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

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dc.contributor.author Ganel, Liron
dc.contributor.author Chen, Lei
dc.contributor.author Christ, Ryan
dc.contributor.author Vangipurapu, Jagadish
dc.contributor.author Young, Erica
dc.contributor.author Das, Indraniel
dc.contributor.author Kanchi, Krishna
dc.contributor.author Larson, David
dc.contributor.author Regier, Allison
dc.contributor.author Abel, Haley
dc.contributor.author Kang, Chul J.
dc.contributor.author Scott, Alexandra
dc.contributor.author Havulinna, Aki
dc.contributor.author Chiang, Charleston W. K.
dc.contributor.author Service, Susan
dc.contributor.author Freimer, Nelson
dc.contributor.author Palotie, Aarno
dc.contributor.author Ripatti, Samuli
dc.contributor.author Kuusisto, Johanna
dc.contributor.author Boehnke, Michael
dc.contributor.author Laakso, Markku
dc.contributor.author Locke, Adam
dc.contributor.author Stitziel, Nathan O.
dc.contributor.author Hall, Ira M.
dc.date.accessioned 2021-06-14T19:59:19Z
dc.date.available 2021-06-14T19:59:19Z
dc.date.issued 2021-06-07
dc.identifier.citation Human Genomics. 2021 Jun 07;15(1):34
dc.identifier.uri http://hdl.handle.net/10138/330957
dc.description.abstract 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.
dc.publisher BioMed Central
dc.subject Metabolic syndrome
dc.subject Mitochondrial content
dc.subject Human genetics
dc.subject Human genome sequencing
dc.subject Genome-wide association studies
dc.subject Mendelian randomization
dc.title Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences
dc.date.updated 2021-06-14T19:59:19Z
dc.language.rfc3066 en
dc.rights.holder The Author(s)
dc.type.uri http://purl.org/eprint/entityType/ScholarlyWork
dc.type.uri http://purl.org/eprint/entityType/Expression
dc.type.uri http://purl.org/eprint/type/JournalArticle

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