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cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions

Nature Methods (2025)Cite this article

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Abstract

Understanding how rare genetic variants influence complex traits remains a major challenge, particularly when these variants lie in noncoding regions of the genome. The effects of variants within candidate cis-regulatory elements (cCREs) often depend on the cell type, making interpretation difficult. Here we introduce cellSTAAR, which integrates whole-genome sequencing data with single-cell assay for transposase-accessible chromatin using sequencing data to capture variability in chromatin accessibility across cell types via the construction of cell-type-specific functional annotations and regulatory elements. To reflect the uncertainty in cCRE–gene linking, cellSTAAR uses a comprehensive strategy to link cCREs to their target genes. We applied cellSTAAR to data from the Trans-Omics for Precision Medicine consortium (n ≈ 60,000) and replicated our findings using the UK Biobank (n ≈ 190,000). Across four lipid traits, cellSTAAR improved the detection of biologically meaningful associations and enhanced biological interpretability. These results demonstrate the potential of cell-type-aware approaches to boost discovery in rare variant whole-genome sequencing association studies.

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Fig. 1: cellSTAAR overview.
Fig. 2: Variability in association across linking approaches and cell types (including three bulk comparisons from liver).
Fig. 3: Percentage enrichment by cell type.

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Data availability

This paper used the TOPMed Freeze 8 WGS data and lipid phenotype data. Genotype and phenotype data are both available in the database of Genotypes and Phenotypes. The TOPMed WGS data were from the following 20 study phases (accession numbers provided in parentheses): Old Order Amish (phs000956.v1.p1), Atherosclerosis Risk in Communities Study (phs001211), Mt Sinai BioMe Biobank (phs001644), Coronary Artery Risk Development in Young Adults (phs001612), Cleveland Family Study (phs000954), Cardiovascular Health Study (phs001368), Diabetes Heart Study (phs001412), FHS (phs000974), Genetic Study of Atherosclerosis Risk (phs001218), Genetic Epidemiology Network of Arteriopathy (phs001345), Genetic Epidemiology Network of Salt Sensitivity (phs001217), Genetics of Lipid Lowering Drugs and Diet Network (phs001359), Hispanic Community Health Study - Study of Latinos (phs001395), Hypertension Genetic Epidemiology Network and Genetic Epidemiology Network of Arteriopathy (phs001293), JHS (phs000964), Multi-Ethnic Study of Atherosclerosis (phs001416), San Antonio Family Heart Study (phs001215), Genome-wide Association Study of Adiposity in Samoans (phs000972), Taiwan Study of Hypertension using Rare Variants (phs001387) and Women’s Health Initiative (phs001237). UKB WGS data are available from the UKB Research Analysis Platform, and the UKB analyses were conducted using the UKB resource under application 52008. The single-cell ATAC-seq used from CATlas is publicly available at http://catlas.org/humanenhancer/.

Code availability

cellSTAAR is freely available as an R package at https://github.com/edvanburen/cellSTAAR/, vcf2agds68 was used to preprocess the UKB WGS data and is freely available as a collection of applets in the UKB RAP at https://github.com/drarwood/vcf2agds_overview. GENESIS18, available at https://bioconductor.org/packages/release/bioc/html/GENESIS.html and FastSparseGRM69, available at https://github.com/rounakdey/FastSparseGRM are freely available as R packages, and were used to calculate the ancestral principal components and sparse GRMs for TOPMed and UKB data, respectively. Code used in the analysis has been archived on Zenodo at https://doi.org/10.5281/zenodo.16113567 (ref. 70).

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Acknowledgements

This work was supported by grants R35-CA197449, U19-CA203654, U01-HG012064 and U01-HG009088 (to X. Lin); R01-HL142711 and R01-HL127564 (to P.N. and G.M.P.); 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR001881, DK063491, R01-HL071051, R01-HL071205, R01-HL071250, R01-HL071251, R01-HL071258, R01-HL071259 and UL1-RR033176 (to J.R. and Y.C.); 1R35-HL135818, R01-HL113338 and HL046389 (to S.R.); HL105756 (to B.P.); HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C (to C.K.); R01-MD012765 and R01-DK117445 (to N.F.); R01-HL153805 and R03-HL154284 (to B.E.C.); HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I and HHSN268201700004I (to E.B.); U01- HL072524, R01-HL104135-04S1, U01-HL054472, U01-HL054473, U01-HL054495, U01-HL054509 and R01-HL055673-18S1 (to D.K.A.); U01-HL72518, HL087698, HL49762, HL59684, HL58625, HL071025, HL112064, NR0224103 and M01-RR000052 (to the Johns Hopkins General Clinical Research Center); R01-HL133040 (to R.L.M.); R01-HL093093 (to S. T. McGarvey); R01-HL173044 and R01-AG085581 (to X. Li); and NHLBI TOPMed Fellowship 75N92021F00229 (to X. Li and M.S.S.). The Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and 75N92021D00006; and NHLBI grants R01-HL172803, U01HL080295, R01-HL087652, R01-HL105756, R01-HL103612, R01-HL120393 and U01HL130114, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI (https://chs-nhlbi.org/). This work was also supported by R01-HL92301, R01-HL67348, R01-NS058700, R01-AR48797, R01-DK071891, R01-AG058921, the General Clinical Research Center of the Wake Forest University School of Medicine (M01-RR07122, F32 HL085989), the American Diabetes Association and a pilot grant from the Claude Pepper Older Americans Independence Center of Wake Forest University Health Sciences (P60 AG10484). The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (75N92023D00002, 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006) and Kaiser Foundation Research Institute (75N92023D00003). The FHS acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I and 75N92019D00031 from the NHLBI and grant supplement R01-HL092577-06S1 for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. R.S.V. is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. The JHS is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. We also thank the staff and participants of the JHS. Support for GENOA was provided by the NHLBI (U01HL054457, U01HL054464, U01HL054481, R01-HL119443 and R01-HL087660) of the National Institutes of Health. Collection of the San Antonio Family Study data was supported in part by National Institutes of Health grants P01 HL045522, MH078143, MH078111 and MH083824; and WGS of SAFS participants was supported by U01 DK085524 and R01-HL113323. The Diabetes Heart Study was supported by R01-HL92301, R01-HL67348, R01-NS058700, R01-AR48797, R01-DK071891, R01-AG058921, the General Clinical Research Center of the Wake Forest University School of Medicine (M01-RR07122, F32 HL085989), the American Diabetes Association and a pilot grant from the Claude Pepper Older Americans Independence Center of Wake Forest University Health Sciences (P60 AG10484). Molecular data for the TOPMed program was supported by the NHLBI. Genome sequencing for ‘NHLBI TOPMed: Coronary Artery Risk Development in Young Adults (CARDIA)’ (phs001612.v1.p1) was performed at the Baylor Sequencing Center (HHSN268201600033I). Core support, including centralized genomic read mapping and genotype calling, variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control and general program coordination, was provided by the TOPMed Data Coordinating Center (R01-HL120393, U01HL-120393; contract HHSN268201800001I). Support for the Multi-Ethnic Study of Atherosclerosis was provided by contracts 75N92025D00022, 75N92025D00026, 75N92025D00024, 75N92025D00027, 75N92025D00025 and 75N92025D00028. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The full study-specific acknowledgements are detailed in the Supplementary Note.

Author information

Authors and Affiliations

  1. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Cambridge, MA, USA

    Eric Van Buren, Hufeng Zhou & Xihong Lin

  2. Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA

    Yi Zhang

  3. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA

    Yi Zhang

  4. Duke Cancer Institute, Durham, NC, USA

    Yi Zhang

  5. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Xihao Li

  6. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Xihao Li, Nora Franceschini & Laura M. Raffield

  7. Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    Margaret Sunitha Selvaraj & Pradeep Natarajan

  8. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Margaret Sunitha Selvaraj, Brian E. Cade & Pradeep Natarajan

  9. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Margaret Sunitha Selvaraj & Pradeep Natarajan

  10. School of Mathematics and Statistics, Northeast Normal University, Changchun, China

    Zilin Li

  11. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Nicholette D. Palmer & Donald W. Bowden

  12. Provost Office, University of South Carolina, Columbia, SC, USA

    Donna K. Arnett

  13. Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA

    John Blangero, Joanne Curran & Ravindranath Duggirala

  14. 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

    Eric Boerwinkle & Myriam Fornage

  15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Eric Boerwinkle

  16. Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA

    Brian E. Cade & Susan Redline

  17. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    Brian E. Cade & Susan Redline

