Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

Human Genomics

Charleston W. K. Chiang¹  Nelson Freimer²  Susan Service²  Michael Boehnke³  Aarno Palotie⁴  Aki Havulinna⁴  Samuli Ripatti⁴  Markku Laakso⁵  Jagadish Vangipurapu⁵  Johanna Kuusisto⁵  Erica Young⁶  Allison Regier⁶  Lei Chen⁶  Haley Abel⁶  Krishna Kanchi⁶  Chul Joo Kang⁶  Alexandra Scott⁶  Ira M. Hall⁶  Adam Locke⁶  Nathan O. Stitziel⁶  Liron Ganel⁶  Indraniel Das⁶  Ryan Christ⁶  David Larson⁶ 

[1] Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California;Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles;Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health;Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki;Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland;McDonnell Genome Institute, Washington University School of Medicine;

关键词: Metabolic syndrome;    Mitochondrial content;    Human genetics;    Human genome sequencing;    Genome-wide association studies;    Mendelian randomization;   

DOI  :  10.1186/s40246-021-00335-2

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown