Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Aldi T. Kraja; Chunyu Liu; Jessica L. Fetterman; Mariaelisa Graff; Christian Theil Have; Charles Gu; Lisa R. Yanek; Mary F. Feitosa; Dan E. Arking; Daniel I. Chasman; Kristin Young; Symen Ligthart; W. David Hill; Stefan Weiss; Jian'an Luan; Franco Giulianini; Ruifang Li-Gao; Fernando P. Hartwig; Shiow J. Lin; Lihua Wang; Tom G. Richardson; Jie Yao; Eliana P. Fernandez; Mohsen Ghanbari; Mary K. Wojczynski; Wen Jane Lee; Maria Argos; Sebastian M. Armasu; Ruteja A. Barve; Kathleen A. Ryan; Ping An; Thomas J. Baranski; Suzette J. Bielinski; Donald W. Bowden; Ulrich Broeckel; Kaare Christensen; Audrey Y. Chu; Janie Corley; Simon R. Cox; Andre G. Uitterlinden; Fernando Rivadeneira; Cheryl D. Cropp; E. Warwick Daw; Diana van Heemst; Lisa de las Fuentes; He Gao; Ioanna Tzoulaki; Tarunveer S. Ahluwalia; Renée de Mutsert; Leslie S. Emery; A. Mesut Erzurumluoglu; James A. Perry; Mao Fu; Nita G. Forouhi; Zhenglong Gu; Yang Hai; Sarah E. Harris; Gibran Hemani; Steven C. Hunt; Marguerite R. Irvin; Anna E. Jonsson; Anne E. Justice; Nicola D. Kerrison; Nicholas B. Larson; Keng Hung Lin; Latisha D. Love-Gregory; Rasika A. Mathias; Joseph H. Lee; Matthias Nauck; Raymond Noordam; Ken K. Ong; James Pankow; Amit Patki; Alison Pattie; Astrid Petersmann; Qibin Qi; Rasmus Ribel-Madsen; Rebecca Rohde; Kevin Sandow; Theresia M. Schnurr; Tamar Sofer; John M. Starr; Adele M. Taylor; Alexander Teumer; Nicholas J. Timpson; Hugoline G. de Haan; Yujie Wang; Peter E. Weeke; Christine Williams; Hongsheng Wu; Wei Yang; Donglin Zeng; Daniel R. Witte; Bruce S. Weir; Nicholas J. Wareham; Henrik Vestergaard; Stephen T. Turner; Christian Torp-Pedersen; Evie Stergiakouli; Wayne Huey Herng Sheu; Frits R. Rosendaal; M. Arfan Ikram; Oscar H. Franco; Paul M. Ridker; Thomas T. Perls; Oluf Pedersen; Ellen A. Nohr; Anne B. Newman; Allan Linneberg; Claudia Langenberg; Tuomas O. Kilpeläinen; Sharon L.R. Kardia; Marit E. Jørgensen; Torben Jørgensen; Thorkild I.A. Sørensen; Georg Homuth; Torben Hansen; Mark O. Goodarzi; Ian J. Deary; Cramer Christensen; Yii Der Ida Chen; Aravinda Chakravarti; Ivan Brandslund; Klaus Bonnelykke; Kent D. Taylor; James G. Wilson; Santiago Rodriguez; Gail Davies; Bernardo L. Horta; Bharat Thyagarajan; D. C. Rao; Niels Grarup; Victor G. Davila-Roman; Gavin Hudson; Xiuqing Guo; Donna K. Arnett; Caroline Hayward; Dhananjay Vaidya; Dennis O. Mook-Kanamori; Hemant K. Tiwari; Daniel Levy; Ruth J.F. Loos; Abbas Dehghan; Paul Elliott; Afshan N. Malik; Robert A. Scott; Diane M. Becker; Mariza de Andrade; Michael A. Province; James B. Meigs; Jerome I. Rotter; Kari E. North

