Functional dissection of complex and molecular trait variants at single nucleotide resolution.

Autor:	Siraj L; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Program in Biophysics, Harvard Graduate School of Arts and Sciences, Boston, MA, USA.; Harvard-Massachusetts Institute of Technology MD/PhD Program, Harvard Medical School, Boston, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Castro RI; The Jackson Laboratory, Bar Harbor, ME, USA., Dewey H; The Jackson Laboratory, Bar Harbor, ME, USA., Kales S; The Jackson Laboratory, Bar Harbor, ME, USA., Nguyen TTL; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Kanai M; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; 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.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA., Berenzy D; The Jackson Laboratory, Bar Harbor, ME, USA., Mouri K; The Jackson Laboratory, Bar Harbor, ME, USA., Wang QS; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; 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.; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan., McCaw ZR; Insitro, South San Francisco, California, USA., Gosai SJ; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA., Aguet F; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA., Cui R; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; 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.; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Vockley CM; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Lareau CA; Program in Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Okada Y; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan., Gusev A; Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA, USA., Jones TR; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lander ES; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Department of Biology, MIT, Cambridge, MA, USA.; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Sabeti PC; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA., Finucane HK; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; 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., Reilly SK; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Wu Tsai Institute, Yale University, New Haven, CT, USA., Ulirsch JC; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; 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.; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.; Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA., Tewhey R; The Jackson Laboratory, Bar Harbor, ME, USA.; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA.; Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 06. Date of Electronic Publication: 2024 May 06.
DOI:	10.1101/2024.05.05.592437
Abstrakt:	Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk. Competing Interests: Competing Interests PCS is a co-founder of and consultant to Sherlock Biosciences and Board Member of Danaher Corporation. PCS and RT hold patents related to the application of MPRA. JCU and FA are employees of Illumina. QSW is an employee of Calico Life Sciences LLC. ZRM is an employee of insitro.
Databáze:	MEDLINE
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