TY - JOUR
T1 - Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences
AU - Ganel, Liron
AU - Chen, Lei
AU - Christ, Ryan
AU - Vangipurapu, Jagadish
AU - Young, Erica
AU - Das, Indraniel
AU - Kanchi, Krishna
AU - Larson, David
AU - Regier, Allison
AU - Abel, Haley
AU - Kang, Chul Joo
AU - Scott, Alexandra
AU - Havulinna, Aki
AU - Chiang, Charleston W.K.
AU - Service, Susan
AU - Freimer, Nelson
AU - Palotie, Aarno
AU - Ripatti, Samuli
AU - Kuusisto, Johanna
AU - Boehnke, Michael
AU - Laakso, Markku
AU - Locke, Adam
AU - Stitziel, Nathan O.
AU - Hall, Ira M.
N1 - Funding Information:
We thank Hyeim Jung for her help in identifying outlier individuals as well as the WashU data production team, in particular Robert Fulton, Lucinda Fulton, Catrina Fronick, Aye Wollam, and Susan K. Dutcher. This research has been conducted using the UK Biobank Resource under Application Number 56546. The FINRISK samples used for the research were obtained from the FINRISK Study and from THL Biobank. We thank all study participants for their generous participation at THL Biobank and the FINRISK Study.
Funding Information:
NOS has received grant funding from Regeneron Pharmaceuticals for unrelated work. The rest of the authors declare no competing interests.
Funding Information:
This work was funded by the NHGRI Centers for Common Disease Genetics (grant number UM1 HG008853 to IMH and NOS), the NHGRI large-scale sequencing grant (grant number 5U54HG003079), the Sigrid Jusélius Foundation (to SR), the University of Helsinki HiLIFE Fellow grants 2017–2020 (to SR), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant number 312062 to SR), the Academy of Finland (grant number 285380 to SR), the National Heart, Lung and Blood Institute (grant number T32HL007081 to EY), and the National Center for Advancing Translational Sciences (grant number UL1TR002345 to EY). The funders had no role in the design of the study or the collection, analysis, or interpretation of the data.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Genome-wide association studies
KW - Human genetics
KW - Human genome sequencing
KW - Mendelian randomization
KW - Metabolic syndrome
KW - Mitochondrial content
UR - http://www.scopus.com/inward/record.url?scp=85107569923&partnerID=8YFLogxK
U2 - 10.1186/s40246-021-00335-2
DO - 10.1186/s40246-021-00335-2
M3 - Article
C2 - 34099068
AN - SCOPUS:85107569923
SN - 1473-9542
VL - 15
JO - Human Genomics
JF - Human Genomics
IS - 1
M1 - 34
ER -