  18. Department of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    Jenna C. Carlson

  19. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    April P. Carson

  20. 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

    Yii-Der Ida Chen, Xiuqing Guo, Kent D. Taylor & Jerome I. Rotter

  21. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Myriam Fornage

  22. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Nora Franceschini, Misa Graff & Kari North

  23. Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA

    Charles Gu

  24. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

    Jiang He & Changwei Li

  25. Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Nancy Heard-Cosa

  26. Framingham Heart Study, Framingham, MA, USA

    Nancy Heard-Cosa, Dan Levy & Ramachandran S. Vasan

  27. Department of Preventive Medicine, Northwestern University, Chicago, IL, USA

    Lifang Hou

  28. Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Yi-Jen Hung

  29. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rita R. Kalyani, Brian G. Kral & Lisa Yanek

  30. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Sharon L. R. Kardia, Patricia A. Peyser, Jennifer A. Smith & Wei Zhao

  31. Institute for Genomic Health, Icahn School of Medicine, New York, NY, USA

    Eimear Kenny

  32. Center for Translational Genomics, Icahn School of Medicine, New York, NY, USA

    Eimear Kenny

  33. Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, New York, NY, USA

    Eimear Kenny

  34. Departments of Genetics and Genomic Sciences, Icahn School of Medicine, New York, NY, USA

    Eimear Kenny

  35. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Charles Kooperberg & Alex P. Reiner

  36. Department of Biomedical Informatics, University of Colorado, School of Medicine, Aurora, CO, USA

    Leslie Lange

  37. Tulane University Translational Science Institute, New Orleans, LA, USA

    Changwei Li

  38. Department of Epidemiology, Brown University, Providence, RI, USA

    Simin Liu

  39. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Donald Lloyd-Jones

  40. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ruth J. F. Loos

  41. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Ruth J. F. Loos

  42. Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA

    Ani W. Manichaikul, Josyf C. Mychaleckyj & Stephen S. Rich

  43. George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Lisa Warsinger Martin

  44. Laboratory of Allergic Diseases, Genomics and Precision Health Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

    Rasika Mathias

  45. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Ryan L. Minster & Daniel E. Weeks

  46. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Braxton D. Mitchell, Jeff O’Connell & James A. Perry

  47. International Health Institute, Brown University, Providence, RI, USA

    Take Naseri

  48. Naseri & Associates Public Health Consultancy Firm and Public Health Clinic, Apia, Samoa

    Take Naseri

  49. Border Health Research Center, UTHealth Houston School of Public Health-Brownsville Campus, Brownsville, TX, USA

    Kari North

  50. Department of Epidemiology, UTHealth Houston School of Public Health-Brownsville Campus, Brownsville, TX, USA

    Kari North

  51. Department of Internal Medicine, McGovern Medical School, Houston, TX, USA

    Kari North

  52. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    Bruce M. Psaty

  53. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Bruce M. Psaty & Alex P. Reiner

  54. Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA

    Bruce M. Psaty

  55. Department of Quantitative and Qualitative Health Sciences, UT Health San Antonio School of Public Health, San Antonio, TX, USA

    Ramachandran S. Vasan

  56. Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA

    Jennifer A. Smith & Wei Zhao

  57. Brigham and Women’s Hospital, Boston, MA, USA

    Brian Spitzer

  58. Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA

    Hua Tang, Peter Anderson, Jai Broome, Colleen Davis, Leslie Emery, Chris Frazar, Stephanie M. Fullerton, Stephanie Gogarten, Deepti Jain, Craig Johnson, Alyna Khan, Cathy Laurie, Cecelia Laurie, David Levine, Ken Rice, Josh Smith, Adrienne M. Stilp, Adam Szpiro, Timothy A. Thornton, David Tirschwell, Fei Fei Wang, Bruce Weir & Quenna Wong

  59. Department of Pathology and Laboratory Medicine, Larnar College of Medicine, University of Vermont, Burlington, VT, USA

