ArticleNature genetics2020
Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.
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Article in Nature genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 181 papers, 8 of them syntheses that pooled it.
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181citing papers in PubMed, 8 pooled it
27.7field-weighted citation impact, top 1% of its field
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Who cites it
181 citing papers in PubMed, 8 syntheses or guidelines pooled it, 284 citations in OpenAlex.
- Scalable and accurate rare variant meta-analysis with Meta-SAIGE.Nature genetics · 2025Pooled it
- Computationally efficient meta-analysis of gene-based tests using summary statistics in large-scale genetic studies.Nature genetics · 2025Pooled it
- Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.Genome biology · 2025Pooled it
- Assessment of the functionality and usability of open-source rare variant analysis pipelines.Briefings in bioinformatics · 2025Pooled it
- Identification and validation of supervariants reveal novel loci associated with human white matter microstructure.Genome research · 2024Pooled it
- Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.Nature genetics · 2023Pooled it
- Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.Nature genetics · 2022Pooled it
- Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics.American journal of human genetics · 2021Pooled it
- SPLENDID incorporates continuous genetic ancestry in biobank-scale data to improve polygenic risk prediction across diverse populations.Nature methods · 2026Article
- Explaining the unexplained admixture mapping signals via rare variants: the HCHS/SOL.Human molecular genetics · 2026Article
- Glycemic and bodyweight effects ofScience advances · 2026Article
- Rare variant effect estimation and polygenic risk prediction.Nature genetics · 2026Article
- Robust Inference With Ghostknockoffs in Genome-Wide Association Studies With Sample Relatedness.Genetic epidemiology · 2026Article
- Correlations between causal effect sizes of proximal SNPs vary with functional annotations and implicate stabilizing selection.Nature genetics · 2026Article
- Identification of novel loci regulating circulating melatonin and its causal relationship with hypertension.Human genetics · 2026Article
- Atlas of glomerular disease-specific genetic effects on blood transcriptome.medRxiv : the preprint server for health sciences · 2026Article
- Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate.European journal of human genetics : EJHG · 2026Article
- When network biology meets human genetics.Cell genomics · 2026Article
- Hi-C informed kernel association test for integrating 3D genome structure into variant-set analysis.Briefings in bioinformatics · 2026Article
- Shared Genetics of Kidney Function Traits and Bladder Cancer: A Genome-Wide Cross-Trait Analysis.Cancer medicine · 2026Article
121 more citing papers are in PubMed but not listed here.
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Authors and funding
67 authors at 20 institutions in 7 countries.
Xihao Li *Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8151-0106
Zilin Li *Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0003-1521-8945
Hufeng ZhouDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Sheila M GaynorDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Yaowu LiuSchool of Statistics, Southwestern University of Finance and Economics, Chengdu, China.
Han ChenHuman 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.
Ryan SunDepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rounak DeyDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Donna K ArnettCollege of Public Health, University of Kentucky, Lexington, KY, USA.
Stella AslibekyanDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Christie M BallantyneDepartment of Medicine, Baylor College of Medicine, Houston, TX, USA.ORCID http://orcid.org/0000-0002-6432-1730
Lawrence F BielakDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.ORCID http://orcid.org/0000-0001-6250-5723
Eric BoerwinkleHuman 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.
Donald W BowdenDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jai G BroomeDivision of Medical Genetics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-7638-0749
Matthew P ConomosDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-9744-0851
Adolfo CorreaJackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.ORCID http://orcid.org/0000-0002-9501-600X
L Adrienne CupplesDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0273-7965
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
Barry I FreedmanDepartment of Internal Medicine, Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
George HindyDepartment of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
Marguerite R IrvinDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Sharon L R KardiaDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Sekar KathiresanVerve Therapeutics, Cambridge, MA, USA.
Alyna T KhanDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Charles L KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Cathy C LaurieDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
X Shirley LiuDepartment of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0003-4736-7339
Michael C MahaneyDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
Ani W ManichaikulCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Lisa W MartinDivision of Cardiology, George Washington School of Medicine and Health Sciences, Washington, DC, USA.ORCID http://orcid.org/0000-0003-4352-0914
Rasika A MathiasGeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Stephen T McGarveyDepartment of Epidemiology, International Health Institute, Department of Anthropology, Brown University, Providence, RI, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
May E MontasserDivision of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Jill E MooreProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0002-3023-0806
Alanna C MorrisonHuman 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.