doi:10.1016/j.ajhg.2018.12.001

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Aldi T. Kraja, Chunyu Liu, Jessica L. Fetterman, Mariaelisa Graff, Christian Theil Have, Charles Gu, Lisa R. Yanek, Mary F. Feitosa, Dan E. Arking, Daniel I. Chasman, Kristin Young, Symen Ligthart, W. David Hill, Stefan Weiss, Jian'an Luan, Franco Giulianini, Ruifang Li-Gao, Fernando P. Hartwig, Shiow J. Lin, Lihua WangTom G. Richardson, Jie Yao, Eliana P. Fernandez, Mohsen Ghanbari, Mary K. Wojczynski, Wen Jane Lee, Maria Argos, Sebastian M. Armasu, Ruteja A. Barve, Kathleen A. Ryan, Ping An, Thomas J. Baranski, Suzette J. Bielinski, Donald W. Bowden, Ulrich Broeckel, Kaare Christensen, Audrey Y. Chu, Janie Corley, Simon R. Cox, Andre G. Uitterlinden, Fernando Rivadeneira, Cheryl D. Cropp, E. Warwick Daw, Diana van Heemst, Lisa de las Fuentes, He Gao, Ioanna Tzoulaki, Tarunveer S. Ahluwalia, Renée de Mutsert, Leslie S. Emery, A. Mesut Erzurumluoglu, James A. Perry, Mao Fu, Nita G. Forouhi, Zhenglong Gu, Yang Hai, Sarah E. Harris, Gibran Hemani, Steven C. Hunt, Marguerite R. Irvin, Anna E. Jonsson, Anne E. Justice, Nicola D. Kerrison, Nicholas B. Larson, Keng Hung Lin, Latisha D. Love-Gregory, Rasika A. Mathias, Joseph H. Lee, Matthias Nauck, Raymond Noordam, Ken K. Ong, James Pankow, Amit Patki, Alison Pattie, Astrid Petersmann, Qibin Qi, Rasmus Ribel-Madsen, Rebecca Rohde, Kevin Sandow, Theresia M. Schnurr, Tamar Sofer, John M. Starr, Adele M. Taylor, Alexander Teumer, Nicholas J. Timpson, Hugoline G. de Haan, Yujie Wang, Peter E. Weeke, Christine Williams, Hongsheng Wu, Wei Yang, Donglin Zeng, Daniel R. Witte, Bruce S. Weir, Nicholas J. Wareham, Henrik Vestergaard, Stephen T. Turner, Christian Torp-Pedersen, Evie Stergiakouli, Wayne Huey Herng Sheu, Frits R. Rosendaal, M. Arfan Ikram, Oscar H. Franco, Paul M. Ridker, Thomas T. Perls, Oluf Pedersen, Ellen A. Nohr, Anne B. Newman, Allan Linneberg, Claudia Langenberg, Tuomas O. Kilpeläinen, Sharon L.R. Kardia, Marit E. Jørgensen, Torben Jørgensen, Thorkild I.A. Sørensen, Georg Homuth, Torben Hansen, Mark O. Goodarzi, Ian J. Deary, Cramer Christensen, Yii Der Ida Chen, Aravinda Chakravarti, Ivan Brandslund, Klaus Bonnelykke, Kent D. Taylor, James G. Wilson, Santiago Rodriguez, Gail Davies, Bernardo L. Horta, Bharat Thyagarajan, D. C. Rao, Niels Grarup, Victor G. Davila-Roman, Gavin Hudson, Xiuqing Guo, Donna K. Arnett, Caroline Hayward, Dhananjay Vaidya, Dennis O. Mook-Kanamori, Hemant K. Tiwari, Daniel Levy, Ruth J.F. Loos, Abbas Dehghan, Paul Elliott, Afshan N. Malik, Robert A. Scott, Diane M. Becker, Mariza de Andrade, Michael A. Province, James B. Meigs, Jerome I. Rotter, Kari E. North

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

Original language	English (US)
Pages (from-to)	112-138
Number of pages	27
Journal	American journal of human genetics
Volume	104
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2018.12.001
State	Published - Jan 3 2019

Keywords

BMI
HOMA-B
HOMA-IR
HbA1c
MT-nDNA candidate genes
glucose
insulin
mitochondria
mtDNA
waist-to-hip ratio

