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Human Molecular Genetics Advance Access published online on April 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm101
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic Determinants of Mitochondrial Content

Joanne E. Curran1,*, Matthew P. Johnson1, Thomas D. Dyer1, Harald H.H. Göring1, W. Kent Jack, Jr.1, Jac C. Charlesworth1, Anthony J. Borg1,2, Jeremy B.M. Jowett3,4, Shelley A. Cole1, Jean W. MacCluer1, Ahmed H. Kissebah5, Eric K. Moses1 and John Blangero1,4

1 Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA 2 Perinatal Medicine, The Royal Women's Hospital, Melbourne, Victoria 3053, Australia 3 Genetics, International Diabetes Institute, Caulfield, Victoria 3162, Australia 4 Human Genomics, Chemgenex Pharmaceuticals, Geelong, Victoria 3216, Australia 5 Take Off Pounds Sensibly (TOPS) Center for Obesity and Metabolic Research, Medical College of Wisconsin, Wisconsin 53226, USA

* Correspondence should be addressed to: Joanne E. Curran, Ph.D., Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, Texas 78245-0549 USA. Ph: +1 210 258 9828, Fax: +1 210 258 9444, Email: jcurran{at}sfbrgenetics.org

Received March 1, 2007; Revised April 11, 2007; Accepted April 11, 2007

The mitochondria are the major cellular site of energy production and respiration. Recent research has focused on investigating the role of mitochondria in disease development and it has become increasingly evident that mitochondrial dysfunction contributes to a variety of human diseases. Mitochondrial DNA (mtDNA) quantity is very important for maintaining mitochondrial function and meeting the energy needs of the body. We have measured mitochondrial content in 1,259 Mexican American individuals (from 42 extended families) and have shown that mtDNA quantity (a surrogate measure of mitochondrial integrity) has a large genetic component. We performed a genome scan and a genome-wide quantitative transcriptomic scan to identify QTLs influencing mitochondrial content. A variance components linkage-based genome scan utilizing 439 STR markers was used to localize a QTL for mitochondrial content on chromosome 10q (LOD = 3.83). Significant linkage to the mitochondrial genome was also detected for mitochondrial transmission (LOD = 3.39). For replication, we measured mitochondrial content in an independent Caucasian population (1,088 individuals) finding evidence for linkage in these same regions. As part of the San Antonio Family Heart Study, we obtained genome-wide quantitative transcriptional profiles from 1,240 individuals. Using lymphocyte samples, we quantitated 20,413 transcripts and examined correlations between the expression levels of these transcripts and mitochondrial content using the variance components method. Using regression analysis allowing for residual genetic components, we identified 829 transcripts (including many novel genes) influencing mitochondrial content that vary in their general biological actions, from cell signaling to cell trafficking and ion binding.


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