    Russell Tracy

  60. Oceania University of Medicine, School of Medicine, National University of Samoa, Apia, Samoa

    Satupa’itea Viali

  61. Department of Chronic Disease Epidemiology, Yale University, New Haven, CT, USA

    Satupa’itea Viali & Nicola L. Hawley

  62. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Gina M. Peloso

  63. Department of Statistics, Harvard University, Cambridge, MA, USA

    Xihong Lin

  64. New York Genome Center, New York, NY, USA

    Namiko Abe, Karen Bunting, Bo-Juen Chen, Heather Geiger, Soren Germer, Melissa Marton, Catherine Reeves, Nicolas Robine, Alexi Runnels, Tanja Smith, Lara Winterkorn & Michael Zody

  65. University of Michigan, Ann Arbor, MI, USA

    Gonçalo Abecasis, Larry Bielak, Thomas Blackwell, Matthew Flickinger, Colin Gross, Jonathon LeFaive, Jacob Pleiness, Albert Vernon Smith, Daniel Taliun, Peter VandeHaar, Ketian Yu & Sebastian Zoellner

  66. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Francois Aguet, Kristin Ardlie, Mark Chaffin, Seung Hoan Choi, Stacey Gabriel, Namrata Gupta, Alisa Manning, Carolina Roselli & Seyedeh Maryam Zekavat

  67. Cedars Sinai, Boston, MA, USA

    Christine Albert

  68. Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

    Laura Almasy

  69. Emory University, Atlanta, GA, USA

    Alvaro Alonso, Rich Johnston, Lawrence S. Phillips & Zhaohui Qin

  70. University of Maryland, Baltimore, MD, USA

    Seth Ament, Amber Beitelshees, Christy Chang, Coleen Damcott, Scott Devine, Mao Fu, Da-Wei Gong, Yue Guan, Elliott Hong, Michael Kessler, Joshua Lewis, Patrick McArdle, May E. Montasser, Tim O’Connor, Toni Pollin, Robert Reed, Kathleen Ryan, Amol Shetty, Elizabeth Streeten, Simeon Taylor & Huichun Xu

  71. University of Mississippi, Jackson, MS, USA

    Pramod Anugu, Lynette Ekunwe, Yan Gao, Hao Mei & Nancy Min

  72. National Institutes of Health, Bethesda, MD, USA

    Deborah Applebaum-Bowden

  73. Johns Hopkins University, Baltimore, MD, USA

    Dan Arking, Dimitrios Avramopoulos, Emily Barron-Casella, Terri Beaty, Lewis Becker, James Casella, Kimberly Jones, Barry Make, Rakhi Naik, Ingo Ruczinski, Steven Salzberg, Margaret Taub, Dhananjay Vaidya & Lisa Yanek

  74. Duke University, Durham, NC, USA

    Allison Ashley-Koch & Marilyn Telen

  75. University of Alabama, Birmingham, AL, USA

    Stella Aslibekyan, Bertha Hidalgo & Marguerite Ryan Irvin

  76. Stanford University, Stanford, CA, USA

    Tim Assimes, Chris Gignoux & Marco Perez

  77. Medical College of Wisconsin, Milwaukee, WI, USA

    Paul Auer

  78. Providence Health Care, Medicine, Vancouver, CA, USA

    Najib Ayas

  79. Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA

    Adithya Balasubramanian, Huyen Dinh, Harsha Doddapaneni, Jesse Farek, Richard Gibbs, Yi Han, Jianhong Hu, Ziad Khan, Sandra Lee, Vipin Menon, Ginger Metcalf, Zeineen Momin, Donna Muzny, Caitlin Nessner, Osuji Nkechinyere, Geoffrey Okwuonu, Mahitha Rajendran, Sejal Salvi, Jireh Santibanez & Jennifer Watt

  80. Cleveland Clinic, Cleveland, OH, USA

    John Barnard & Mina Chung

  81. Tempus, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Kathleen Barnes

  82. Columbia University, New York, NY, USA

    R. Graham Barr

  83. The Emmes Corporation, LTRC, Rockville, MD, USA

    Lucas Barwick

  84. Cleveland Clinic, Quantitative Health Sciences, Cleveland, OH, USA

    Gerald Beck

  85. Johns Hopkins University, Medicine, Baltimore, MD, USA

    Diane Becker

  86. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Rebecca Beer, Weiniu Gan, Andrew Johnson, James Luo, Julie Mikulla, George Papanicolaou & Pankaj Qasba