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1016/j.ajhg.2018.12.001

Cite this

Kraja, A. T., Liu, C., Fetterman, J. L., Graff, M., Have, C. T., Gu, C., Yanek, L. R., Feitosa, M. F., Arking, D. E., Chasman, D. I., Young, K., Ligthart, S., Hill, W. D., Weiss, S., Luan, J., Giulianini, F., Li-Gao, R., Hartwig, F. P., Lin, S. J., ... North, K. E. (2019). Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. American journal of human genetics, 104(1), 112-138. https://doi.org/10.1016/j.ajhg.2018.12.001

Kraja, AT, Liu, C, Fetterman, JL, Graff, M, Have, CT, Gu, C, Yanek, LR, Feitosa, MF, Arking, DE, Chasman, DI, Young, K, Ligthart, S, Hill, WD, Weiss, S, Luan, J, Giulianini, F, Li-Gao, R, Hartwig, FP, Lin, SJ, Wang, L, Richardson, TG, Yao, J, Fernandez, EP, Ghanbari, M, Wojczynski, MK, Lee, WJ, Argos, M, Armasu, SM, Barve, RA, Ryan, KA, An, P, Baranski, TJ, Bielinski, SJ, Bowden, DW, Broeckel, U, Christensen, K, Chu, AY, Corley, J, Cox, SR, Uitterlinden, AG, Rivadeneira, F, Cropp, CD, Daw, EW, van Heemst, D, de las Fuentes, L, Gao, H, Tzoulaki, I, Ahluwalia, TS, de Mutsert, R, Emery, LS, Erzurumluoglu, AM, Perry, JA, Fu, M, Forouhi, NG, Gu, Z, Hai, Y, Harris, SE, Hemani, G, Hunt, SC, Irvin, MR, Jonsson, AE, Justice, AE, Kerrison, ND, Larson, NB, Lin, KH, Love-Gregory, LD, Mathias, RA, Lee, JH, Nauck, M, Noordam, R, Ong, KK, Pankow, J, Patki, A, Pattie, A, Petersmann, A, Qi, Q, Ribel-Madsen, R, Rohde, R, Sandow, K, Schnurr, TM, Sofer, T, Starr, JM, Taylor, AM, Teumer, A, Timpson, NJ, de Haan, HG, Wang, Y, Weeke, PE, Williams, C, Wu, H, Yang, W, Zeng, D, Witte, DR, Weir, BS, Wareham, NJ, Vestergaard, H, Turner, ST, Torp-Pedersen, C, Stergiakouli, E, Sheu, WHH, Rosendaal, FR, Ikram, MA, Franco, OH, Ridker, PM, Perls, TT, Pedersen, O, Nohr, EA, Newman, AB, Linneberg, A, Langenberg, C, Kilpeläinen, TO, Kardia, SLR, Jørgensen, ME, Jørgensen, T, Sørensen, TIA, Homuth, G, Hansen, T, Goodarzi, MO, Deary, IJ, Christensen, C, Chen, YDI, Chakravarti, A, Brandslund, I, Bonnelykke, K, Taylor, KD, Wilson, JG, Rodriguez, S, Davies, G, Horta, BL, Thyagarajan, B, Rao, DC, Grarup, N, Davila-Roman, VG, Hudson, G, Guo, X, Arnett, DK, Hayward, C, Vaidya, D, Mook-Kanamori, DO, Tiwari, HK, Levy, D, Loos, RJF, Dehghan, A, Elliott, P, Malik, AN, Scott, RA, Becker, DM, de Andrade, M, Province, MA, Meigs, JB, Rotter, JI & North, KE 2019, 'Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits', American journal of human genetics, vol. 104, no. 1, pp. 112-138. https://doi.org/10.1016/j.ajhg.2018.12.001

