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Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits

Author

Listed:
  • Ayellet V Segrè
  • DIAGRAM Consortium
  • MAGIC investigators
  • Leif Groop
  • Vamsi K Mootha
  • Mark J Daly
  • David Altshuler

Abstract

Mitochondrial dysfunction has been observed in skeletal muscle of people with diabetes and insulin-resistant individuals. Furthermore, inherited mutations in mitochondrial DNA can cause a rare form of diabetes. However, it is unclear whether mitochondrial dysfunction is a primary cause of the common form of diabetes. To date, common genetic variants robustly associated with type 2 diabetes (T2D) are not known to affect mitochondrial function. One possibility is that multiple mitochondrial genes contain modest genetic effects that collectively influence T2D risk. To test this hypothesis we developed a method named Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA; http://www.broadinstitute.org/mpg/magenta). MAGENTA, in analogy to Gene Set Enrichment Analysis, tests whether sets of functionally related genes are enriched for associations with a polygenic disease or trait. MAGENTA was specifically designed to exploit the statistical power of large genome-wide association (GWA) study meta-analyses whose individual genotypes are not available. This is achieved by combining variant association p-values into gene scores and then correcting for confounders, such as gene size, variant number, and linkage disequilibrium properties. Using simulations, we determined the range of parameters for which MAGENTA can detect associations likely missed by single-marker analysis. We verified MAGENTA's performance on empirical data by identifying known relevant pathways in lipid and lipoprotein GWA meta-analyses. We then tested our mitochondrial hypothesis by applying MAGENTA to three gene sets: nuclear regulators of mitochondrial genes, oxidative phosphorylation genes, and ∼1,000 nuclear-encoded mitochondrial genes. The analysis was performed using the most recent T2D GWA meta-analysis of 47,117 people and meta-analyses of seven diabetes-related glycemic traits (up to 46,186 non-diabetic individuals). This well-powered analysis found no significant enrichment of associations to T2D or any of the glycemic traits in any of the gene sets tested. These results suggest that common variants affecting nuclear-encoded mitochondrial genes have at most a small genetic contribution to T2D susceptibility.Author Summary: Mitochondria play a crucial role in metabolic homeostasis, and alteration of mitochondrial function is a hallmark of diabetes. While mitochondrial activity is reduced in people with diabetes, it is unclear whether mitochondrial dysfunction is a cause or effect of type 2 diabetes. Genome-wide association studies for type 2 diabetes have explained ≈10% of the heritability of the disease, but none of the loci are known to affect mitochondrial activity. It is possible though that a mitochondrial contribution is hidden in the remaining 90%. Hence, we tested the hypothesis that multiple mitochondria-related genes encoded in the nucleus, each having a weak effect (hard to detect individually), can collectively influence type 2 diabetes. To address this, we developed a computational method (MAGENTA) that allowed us to adequately analyze large collective datasets of human genetic variation obtained from collaborative studies of type 2 diabetes and related glycemic traits. Despite the increased sensitivity of MAGENTA compared to single-DNA variant analysis, we found no support for a causal relationship between mitochondrial dysfunction and type 2 diabetes. These results may help steer future efforts in understanding the pathogenesis of the disease. MAGENTA is broadly applicable to testing associations between other biological pathways and common diseases or traits.

Suggested Citation

  • Ayellet V Segrè & DIAGRAM Consortium & MAGIC investigators & Leif Groop & Vamsi K Mootha & Mark J Daly & David Altshuler, 2010. "Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits," PLOS Genetics, Public Library of Science, vol. 6(8), pages 1-19, August.
  • Handle: RePEc:plo:pgen00:1001058
    DOI: 10.1371/journal.pgen.1001058
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    1. Hariklia Eleftherohorinou & Victoria Wright & Clive Hoggart & Anna-Liisa Hartikainen & Marjo-Riitta Jarvelin & David Balding & Lachlan Coin & Michael Levin, 2009. "Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases," PLOS ONE, Public Library of Science, vol. 4(11), pages 1-11, November.
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    1. Junjiao Feng & Liang Zhang & Chunhui Chen & Jintao Sheng & Zhifang Ye & Kanyin Feng & Jing Liu & Ying Cai & Bi Zhu & Zhaoxia Yu & Chuansheng Chen & Qi Dong & Gui Xue, 2022. "A cognitive neurogenetic approach to uncovering the structure of executive functions," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. David Lamparter & Daniel Marbach & Rico Rueedi & Zoltán Kutalik & Sven Bergmann, 2016. "Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics," PLOS Computational Biology, Public Library of Science, vol. 12(1), pages 1-20, January.
    3. Niina Sandholm & Rany M Salem & Amy Jayne McKnight & Eoin P Brennan & Carol Forsblom & Tamara Isakova & Gareth J McKay & Winfred W Williams & Denise M Sadlier & Ville-Petteri Mäkinen & Elizabeth J Swa, 2012. "New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes," PLOS Genetics, Public Library of Science, vol. 8(9), pages 1-13, September.
    4. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    5. Nadja Knoll & Ivonne Jarick & Anna-Lena Volckmar & Martin Klingenspor & Thomas Illig & Harald Grallert & Christian Gieger & Heinz-Erich Wichmann & Annette Peters & Johannes Hebebrand & André Scherag &, 2013. "Gene Set of Nuclear-Encoded Mitochondrial Regulators Is Enriched for Common Inherited Variation in Obesity," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    6. Kristina M. Garske & Asha Kar & Caroline Comenho & Brunilda Balliu & David Z. Pan & Yash V. Bhagat & Gregory Rosenberg & Amogha Koka & Sankha Subhra Das & Zong Miao & Janet S. Sinsheimer & Jaakko Kapr, 2023. "Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Benjamin Lehne & Cathryn M Lewis & Thomas Schlitt, 2011. "From SNPs to Genes: Disease Association at the Gene Level," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-10, June.
    8. Lina Cai & Tomas Gonzales & Eleanor Wheeler & Nicola D. Kerrison & Felix R. Day & Claudia Langenberg & John R. B. Perry & Soren Brage & Nicholas J. Wareham, 2023. "Causal associations between cardiorespiratory fitness and type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Ville-Petteri Mäkinen & Mete Civelek & Qingying Meng & Bin Zhang & Jun Zhu & Candace Levian & Tianxiao Huan & Ayellet V Segrè & Sujoy Ghosh & Juan Vivar & Majid Nikpay & Alexandre F R Stewart & Christ, 2014. "Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease," PLOS Genetics, Public Library of Science, vol. 10(7), pages 1-14, July.
    10. Joshua C Randall & Thomas W Winkler & Zoltán Kutalik & Sonja I Berndt & Anne U Jackson & Keri L Monda & Tuomas O Kilpeläinen & Tõnu Esko & Reedik Mägi & Shengxu Li & Tsegaselassie Workalemahu & Mary F, 2013. "Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits," PLOS Genetics, Public Library of Science, vol. 9(6), pages 1-19, June.

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