Peer-Reviewed Publication
Nature2026February 25, 2026Journal Article
Functional dissection of complex trait variants at single-nucleotide resolution.
Layla Siraj1,2,3,4, Rodrigo I Castro5, Hannah B Dewey5,6, Susan Kales5, John C Butts5,7, Thanh Thanh L Nguyen8, Masahiro Kanai4,9,10,11, Daniel Berenzy5, Kousuke Mouri5, Qingbo S Wang4,9,10,12,13, Petko P Fiziev14, Kristin Tsuo4,9,10, Zachary R McCaw15, Sager J Gosai1,16,17,18, François Aguet1,14, Ran Cui4,9,10,19, Irfahan Kassam14, Jeremy McRae14, Christopher M Vockley1,20, Caleb A Lareau21, Sergey Abramov22, Alexandr Boystov22, Jeff Vierstra22, Yukinori Okada12,13,23, Alexander Gusev24, Thouis R Jones1,19, Eric S Lander1,25,26, Pardis C Sabeti1,17,18, Hilary K Finucane27,28,29, Steven K Reilly30,31, Jacob C Ulirsch32,33,34,35,36, Ryan Tewhey37,38,39
1Broad Institute of Harvard and MIT, Cambridge, MA, USA.
2Program in Biophysics, Harvard Graduate School of Arts and Sciences, Boston, MA, USA.
3Harvard-Massachusetts Institute of Technology MD/PhD Program, Harvard Medical School, Boston, MA, USA.
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
5The Jackson Laboratory, Bar Harbor, ME, USA.
6Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
7Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA.
8Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
9Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
10Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
11Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
12Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
13Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
14Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA.
15Insitro, South San Francisco, CA, USA.
16Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
17Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
18Howard Hughes Medical Institute, Chevy Chase, MD, USA.
19The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
20Eli Lilly and Company, Boston, MA, USA.
21Program in Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
22Altius Institute for Biomedical Sciences, Seattle, WA, USA.
23Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
24Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA, USA.
25Department of Biology, MIT, Cambridge, MA, USA.
26Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
27Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. finucane@broadinstitute.org.
28Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. finucane@broadinstitute.org.
29Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. finucane@broadinstitute.org.
30Department of Genetics, Yale School of Medicine, New Haven, CT, USA. steven.k.reilly@yale.edu.
31Wu Tsai Institute, Yale University, New Haven, CT, USA. steven.k.reilly@yale.edu.
32Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. julirsch@illumina.com.
33Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. julirsch@illumina.com.
34Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. julirsch@illumina.com.
35Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA. julirsch@illumina.com.
36Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA. julirsch@illumina.com.
37The Jackson Laboratory, Bar Harbor, ME, USA. Ryan.Tewhey@jax.org.
38Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA. Ryan.Tewhey@jax.org.
39Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA. Ryan.Tewhey@jax.org.
Abstract
Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics1-5. Most of these variants individually have weak effects6 and lie in non-coding gene-regulatory elements7-10, for which we lack a complete understanding of how single-nucleotide alterations modulate transcriptional processes to affect human phenotypes5,11-15. To address t…
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