@article{4474c245150e43fd8a1ecd8130c49fe0,

title = "Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits",

abstract = "Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.",

keywords = "BMI, HOMA-B, HOMA-IR, HbA1c, MT-nDNA candidate genes, glucose, insulin, mitochondria, mtDNA, waist-to-hip ratio",

author = "Kraja, {Aldi T.} and Chunyu Liu and Fetterman, {Jessica L.} and Mariaelisa Graff and Have, {Christian Theil} and Charles Gu and Yanek, {Lisa R.} and Feitosa, {Mary F.} and Arking, {Dan E.} and Chasman, {Daniel I.} and Kristin Young and Symen Ligthart and Hill, {W. David} and Stefan Weiss and Jian'an Luan and Franco Giulianini and Ruifang Li-Gao and Hartwig, {Fernando P.} and Lin, {Shiow J.} and Lihua Wang and Richardson, {Tom G.} and Jie Yao and Fernandez, {Eliana P.} and Mohsen Ghanbari and Wojczynski, {Mary K.} and Lee, {Wen Jane} and Maria Argos and Armasu, {Sebastian M.} and Barve, {Ruteja A.} and Ryan, {Kathleen A.} and Ping An and Baranski, {Thomas J.} and Bielinski, {Suzette J.} and Bowden, {Donald W.} and Ulrich Broeckel and Kaare Christensen and Chu, {Audrey Y.} and Janie Corley and Cox, {Simon R.} and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Cropp, {Cheryl D.} and Daw, {E. Warwick} and {van Heemst}, Diana and {de las Fuentes}, Lisa and He Gao and Ioanna Tzoulaki and Ahluwalia, {Tarunveer S.} and {de Mutsert}, Ren{\'e}e and Emery, {Leslie S.} and Erzurumluoglu, {A. Mesut} and Perry, {James A.} and Mao Fu and Forouhi, {Nita G.} and Zhenglong Gu and Yang Hai and Harris, {Sarah E.} and Gibran Hemani and Hunt, {Steven C.} and Irvin, {Marguerite R.} and Jonsson, {Anna E.} and Justice, {Anne E.} and Kerrison, {Nicola D.} and Larson, {Nicholas B.} and Lin, {Keng Hung} and Love-Gregory, {Latisha D.} and Mathias, {Rasika A.} and Lee, {Joseph H.} and Matthias Nauck and Raymond Noordam and Ong, {Ken K.} and James Pankow and Amit Patki and Alison Pattie and Astrid Petersmann and Qibin Qi and Rasmus Ribel-Madsen and Rebecca Rohde and Kevin Sandow and Schnurr, {Theresia M.} and Tamar Sofer and Starr, {John M.} and Taylor, {Adele M.} and Alexander Teumer and Timpson, {Nicholas J.} and {de Haan}, {Hugoline G.} and Yujie Wang and Weeke, {Peter E.} and Christine Williams and Hongsheng Wu and Wei Yang and Donglin Zeng and Witte, {Daniel R.} and Weir, {Bruce S.} and Wareham, {Nicholas J.} and Henrik Vestergaard and Turner, {Stephen T.} and Christian Torp-Pedersen and Evie Stergiakouli and Sheu, {Wayne Huey Herng} and Rosendaal, {Frits R.} and Ikram, {M. Arfan} and Franco, {Oscar H.} and Ridker, {Paul M.} and Perls, {Thomas T.} and Oluf Pedersen and Nohr, {Ellen A.} and Newman, {Anne B.} and Allan Linneberg and Claudia Langenberg and Kilpel{\"a}inen, {Tuomas O.} and Kardia, {Sharon L.R.} and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and S{\o}rensen, {Thorkild I.A.} and Georg Homuth and Torben Hansen and Goodarzi, {Mark O.} and Deary, {Ian J.} and Cramer Christensen and Chen, {Yii Der Ida} and Aravinda Chakravarti and Ivan Brandslund and Klaus Bonnelykke and Taylor, {Kent D.} and Wilson, {James G.} and Santiago Rodriguez and Gail Davies and Horta, {Bernardo L.} and Bharat Thyagarajan and Rao, {D. C.} and Niels Grarup and Davila-Roman, {Victor G.} and Gavin Hudson and Xiuqing Guo and Arnett, {Donna K.} and Caroline Hayward and Dhananjay Vaidya and Mook-Kanamori, {Dennis O.} and Tiwari, {Hemant K.} and Daniel Levy and Loos, {Ruth J.F.} and Abbas Dehghan and Paul Elliott and Malik, {Afshan N.} and Scott, {Robert A.} and Becker, {Diane M.} and {de Andrade}, Mariza and Province, {Michael A.} and Meigs, {James B.} and Rotter, {Jerome I.} and North, {Kari E.}",

