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 | |
| 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)
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Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. / Kraja, Aldi T.; Liu, Chunyu; Fetterman, Jessica L.; Graff, Mariaelisa; Have, Christian Theil; Gu, Charles; Yanek, Lisa R.; Feitosa, Mary F.; Arking, Dan E.; Chasman, Daniel I.; Young, Kristin; Ligthart, Symen; Hill, W. David; Weiss, Stefan; Luan, Jian'an; Giulianini, Franco; Li-Gao, Ruifang; Hartwig, Fernando P.; Lin, Shiow J.; Wang, Lihua; Richardson, Tom G.; Yao, Jie; Fernandez, Eliana P.; Ghanbari, Mohsen; Wojczynski, Mary K.; Lee, Wen Jane; Argos, Maria; Armasu, Sebastian M.; Barve, Ruteja A.; Ryan, Kathleen A.; An, Ping; Baranski, Thomas J.; Bielinski, Suzette J.; Bowden, Donald W.; Broeckel, Ulrich; Christensen, Kaare; Chu, Audrey Y.; Corley, Janie; Cox, Simon R.; Uitterlinden, Andre G.; Rivadeneira, Fernando; Cropp, Cheryl D.; Daw, E. Warwick; van Heemst, Diana; de las Fuentes, Lisa; Gao, He; Tzoulaki, Ioanna; Ahluwalia, Tarunveer S.; de Mutsert, Renée; Emery, Leslie S.; Erzurumluoglu, A. Mesut; Perry, James A.; Fu, Mao; Forouhi, Nita G.; Gu, Zhenglong; Hai, Yang; Harris, Sarah E.; Hemani, Gibran; Hunt, Steven C.; Irvin, Marguerite R.; Jonsson, Anna E.; Justice, Anne E.; Kerrison, Nicola D.; Larson, Nicholas B.; Lin, Keng Hung; Love-Gregory, Latisha D.; Mathias, Rasika A.; Lee, Joseph H.; Nauck, Matthias; Noordam, Raymond; Ong, Ken K.; Pankow, James; Patki, Amit; Pattie, Alison; Petersmann, Astrid; Qi, Qibin; Ribel-Madsen, Rasmus; Rohde, Rebecca; Sandow, Kevin; Schnurr, Theresia M.; Sofer, Tamar; Starr, John M.; Taylor, Adele M.; Teumer, Alexander; Timpson, Nicholas J.; de Haan, Hugoline G.; Wang, Yujie; Weeke, Peter E.; Williams, Christine; Wu, Hongsheng; Yang, Wei; Zeng, Donglin; Witte, Daniel R.; Weir, Bruce S.; Wareham, Nicholas J.; Vestergaard, Henrik; Turner, Stephen T.; Torp-Pedersen, Christian; Stergiakouli, Evie; Sheu, Wayne Huey Herng; Rosendaal, Frits R.; Ikram, M. Arfan; Franco, Oscar H.; Ridker, Paul M.; Perls, Thomas T.; Pedersen, Oluf; Nohr, Ellen A.; Newman, Anne B.; Linneberg, Allan; Langenberg, Claudia; Kilpeläinen, Tuomas O.; Kardia, Sharon L.R.; Jørgensen, Marit E.; Jørgensen, Torben; Sørensen, Thorkild I.A.; Homuth, Georg; Hansen, Torben; Goodarzi, Mark O.; Deary, Ian J.; Christensen, Cramer; Chen, Yii Der Ida; Chakravarti, Aravinda; Brandslund, Ivan; Bonnelykke, Klaus; Taylor, Kent D.; Wilson, James G.; Rodriguez, Santiago; Davies, Gail; Horta, Bernardo L.; Thyagarajan, Bharat; Rao, D. C.; Grarup, Niels; Davila-Roman, Victor G.; Hudson, Gavin; Guo, Xiuqing; Arnett, Donna K.; Hayward, Caroline; Vaidya, Dhananjay; Mook-Kanamori, Dennis O.; Tiwari, Hemant K.; Levy, Daniel; Loos, Ruth J.F.; Dehghan, Abbas; Elliott, Paul; Malik, Afshan N.; Scott, Robert A.; Becker, Diane M.; de Andrade, Mariza; Province, Michael A.; Meigs, James B.; Rotter, Jerome I.; North, Kari E.
In: American journal of human genetics, Vol. 104, No. 1, 03.01.2019, p. 112-138.Research output: Contribution to journal › Article › peer-review
}
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.
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
UR - http://www.scopus.com/inward/citedby.url?scp=85059497971&partnerID=8YFLogxK
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 -