  87. Boston University, Massachusetts General Hospital, Boston University School of Medicine, Boston, MA, USA

    Emelia Benjamin

  88. Epidemiology Department, University of Florida, Gainesville, FL, USA

    Takis Benos

  89. Fundação de Hematologia e Hemoterapia de PernambucoHemope, Recife, Brazil

    Marcos Bezerra

  90. Department of Medicine, University of Washington, Cardiovascular Health Research Unit, Seattle, WA, USA

    Joshua Bis, Jennifer Brody & Nona Sotoodehnia

  91. Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA

    Nathan Blue

  92. National Jewish Health, National Jewish Health, Denver, CO, USA

    Russell Bowler

  93. Pediatrics Department, Medical College of Wisconsin, Milwaukee, WI, USA

    Ulrich Broeckel

  94. Pediatrics Department, University of Texas Health at Houston, Houston, TX, USA

    Deborah Brown

  95. University of California, San Francisco, San Francisco, CA, USA

    Esteban Burchard & Ryan Hernandez

  96. Biomedical Data Science, Stanford University, Stanford, CA, USA

    Carlos Bustamante

  97. Biostatistics Department, University of Washington, Seattle, WA, USA

    Erin Buth, Matthew Conomos, Ben Heavner, Susanne May, Caitlin McHugh, Sarah C. Nelson & Kayleen Williams

  98. University of Colorado at Denver, Denver, CO, USA

    Jonathan Cardwell, Sameer Chavan, Michelle Daya, Shanshan Gao, Daniel Grine, John Hokanson, Ethan Lange, Susan Mathai, Bonnie Neltner, Meher Preethi Boorgula, Pamela Russell, David Schwartz, Aniket Shetty, Tarik Walker, Avram Walts & Ivana Yang

  99. Brigham & Women’s Hospital, Boston, MA, USA

    Vincent Carey, Juan P. Casas Romero, Michael Cho, Dawn DeMeo, Auyon Ghosh, Meryl LeBoff, Jiwon Lee, JoAnn Manson, Dandi Qiao, Edwin Silverman, Jody Sylvia & Carla Wilson

  100. University of Montreal, Montreal, Québec, Canada

    Julie Carrier

  101. Washington State University, Pullman, WA, USA

    Cara Carty

  102. University of California, Los Angeles, Los Angeles, CA, USA

    Richard Casaburi, Carolyn Crandall & Karol Watson

  103. Division of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Peter Castaldi & Matt Moll

  104. National Taiwan University, Taipei, Taiwan

    Yi-Cheng Chang

  105. Division of Preventive Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Daniel Chasman

  106. University of Virginia, Charlottesville, VA, USA

    Wei-Min Chen, Charles Farber & Aakrosh Ratan

  107. National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan

    Lee-Ming Chuang

  108. National Health Research Institute Taiwan, Zhunan, Taiwan

    Ren-Hua Chung

  109. Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Clary Clish

  110. Immunity and Immunology, Cleveland Clinic, Cleveland, OH, USA

    Suzy Comhair

  111. University of Vermont, Burlington, VT, USA

    Elaine Cornell

  112. Population Health Science, University of Mississippi, Jackson, MI, USA

    Adolfo Correa

  113. National Jewish Health, Denver, CO, USA

    James Crapo & Snow Xueyan Zhao

  114. Biostatistics, Boston University, Boston, MA, USA

    L. Adrienne Cupples

  115. Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Jeffrey Curtis & Cristen Willer

