Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences
Year: 2021
Type: article
Study design: Observational Study
Abstract: Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10 −8 ), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10 −8 ), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10 −21 ) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.
Source: Human Genomics
Authors: Liron Ganel, Lei Chen, Ryan Christ, Jagadish Vangipurapu, Erica Young, Indraniel Das, Krishna Kanchi, David Larson, Allison Regier, Haley Abel, Chul Joo Kang, Alexandra Scott, Aki Havulinna, Charleston W. K. Chiang, Susan Service, Nelson Freimer, Aarno Palotie, Samuli Ripatti, Johanna Kuusisto, Michael Boehnke, Markku Laakso, Adam Locke, Nathan O. Stitziel, Ira M. Hall
Institutions: Washington University in St. Louis, University of Eastern Finland, University of Helsinki, Finnish Institute for Health and Welfare, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, University of Southern California, University of California, Los Angeles, Broad Institute, Massachusetts General Hospital, Kuopio University Hospital, University of Michigan, Yale University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: Helsingin Yliopisto, Academy of Finland, Sigrid Juséliuksen Säätiö, National Institutes of Health, Helsinki Institute of Life Science, Helsingin Yliopisto, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: A Platform for Large-Scale Genomic Discovery, G2900443037, Identifying Genes for Type 2 Diabetes: FUSION, G5850737185, G6338555486, G7298554490, A Platform for Large-Scale Discovery in Common Disease, G8311891658, Michigan Diabetes Research Center (MDRC), Principles in Cardiovascular Research Training Program, Washington University Institute of Clinical and Translational Sciences, Identifying Genes for Type 2 Diabetes: FUSION
OpenAlex ID: W3167090705