol. 52 (9), pp. 969-983. Date of Electronic Publication: 2020 Aug 24.
DOI: 10.1038/s41588-020-0676-4
Abstrakt: Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
Databáze: MEDLINE