  116. Vitalant Research Institute, San Francisco, CA, USA

    Brian Custer

  117. University of Illinois at Chicago, Chicago, IL, USA

    Dawood Darbar

  118. University of Chicago, Chicago, IL, USA

    Sean David

  119. Vanderbilt University, Nashville, TN, USA

    Michael DeBaun

  120. University of Cincinnati, Cincinnati, OH, USA

    Ranjan Deka

  121. University of North Carolina, Chapel Hill, NC, USA

    Qing Duan & Yun Li

  122. Baylor College of Medicine Human Genome Sequencing Center, BCM, Houston, TX, USA

    Shannon Dugan-Perez

  123. Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA

    Jon Peter Durda

  124. Genetics, Washington University in St. Louis, St. Louis, MO, USA

    Susan K. Dutcher

  125. Brown University, Providence, RI, USA

    Charles Eaton

  126. Channing Division of Network Medicine, Harvard University, Cambridge, MA, USA

    Adel El Boueiz

  127. Massachusetts General Hospital, Boston, MA, USA

    Patrick Ellinor, Steven Lubitz & Lu-Chen Weng

  128. Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA

    Serpil Erzurum

  129. National Jewish Health, Center for Genes, Environment and Health, Denver, CO, USA

    Tasha Fingerlin

  130. Washington University in St. Louis, St. Louis, MO, USA

    Lucinda Fulton, D. C. Rao, Karen Schwander & Yun Ju Sung

  131. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Margery Gass, Jeff Haessler & Ulrike Peters

  132. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bruce Gelb, Girish Nadkarni & Michael Preuss

  133. University of Pittsburgh, Pittsburgh, PA, USA

    Mark Geraci

  134. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Robert Gerszten & Tamar Sofer

  135. Boston Children’s Hospital, Harvard Medical School, Department of Psychiatry, Boston, MA, USA

    David Glahn

  136. University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA

    Harald Goring

  137. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Sharon Graw, Luisa Mestroni & Matthew Taylor

  138. Obstetrics and Gynecology, Mass General Brigham, Boston, MA, USA

    Kathryn J. Gray

  139. Cardiology, University of Mississippi, Jackson, MS, USA

    Michael Hall

  140. Medicine, University of Calgary, Calgary, CA, USA

    Patrick Hanly

  141. Genetics, University of Maryland, Philadelphia, PA, USA

    Daniel Harris

  142. Epidemiology, University of Washington, Seattle, WA, USA

    Susan Heckbert

  143. Wake Forest Baptist Health, Winston-Salem, NC, USA

    David Herrington

  144. Brigham & Women’s Hospital, Channing Division of Network Medicine, Boston, MA, USA

    Craig Hersh

  145. University of Texas Health at Houston, Houston, TX, USA

    James Hixson

  146. Regeneron Genetics Center, Boston, MA, USA

    Brian Hobbs

  147. University of Iowa, Iowa City, IA, USA

    Karin Hoth & Robert Wallace

  148. National Health Research Institute Taiwan, Institute of Population Health Sciences, NHRI, Zhunan, Taiwan

    Chao Agnes Hsiung

  149. Tri-Service General Hospital National Defense Medical Center, Taichung City, Taiwan

    Yi-Jen Hung

  150. Blood Works Northwest, Seattle, WA, USA

    Haley Huston

  151. Taichung Veterans General Hospital Taiwan, Taichung City, Taiwan

    Chii Min Hwu, Wen-Jane Lee & Wayne Hui-Heng Sheu

  152. Oklahoma State University Medical Center, Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Tulsa, OK, USA

    Rebecca Jackson

  153. National Heart, Lung, and Blood Institute, National Institutes of Health, NHLBI, Bethesda, MD, USA

    Cashell Jaquish

  154. Medicine, University of Washington, Seattle, WA, USA

    Jill Johnsen

  155. Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Hyun Min Kang & Joshua Weinstock

