TY - JOUR
T1 - Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes
AU - Ali, Aminah Tasnim
AU - Idaghdour, Youssef
AU - Hodgkinson, Alan
N1 - Funding Information:
We thank the CARTaGENE platform, GTEx, TwinsUK, the NIMH Genomics Resource and the Geuvadis project for use of RNA sequencing data. A.H. holds a Medical Research Council (MRC) eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. A.H. also holds a WHRI-Academy Marie Curie (COFUND) Fellowship and the research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 608765. Work presented here reflects only the author’s views and not the views of the European Commission. A.T.A. is supported by the Generation Trust. Y.I. is funded by a New York University Abu Dhabi research grant (AD105). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. For GTEx data: the Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enroled at Bios-pecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina - Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). For NIMH data: data was provided by Dr. Douglas F. Levinson (dflev@stanford.edu). We gratefully acknowledge the resources were supported by National Institutes of Health/National Institute of Mental Health Grants 5RC2MH089916 (PI: Douglas F. Levinson, M.D.; Coinvestigators: Myrna M. Weissman, Ph.D., James B. Potash, M.D., MPH, Daphne Koller, Ph.D., and Alexander E. Urban, Ph.D.) and 3R01MH090941 (Co-investigator: Daphne Koller, Ph.D.). For TwinsUK data: The TwinsUK study was funded by the Wellcome Trust and European Community’s Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - RNA modifications affect the stability and function of RNA species, regulating important downstream processes. Modification levels are often dynamic, varying between tissues and individuals, although it is not always clear what modulates this or what impact it has on biological systems. Here, we quantify variation in m1A/G RNA modification levels at functionally important positions in the human mitochondrial genome across 11,552 samples from 39 tissue/cell types and find that modification levels are associated with mitochondrial transcript processing. We identify links between mitochondrial RNA modification levels and genetic variants in the nuclear genome, including a missense mutation in LONP1, and find that genetic variants within MRPP3 and TRMT61B are associated with RNA modification levels across a large number of tissues. Genetic variants linked to RNA modification levels are associated with multiple disease/disease-related phenotypes, including blood pressure, breast cancer and psoriasis, suggesting a role for mitochondrial RNA modification in complex disease.
AB - RNA modifications affect the stability and function of RNA species, regulating important downstream processes. Modification levels are often dynamic, varying between tissues and individuals, although it is not always clear what modulates this or what impact it has on biological systems. Here, we quantify variation in m1A/G RNA modification levels at functionally important positions in the human mitochondrial genome across 11,552 samples from 39 tissue/cell types and find that modification levels are associated with mitochondrial transcript processing. We identify links between mitochondrial RNA modification levels and genetic variants in the nuclear genome, including a missense mutation in LONP1, and find that genetic variants within MRPP3 and TRMT61B are associated with RNA modification levels across a large number of tissues. Genetic variants linked to RNA modification levels are associated with multiple disease/disease-related phenotypes, including blood pressure, breast cancer and psoriasis, suggesting a role for mitochondrial RNA modification in complex disease.
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U2 - 10.1038/s42003-020-0879-3
DO - 10.1038/s42003-020-0879-3
M3 - Article
C2 - 32221480
AN - SCOPUS:85082759435
VL - 3
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 147
ER -