Jeffrey R O'ConnellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.ORCID http://orcid.org/0000-0001-8883-2511
Akhil PampanaProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-4167-0540
Juan M PeraltaDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.ORCID http://orcid.org/0000-0002-8811-5579
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-9717-8459
Bruce M PsatyCardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
Susan RedlineDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-3071-7278
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-3872-7793
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-3575-5468
Hemant K TiwariDepartment of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Michael Y TsaiDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Ramachandran S VasanFramingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA, USA.ORCID http://orcid.org/0000-0001-7357-5970
Fei Fei WangDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Daniel E WeeksDepartment of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0001-9410-7228
Zhiping WengProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0002-3032-7966
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
Lisa R YanekGeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-7117-1075
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
TOPMed Lipids Working Group
Benjamin M NealeProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1513-6077
Shamil R SunyaevProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-5715-5677
Gonçalo R AbecasisRegeneron Pharmaceuticals, Tarrytown, NY, USA.ORCID http://orcid.org/0000-0003-1509-1825
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0001-7191-1723
Cristen J WillerDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-5645-4966
Gina M PelosoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Pradeep NatarajanDepartment of Medicine, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8402-7435
Xihong LinDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. xlin@hsph.harvard.edu.ORCID http://orcid.org/0000-0001-7067-7752
University of Maryland, Baltimore · USBroad Institute · USUniversity of Washington · USBrigham and Women's Hospital · USUniversity of Michigan · USJohns Hopkins University · USHarvard University · USNational Institutes of Health · USBoston University · USUniversity of North Carolina at Chapel Hill · USUniversity of Pittsburgh · USBaylor College of Medicine · USCleveland Clinic · USUniversity of Alabama at Birmingham · USUniversity of Minnesota · USUniversity of Mississippi · USBeth Israel Deaconess Medical Center · USUniversity of Vermont · USThe University of Texas Rio Grande Valley · USVanderbilt University · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DIANE BODURKA · 1985 to 2026
$290.8MUCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MInstitute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1MTranslational Research Support CoreP30ES000002 · NIEHS · HARVARD UNIVERSITY (SCH OF PUBLIC HLTH) · PI JAIME ELIZABETH HART · 1985 to 2026
$44.6MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MILES Frome WILKINSON · 2003 to 2026
$40.4MZINC AND CA EDTA THERAPY OF PLUMBISMM01RR000052 · NCRR · JOHNS HOPKINS UNIVERSITY · PI VINING, EILEEN PATRICE · 1985 to 2007
$37.3MUNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Hazel B Nichols · 2001 to 2026
$36.3MWORKER PROTECTION AGAINST AIRBORNE INFLUENZA - A PILOT STUDYM01RR007122 · NCRR · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI WASHBURN, LISA K · 1992 to 2010
$35.2MWake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3MFRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8MPEDIGREE ANALYSIS OF LIPOPROTEIN PHENOTYPESP01HL045522 · NHLBI · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI BLANGERO, JOHN · 1991 to 2012
$27.6MClinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2MNCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCI NIH HHS P01 CA134294NCI NIH HHS P30 CA016672NCI NIH HHS R13 CA124365NCI NIH HHS R35 CA197449NCI NIH HHS U19 CA203654NCI NIH HHS U24 CA237617NCRR NIH HHS M01 RR000052NCRR NIH HHS M01 RR007122NHGRI NIH HHS T32 HG000040NHGRI NIH HHS U01 HG009088NHGRI NIH HHS U24 HG009446NHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS F32 HL085989NHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201600001CNHLBI NIH HHS HHSN268201600002CNHLBI NIH HHS HHSN268201600003CNHLBI NIH HHS HHSN268201600004CNHLBI NIH HHS HHSN268201600018CNHLBI NIH HHS HHSN268201700001CNHLBI NIH HHS HHSN268201700001INHLBI NIH HHS HHSN268201700002CNHLBI NIH HHS HHSN268201700002INHLBI NIH HHS HHSN268201700003CNHLBI NIH HHS HHSN268201700003INHLBI NIH HHS HHSN268201700004CNHLBI NIH HHS HHSN268201700004INHLBI NIH HHS HHSN268201700005CNHLBI NIH HHS HHSN268201700005INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS HHSN268201800010INHLBI NIH HHS HHSN268201800011CNHLBI NIH HHS HHSN268201800011INHLBI NIH HHS HHSN268201800012CNHLBI NIH HHS HHSN268201800012INHLBI NIH HHS HHSN268201800014CNHLBI NIH HHS HHSN268201800014INHLBI NIH HHS HHSN268201800015INHLBI NIH HHS K01 HL125751NHLBI NIH HHS K08 HL141601NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS P01 HL045522NHLBI NIH HHS P50 HL118006NHLBI NIH HHS R01 HL049762NHLBI NIH HHS R01 HL055673NHLBI NIH HHS R01 HL059684NHLBI NIH HHS R01 HL067348NHLBI NIH HHS R01 HL071025NHLBI NIH HHS R01 HL087698NHLBI NIH HHS R01 HL092301NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL093093NHLBI NIH HHS R01 HL104135NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL112064NHLBI NIH HHS R01 HL113323NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL119443NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL133040NHLBI NIH HHS R01 HL134320NHLBI NIH HHS R01 HL142711NHLBI NIH HHS R03 HL141439NHLBI NIH HHS R35 HL135818NHLBI NIH HHS R35 HL135824NHLBI NIH HHS U01 HL054472NHLBI NIH HHS U01 HL054473NHLBI NIH HHS U01 HL054495NHLBI NIH HHS U01 HL054509NHLBI NIH HHS U01 HL072518NHLBI NIH HHS U01 HL072524NHLBI NIH HHS U01 HL130114NHLBI NIH HHS U01 HL137162NHLBI NIH HHS U01 HL137181NIAMS NIH HHS R01 AR048797NIA NIH HHS K01 AG059898NIA NIH HHS R01 AG058921NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK071891NIDDK NIH HHS U01 DK085524NIEHS NIH HHS P30 ES000002NIEHS NIH HHS P30 ES010126NIEHS NIH HHS P42 ES016454NIGMS NIH HHS R35 GM127131NIGMS NIH HHS T32 GM074897NIGMS NIH HHS T32 GM135117NIMHD NIH HHS HHSN268201800013INIMH NIH HHS R01 MH078111NIMH NIH HHS R01 MH078143NIMH NIH HHS R01 MH083824NIMH NIH HHS R01 MH101244NINDS NIH HHS R01 NS058700
Abstract
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.
Indexed as
Cholesterol, LDLComputer SimulationGenetic Predisposition to DiseaseGenetic VariationGenomeGenome-Wide Association StudyHumansModels, GeneticMolecular Sequence AnnotationPhenotypeWhole Genome SequencingCholesterol, LDL
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