  156. Albert Einstein College of Medicine, New York, NY, USA

    Robert Kaplan & Sylvia Smoller

  157. Harvard University, Cambridge, MA, USA

    Wonji Kim & Sean McFarland

  158. McGill University, Montreal, Québec, Canada

    John Kimoff

  159. Department of Epidemiology, University of Colorado at Denver, Aurora, CO, USA

    Greg Kinney

  160. Department of Medicine, Blood Works Northwest, Seattle, WA, USA

    Barbara Konkle

  161. Loyola University, Public Health Sciences, Maywood, IL, USA

    Holly Kramer

  162. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    Christoph Lange

  163. Lundquist Institute, Torrance, CA, USA

    Xiaohui Li & Henry Lin

  164. University of Massachusetts, Chan Medical School, Worcester, MA, USA

    Honghuang Lin

  165. Department of Cardiology, Duke University, Durham, NC, USA

    Yongmei Liu

  166. Cardiovascular Institute, Stanford University, Stanford, CA, USA

    Yu Liu

  167. Boston University, Boston, MA, USA

    Kathryn Lunetta

  168. Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA

    Ulysses Magalang

  169. University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA

    Michael Mahaney

  170. University of Alabama at Birmingham, Birmingham, AL, USA

    Merry-Lynn McDonald

  171. Epidemiology, Brown University, Providence, RI, USA

    Stephen McGarvey

  172. Genome Sciences, University of Washington, Seattle, WA, USA

    Daniel McGoldrick

  173. RTI International, Research Triangle Park, NC, USA

    Becky McNeil

  174. Medicine, Massachusetts General Hospital, Boston, MA, USA

    James Meigs

  175. University of Arizona, Tucson, AZ, USA

    Deborah A. Meyers

  176. Center For Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA

    Emmanuel Mignot

  177. National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Mollie Minear

  178. Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Courtney Montgomery

  179. Howard University, Washington, DC, USA

    Sergei Nekhai

  180. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Deborah Nickerson

  181. University at Buffalo, Buffalo, NY, USA

    Heather Ochs-Balcom

  182. Division of Sleep Medicine/Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Allan Pack

  183. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA

    David T. Paik & Joseph Wu

  184. Biochemistry, Wake Forest Baptist Health, Winston-Salem, NC, USA

    Nicholette Palmer

  185. University of Minnesota, Minneapolis, MN, USA

    James Pankow, Michael Tsai & Scott Vrieze

  186. RTI International, Biostatistics and Epidemiology Division, Research Triangle Park, NC, USA

    Cora Parker

  187. University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA

    Juan Manuel Peralta

  188. Cardiology/Medicine, Johns Hopkins University, Baltimore, MD, USA

    Wendy Post

  189. Medicine, University of Colorado at Denver, Denver, CO, USA

    Julia Powers Becker

  190. CCPM, University of Colorado at Denver, Denver, CO, USA

    Nicholas Rafaels

  191. Northwestern University, Chicago, IL, USA

    Laura Rasmussen-Torvik

  192. Medicine, National Jewish Health, Denver, CO, USA

    Elizabeth Regan

  193. Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa

    Muagututi’a Sefuiva Reupena

  194. University of Ottawa Institute for Mental Health Research, University of Ottawa, Sleep Research Unit, Ottawa, Ontario, Canada

    Rebecca Robillard

  195. Biomedical Informatics, Vanderbilt University, Medicine, Pharmacology, Nashville, TN, USA

    Dan Roden

  196. University of Washington, Seattle, WA, USA

    Sarah Ruuska

  197. Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

    Ester Cerdeira Sabino

  198. Pathology, University of Washington, Seattle, WA, USA

    Shabnam Salimi

  199. Lundquist Institute, TGPS, Torrance, CA, USA

    Kevin Sandow

  200. Division of Hematology/Oncology, Harvard University, Boston, MA, USA

    Vijay G. Sankaran

  201. Genetics, Harvard Medical School, Boston, MA, USA

    Christine Seidman

  202. Harvard Medical School, Boston, MA, USA

    Jonathan Seidman

  203. Pediatrics, Emory University, Atlanta, GA, USA

    Vivien Sheehan

  204. Human Genetics, Emory University, Atlanta, GA, USA

    Stephanie L. Sherman

  205. Medicine/Cardiology, Vanderbilt University, Nashville, TN, USA

    M. Benjamin Shoemaker

  206. UMass Memorial Medical Center, Worcester, MA, USA

    Brian Silver

  207. University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Robert Skomro

  208. Biostatistical Sciences, Wake Forest Baptist Health, Winston-Salem, NC, USA

    Beverly Snively

  209. Department of Genetics, Stanford University, Stanford, CA, USA

    Michael Snyder

  210. Genomic Cardiology, University of Colorado at Denver, Aurora, CO, USA

    Garrett Storm

  211. Channing Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Jessica Lasky Su

  212. Université Laval, Quebec City, Quebec, Canada

    Frédéric Sériès

  213. Department of Genome Science, University of Washington, Seattle, WA, USA

    Machiko Threlkeld

  214. Fred Hutchinson Cancer Research Center, Cancer Prevention Division of Public Health Sciences, Seattle, WA, USA

    Lesley Tinker

  215. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA

    Sarah Tishkoff

  216. Department of Biostatistics, University of Alabama, Birmingham, AL, USA

    Hemant Tiwari

  217. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Catherine Tong

  218. University of Southern California, USC Methylation Characterization Center, University of Southern California, California, CA, USA

