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; Rasmus Ribel-Madsen; Qibin Qi; 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, Rasmus Ribel-Madsen, Qibin Qi, 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

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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.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	104
Udgave nummer	1
Sider (fra-til)	112-138
Antal sider	27
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2018.12.001
Status	Udgivet - 3 jan. 2019

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Citationsformater

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

@article{c6fc7b4840e2483295ec4d17d7944955,

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 Wen-Jane Lee 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 Keng-Hung Lin 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 Rasmus Ribel-Madsen and Qibin Qi 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}",

year = "2019",

month = jan,

day = "3",

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

language = "English",

volume = "104",

pages = "112--138",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

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, W-J, 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, K-H, Love-Gregory, LD, Mathias, RA, Lee, JH, Nauck, M, Noordam, R, Ong, KK, Pankow, J, Patki, A, Pattie, A, Petersmann, A, Ribel-Madsen, R, Qi, Q, 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, WH-H, 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, Y-DI, 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, bind 104, nr. 1, s. 112-138. https://doi.org/10.1016/j.ajhg.2018.12.001

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 - Ribel-Madsen, Rasmus

AU - Qi, Qibin

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

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

UR - http://www.scopus.com/inward/record.url?scp=85059497971&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.12.001

DO - 10.1016/j.ajhg.2018.12.001

M3 - Journal article

C2 - 30595373

SN - 0002-9297

VL - 104

SP - 112

EP - 138

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

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

Abstract

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