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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.

SUBMITTER: Kraja AT

PROVIDER: S-EPMC6323610 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Kraja Aldi T AT Liu Chunyu C Fetterman Jessica L JL Graff Mariaelisa M Have Christian Theil CT Gu Charles C Yanek Lisa R LR Feitosa Mary F MF Arking Dan E DE Chasman Daniel I DI Young Kristin K Ligthart Symen S Hill W David WD Weiss Stefan S Luan Jian'an J Giulianini Franco F Li-Gao Ruifang R Hartwig Fernando P FP Lin Shiow J SJ Wang Lihua L Richardson Tom G TG Yao Jie J Fernandez Eliana P EP Ghanbari Mohsen M Wojczynski Mary K MK Lee Wen-Jane WJ Argos Maria M Armasu Sebastian M SM Barve Ruteja A RA Ryan Kathleen A KA An Ping P Baranski Thomas J TJ Bielinski Suzette J SJ Bowden Donald W DW Broeckel Ulrich U Christensen Kaare K Chu Audrey Y AY Corley Janie J Cox Simon R SR Uitterlinden Andre G AG Rivadeneira Fernando F Cropp Cheryl D CD Daw E Warwick EW van Heemst Diana D de las Fuentes Lisa L Gao He H Tzoulaki Ioanna I Ahluwalia Tarunveer S TS de Mutsert Renée R Emery Leslie S LS Erzurumluoglu A Mesut AM Perry James A JA Fu Mao M Forouhi Nita G NG Gu Zhenglong Z Hai Yang Y Harris Sarah E SE Hemani Gibran G Hunt Steven C SC Irvin Marguerite R MR Jonsson Anna E AE Justice Anne E AE Kerrison Nicola D ND Larson Nicholas B NB Lin Keng-Hung KH Love-Gregory Latisha D LD Mathias Rasika A RA Lee Joseph H JH Nauck Matthias M Noordam Raymond R Ong Ken K KK Pankow James J Patki Amit A Pattie Alison A Petersmann Astrid A Qi Qibin Q Ribel-Madsen Rasmus R Rohde Rebecca R Sandow Kevin K Schnurr Theresia M TM Sofer Tamar T Starr John M JM Taylor Adele M AM Teumer Alexander A Timpson Nicholas J NJ de Haan Hugoline G HG Wang Yujie Y Weeke Peter E PE Williams Christine C Wu Hongsheng H Yang Wei W Zeng Donglin D Witte Daniel R DR Weir Bruce S BS Wareham Nicholas J NJ Vestergaard Henrik H Turner Stephen T ST Torp-Pedersen Christian C Stergiakouli Evie E Sheu Wayne Huey-Herng WH Rosendaal Frits R FR Ikram M Arfan MA Franco Oscar H OH Ridker Paul M PM Perls Thomas T TT Pedersen Oluf O Nohr Ellen A EA Newman Anne B AB Linneberg Allan A Langenberg Claudia C Kilpeläinen Tuomas O TO Kardia Sharon L R SLR Jørgensen Marit E ME Jørgensen Torben T Sørensen Thorkild I A TIA Homuth Georg G Hansen Torben T Goodarzi Mark O MO Deary Ian J IJ Christensen Cramer C Chen Yii-Der Ida YI Chakravarti Aravinda A Brandslund Ivan I Bonnelykke Klaus K Taylor Kent D KD Wilson James G JG Rodriguez Santiago S Davies Gail G Horta Bernardo L BL Thyagarajan Bharat B Rao D C DC Grarup Niels N Davila-Roman Victor G VG Hudson Gavin G Guo Xiuqing X Arnett Donna K DK Hayward Caroline C Vaidya Dhananjay D Mook-Kanamori Dennis O DO Tiwari Hemant K HK Levy Daniel D Loos Ruth J F RJF Dehghan Abbas A Elliott Paul P Malik Afshan N AN Scott Robert A RA Becker Diane M DM de Andrade Mariza M Province Michael A MA Meigs James B JB Rotter Jerome I JI North Kari E KE

American journal of human genetics 20181227 1

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 ...[more]

PMID: 30595373

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Project description:In a previous study, we observed that associations between APOE rs439401 and metabolic traits were moderated by chronic stress. Thus, in a population of stressed and non-stressed Danish men, we examined whether associations between APOE rs439401 and a panel of metabolic quantitative traits, all metabolic traits which may lead to T2D and CVD were moderated by psychological stress.Obese young men (n = 475, BMI ? 31.0 kg/m(2)) and a randomly selected control group (n = 709) identified from a population of 141,800 men were re-examined in two surveys (S-46: mean age 46, S-49: mean age 49 years) where anthropometric and biochemical measures were available. Psychological stress factors were assessed by a self-administered 7-item questionnaire. Each item had the possible response categories "yes" and "no" and assessed familial problems and conflicts. Summing positive responses constituted a stress item score, which was then dichotomized into stressed and non-stressed. Logistic regression analysis, applying a recessive genetic model, was used to assess odds ratios (OR) of the associations between APOE rs439401 genotypes and adverse levels of metabolic traits.The APOE rs439401 TT-genotype associated positively with BMI (OR = 1.09 [1.01; 1.17]), waist circumference (OR = 1.09 [1.02; 1.17]) in stressed men at S-46. Positive associations were observed for fasting plasma glucose (OR = 1.42 [1.07; 1.87]), serum triglycerides (OR = 1.41 [1.05; 1.91]) and with fasting plasma insulin (OR = 1.48 [1.05; 2.08]) in stressed men at S-49. Rs439401 TT-genotype also associated positively with surrogate measures of insulin resistance (HOMA-IR; OR = 1.21 [1.03; 1.41]) and inversely with insulin sensitivity (Stumvoll index; OR = 0.90 [0.82; 0.99], BIGTT-S(I); OR = 0.60 [0.43; 0.85]) in stressed men. No significant associations were observed in non-stressed men, albeit the estimates showed similar but weaker trends as in stressed men.The present results suggest that the APOE rs439401 TT-genotype is associated with an adverse metabolic profile in a population of psychologically stressed Danish men.

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

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

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