note = "Funding Information: A.E. Justice is supported by a K99/R00 from the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) ( 5K99HL130580-02 and 5R00HL130580-04 ). G. Hudson has received funding support by Wellcome Trust Centre for Mitochondrial Research , Grant Code G906919 . J.I.R., X.G., Y.-D.I.C., K.D.T., Y.H., K.S., and J.Y. have received NIH support for research related to mitochondria. A.T.K., C. Liu, J.L.F., M. Graff, C.T.H., C.G., L.R.Y., M.F.F., D.E.A., D.I.C., K.Y., W.D.H., S.J.L., L.W., T.J.B., L.D.L.-G., T.I.A.S., G. Hudson, D.L., A.N.M., D.M.B., M.A.P., J.B.M., J.I.R., and K.E.N. were the writing group for this paper. M.A.P. and K.E.N. are from the CHARGE ADIPOSITY working group; J.I.R. and J.B.M. are from the CHARGE DIABETES working group. Publisher Copyright: {\textcopyright} 2018 American Society of Human Genetics",

year = "2019",

month = jan,

day = "3",

doi = "10.1016/j.ajhg.2018.12.001",

language = "English (US)",

volume = "104",

pages = "112--138",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

AU - Kraja, Aldi T.

AU - Liu, Chunyu

AU - Fetterman, Jessica L.

AU - Graff, Mariaelisa

AU - Have, Christian Theil

AU - Gu, Charles

AU - Yanek, Lisa R.

AU - Feitosa, Mary F.

AU - Arking, Dan E.

AU - Chasman, Daniel I.

AU - Young, Kristin

AU - Ligthart, Symen

AU - Hill, W. David

AU - Weiss, Stefan

AU - Luan, Jian'an

AU - Giulianini, Franco

AU - Li-Gao, Ruifang

AU - Hartwig, Fernando P.

AU - Lin, Shiow J.

AU - Wang, Lihua

AU - Richardson, Tom G.

AU - Yao, Jie

AU - Fernandez, Eliana P.

AU - Ghanbari, Mohsen

AU - Wojczynski, Mary K.

AU - Lee, Wen Jane

AU - Argos, Maria

AU - Armasu, Sebastian M.

AU - Barve, Ruteja A.

AU - Ryan, Kathleen A.

AU - An, Ping

AU - Baranski, Thomas J.

AU - Bielinski, Suzette J.

AU - Bowden, Donald W.

AU - Broeckel, Ulrich

AU - Christensen, Kaare

AU - Chu, Audrey Y.

AU - Corley, Janie

AU - Cox, Simon R.

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Cropp, Cheryl D.

AU - Daw, E. Warwick

AU - van Heemst, Diana

AU - de las Fuentes, Lisa

AU - Gao, He

AU - Tzoulaki, Ioanna

AU - Ahluwalia, Tarunveer S.

AU - de Mutsert, Renée

AU - Emery, Leslie S.

AU - Erzurumluoglu, A. Mesut

AU - Perry, James A.

AU - Fu, Mao

AU - Forouhi, Nita G.

AU - Gu, Zhenglong

AU - Hai, Yang

AU - Harris, Sarah E.

AU - Hemani, Gibran

AU - Hunt, Steven C.

AU - Irvin, Marguerite R.

AU - Jonsson, Anna E.

AU - Justice, Anne E.

AU - Kerrison, Nicola D.

AU - Larson, Nicholas B.

AU - Lin, Keng Hung

AU - Love-Gregory, Latisha D.

AU - Mathias, Rasika A.

AU - Lee, Joseph H.

AU - Nauck, Matthias

AU - Noordam, Raymond

AU - Ong, Ken K.

AU - Pankow, James

AU - Patki, Amit

AU - Pattie, Alison

AU - Petersmann, Astrid

AU - Qi, Qibin

AU - Ribel-Madsen, Rasmus

AU - Rohde, Rebecca

AU - Sandow, Kevin

AU - Schnurr, Theresia M.

AU - Sofer, Tamar

AU - Starr, John M.