    David Van Den Berg

  219. Brigham & Women’s Hospital, Mass General Brigham, Boston, MA, USA

    Heming Wang

  220. Department of Medicine, Brigham & Women’s Hospital, Channing Division of Network Medicine, Boston, MA, USA

    Scott T. Weiss

  221. Department of Epidemiology, Indiana University, Indianapolis, IN, USA

    Jennifer Wessel

  222. Henry Ford Health System, Detroit, MI, USA

    L. Keoki Williams

  223. Case Western Reserve University, Cleveland, OH, USA

    Scott Williams

  224. Beth Israel Deaconess Medical Center, Cardiology, Cambridge, MA, USA

    James Wilson

  225. Department of Medicine, Henry Ford Health System, Detroit, MI, USA

    Baojun Wu

  226. Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Yingze Zhang

  227. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Xiaofeng Zhu

  228. Medicine, University of California, San Francisco, San Francisco, CA, USA

    Elad Ziv

  229. Health Quantitative Sciences Research, Mayo Clinic, Rochester, MN, USA

    Mariza de Andrade

  230. Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health at Houston, Human Genetics Center, Houston, TX, USA

    Paul de Vries

  231. Cardiovascular Division, Washington University in St. Louis, Department of Medicine, St. Louis, MO, USA

    Lisa de las Fuentes

Authors
  1. Eric Van Buren
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  2. Yi Zhang
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  22. Jiang He
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  26. Rita R. Kalyani
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  27. Sharon L. R. Kardia
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  31. Leslie Lange
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  32. Dan Levy
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  33. Changwei Li
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  34. Simin Liu
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  35. Donald Lloyd-Jones
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  36. Ruth J. F. Loos
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  37. Ani W. Manichaikul
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  38. Lisa Warsinger Martin
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  39. Rasika Mathias
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  40. Ryan L. Minster
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  41. Braxton D. Mitchell
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Contributions

E.V.B., Y.Z., X. Li, Z. Li and X. Lin designed the experiments. E.V.B., Y.Z., X. Li and X. Lin performed the experiments. E.V.B., Y.Z., X. Li, Z. Li, H.Z., M.S.S., N.D.P., D.K.A., J.B., E.B., B.E.C., J.C.C., A.P.C., Y.D.I.C., J.C., R.D., M.F., N.F., M.G., C.G., X.G., J.H., N.H.C., L.H., Y.J.H., R.R.K., S.L.R.K., E.K., C.K., B.G.K., L.L., D.L., C.L., S.L., D.L.J., R.J.F.L., A.W.M., L.M., R.L.M., R.J.M., B.M., J.C.M., T.N., K.N., J.O., J.P., P.P., B.P., L.R., R.S.V., S.R., A.R., S.S.R., J.S., B.S., H.T., K.D.T., R.T., S.V., L.Y.,W.Z., J.R., G.M.P., P.N. and X. Lin acquired, analyzed or interpreted data. J.R., G.M.P., P.N. and the NHLBI TOPMed Lipids Working Group provided administrative, technical or material support. E.V.B. and X. Lin drafted the manuscript and revised it according to suggestions by the coauthors. All authors critically reviewed the manuscript, suggested revisions as needed and approved the final version.

Corresponding author

Correspondence to Xihong Lin.

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Competing interests

E.K. has received personal fees from Regeneron Pharmaceuticals, 23&Me, Allelica and Illumina; has received research funding from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone and Galateo Bio. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Cleerly, Genentech/Roche, Ionis, Novartis and Silence Therapeutics, personal fees from AIRNA, Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio and Tourmaline Bio; equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli and TenSixteen Bio; royalties from Recora for intensive cardiac rehabilitation; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (ACC) through Westat. X. Lin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. The other authors declare no competing interests.

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Nature Methods thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Lin Tang, in collaboration with the Nature Methods team.

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Van Buren, E., Zhang, Y., Li, X. et al. cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions. Nat Methods (2025). https://doi.org/10.1038/s41592-025-02919-5

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