AU - Taylor, Adele M.

AU - Teumer, Alexander

AU - Timpson, Nicholas J.

AU - de Haan, Hugoline G.

AU - Wang, Yujie

AU - Weeke, Peter E.

AU - Williams, Christine

AU - Wu, Hongsheng

AU - Yang, Wei

AU - Zeng, Donglin

AU - Witte, Daniel R.

AU - Weir, Bruce S.

AU - Wareham, Nicholas J.

AU - Vestergaard, Henrik

AU - Turner, Stephen T.

AU - Torp-Pedersen, Christian

AU - Stergiakouli, Evie

AU - Sheu, Wayne Huey Herng

AU - Rosendaal, Frits R.

AU - Ikram, M. Arfan

AU - Franco, Oscar H.

AU - Ridker, Paul M.

AU - Perls, Thomas T.

AU - Pedersen, Oluf

AU - Nohr, Ellen A.

AU - Newman, Anne B.

AU - Linneberg, Allan

AU - Langenberg, Claudia

AU - Kilpeläinen, Tuomas O.

AU - Kardia, Sharon L.R.

AU - Jørgensen, Marit E.

AU - Jørgensen, Torben

AU - Sørensen, Thorkild I.A.

AU - Homuth, Georg

AU - Hansen, Torben

AU - Goodarzi, Mark O.

AU - Deary, Ian J.

AU - Christensen, Cramer

AU - Chen, Yii Der Ida

AU - Chakravarti, Aravinda

AU - Brandslund, Ivan

AU - Bonnelykke, Klaus

AU - Taylor, Kent D.

AU - Wilson, James G.

AU - Rodriguez, Santiago

AU - Davies, Gail

AU - Horta, Bernardo L.

AU - Thyagarajan, Bharat

AU - Rao, D. C.

AU - Grarup, Niels

AU - Davila-Roman, Victor G.

AU - Hudson, Gavin

AU - Guo, Xiuqing

AU - Arnett, Donna K.

AU - Hayward, Caroline

AU - Vaidya, Dhananjay

AU - Mook-Kanamori, Dennis O.

AU - Tiwari, Hemant K.

AU - Levy, Daniel

AU - Loos, Ruth J.F.

AU - Dehghan, Abbas

AU - Elliott, Paul

AU - Malik, Afshan N.

AU - Scott, Robert A.

AU - Becker, Diane M.

AU - de Andrade, Mariza

AU - Province, Michael A.

AU - Meigs, James B.

AU - Rotter, Jerome I.

AU - North, Kari E.

N1 - Funding Information: A.E. Justice is supported by a K99/R00 from the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) ( 5K99HL130580-02 and 5R00HL130580-04 ). G. Hudson has received funding support by Wellcome Trust Centre for Mitochondrial Research , Grant Code G906919 . J.I.R., X.G., Y.-D.I.C., K.D.T., Y.H., K.S., and J.Y. have received NIH support for research related to mitochondria. A.T.K., C. Liu, J.L.F., M. Graff, C.T.H., C.G., L.R.Y., M.F.F., D.E.A., D.I.C., K.Y., W.D.H., S.J.L., L.W., T.J.B., L.D.L.-G., T.I.A.S., G. Hudson, D.L., A.N.M., D.M.B., M.A.P., J.B.M., J.I.R., and K.E.N. were the writing group for this paper. M.A.P. and K.E.N. are from the CHARGE ADIPOSITY working group; J.I.R. and J.B.M. are from the CHARGE DIABETES working group. Publisher Copyright: © 2018 American Society of Human Genetics

PY - 2019/1/3

Y1 - 2019/1/3

N2 - Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

AB - Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

KW - BMI

KW - HOMA-B

KW - HOMA-IR

KW - HbA1c

KW - MT-nDNA candidate genes

KW - glucose

KW - insulin

KW - mitochondria

KW - mtDNA

KW - waist-to-hip ratio

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U2 - 10.1016/j.ajhg.2018.12.001

DO - 10.1016/j.ajhg.2018.12.001

M3 - Article

C2 - 30595373

AN - SCOPUS:85059497971

VL - 104

SP - 112

EP - 138

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

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