The role of mitochondria in the aetiology of human quantitative traits and morbidity

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

Mitochondria are organelles found in most plant and animal cells. Often described as the ?power house? of the cell, mitochondria are essential to cell survival and function. The role of mitochondria in energy production and programmed cell-death in growth and development is relatively well understood, but less characterised mitochondrial dynamics such as the continual merging and splitting (fusion and fission) between mitochondria in the cell and mitochondrial-led signalling pathways, also play fundamental roles in the healthy functioning of living cells.

We hypothesise that increased rates of mitochondrial fusion and fission controlled by nuclear genes are likely to be associated with reduced morbidity, since content exchange between mitochondria is believed to prevent the accumulation of defective mitochondria in the cell by reducing the deleterious impact of individual mitochondrial DNA mutations and accumulated mitochondrial damage that often occurs during the production of energy. Healthy mitochondria are thought to behave as a super-organelle with continual mitochondrial fusion and fission. However, the mechanism by which the burden of accumulated malfunctioning mitochondria is reduced is unknown. Mitochondrial-shaping proteins encoded by nuclear genes control the process of fusion and fission and the process is observed to be essential for the healthy functioning of mitochondria.

This genetic study will test whether mitochondrial molecular pathways contribute to human health, including myopia, insulin resistance and susceptibility to atherosclerosis in the general population. If mitochondrial fusion and fission rates affect susceptibility to these diseases, this will provide novel molecular insights into the role of mitochondria in human health and disease and have exciting implications for metabolic and aging research.

Technical Summary

Mitochondria provide essential multiple functions for the cell. The role of mitochondria in energy production and apoptosis is relatively well understood, but less characterised mitochondrial dynamics such as fusion and fission and mitochondrial-led signalling also play fundamental roles in cell biology. We postulate that one or more mitochondrial molecular pathways contribute to myopia, insulin resistance and susceptibility to atherosclerosis in the general population. Our previous work shows evidence of association between genes that control mitochondrial fusion and fission and the quantitative traits of myopia and insulin resistance.

In particular, we hypothesise that increased rates of mitochondrial fusion and fission controlled by nuclear genes are likely to be associated with reduced morbidity, since content exchange between mitochondria is believed to prevent the accumulation of defective mitochondria in the cell by reducing the deleterious impact of individual mitochondrial DNA (mtDNA) mutations and mitochondrial damage.
Healthy mitochondria are thought to behave as a super-organelle with continual mitochondrial fusion and fission, controlled by mitochondrial-shaping proteins. However, the mechanism by which the burden of accumulated malfunctioning mitochondria is reduced is unknown. Mitochondrial-shaping proteins encoded by nuclear genes control the process of fusion and fission and the process is observed to be essential for the healthy functioning of mitochondria.

By sequencing the mitochondrial-shaping nuclear genes and genotyping mtDNA to assess mutational load, we will test this theory in humans using a population-based cohort measured for these three phenotypes.

Publications

10 25 50

 
Description MSc course Director in Human Molecular Genetics (Imperial College)
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description The impact of gestational diabetes mellitus (GDM) upon the epigenetics of mother and newborn infant and long-term risk of type 2 diabetes
Amount € 630,000 (EUR)
Funding ID ANR-16-CE17-0017-01 
Organisation French National Research Agency 
Sector Public
Country France
Start 01/2017 
End 01/2021
 
Description The role of mitochondrial genetics in the development of Type 2 Diabetes
Amount £30,000 (GBP)
Funding ID 1745078 
Organisation MRC Doctoral Training Program 
Sector Public
Country United Kingdom
Start 10/2016 
End 10/2020
 
Title Development of fine map methods, Chr3q genotyping and genomic targeted re-sequencing 
Description 1) Development of new genetic association fine mapping methods Specifically we have: a) developed advanced mapping methods to identify novel disease susceptibility variants for Type 2 Diabetes (T2D), which I am now followed up with targeted resequencing for 60 of these loci b) using the same methods applied to previously identified T2D genetic susceptibility loci (approximately 70 across the genome), we have replicated about half these signals in African American populations. This has important implications for disease susceptibility for most human populations. c) characterised the nature of many of these genomic disease loci as conferring risk of T2D through the regulation of tissue-specific gene expression of (multiple) neighbouring genes. 2) Developed powerful new pathway analysis methods applied to genomic data in order to test for evidence of disease association with well-charecterised biochemical pathways. We are currently publishing our results. 3) Over 800 SNPs genotyped for approx. 2800 individuals in order to fine map chromosome 3q for metabolic and myopia traits 4) Targeted re-sequencing data for 60 genomic loci to be made publicly available at publication. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact This is work in progress and is highly productive 
 
Description Fine association mapping of type 2 diabetes susceptibility loci using population-specific genetic maps 
Organisation University College London
Department Department of Genetics, Evolution and Environment
Country United Kingdom 
Sector Academic/University 
PI Contribution 1) identified the research questions and implemented the study design 2) assisted in selecting informative genotypes placed on the LD genetic map 3) analysis of the data, in particular development of pathway analysis methods 4) lead on the write up and publication of the T2D GWAS and 3q pleiotropy studies
Collaborator Contribution In collaboration with Dr Nikolas Maniatis (UCL), we are: 1) developing novel fine mapping methods using genetic maps the analysis of WTCCC1, WTCCC2, NIDDK and other publicly available GWAS data to identify novel susceptibility genes and refine the genetic and physical location of functional variants using advanced LD mapping techniques 2) developing pathway analysis methods applied to functionally well-characterised pathways for nuclear-encoded mitochondria genes.
Impact 1) ABCC5 transporter is a novel type 2 diabetes susceptibility gene for European and African American populations. Direk K, Lau W, Small KS, Maniatis N, Andrew T. Annals of Human Genetics. Accepted Mar 2014. 2) Identification of sixty novel genetic susceptibility risk loci for type 2 diabetes. Submitted to AJHG Oct 2014 3) 3q pleiotropy study of T2D and common myopia - paper in preparation 4) Gene pathway enrichment analysis implicates mitochondrial function in the aetiology of type 2 diabetes - paper in preparation As part of this collaboration, I presented the following posters at the American Diabetes Association conference, June 2015: Three Presidential Address Late Breaking Abstract presentations 1. High-resolution maps identify novel T2D genes and regulatory hot spots in African- Americans and Europeans. Maniatis N, Lau W, Tamanini F, Andrew T Publication: 201-LB - 2015 https://ada.scientificposters.com/epsAbstractADA.cfm?id=1 2. Obtaining more from genome-wide analysis: Localisation of novel European-specific genes for T2D. Lau W, Tamanini F, Andrew T, Maniatis N Publication: 202-LB - 2015 https://ada.scientificposters.com/epsAbstractADA.cfm?id=2 3. RASGRF1 and IGF2BP2 confer pleiotropic risk of susceptibility to both type 2 diabetes and common myopia in Europeans. Andrew T, Lau W, Shehata K, Maniatis N Publication: 203-LB - 2015 https://ada.scientificposters.com/epsAbstractADA.cfm?id=3
Start Year 2009
 
Description Mitochondria morphology pilot study 
Organisation University College London
Department MRC Centre for Neuromuscular Diseases
Country United Kingdom 
Sector Public 
PI Contribution 1) co-ordinate the project 2) analyse the EM retinal images to obtain quantified mitochondrial morphology measures
Collaborator Contribution Chick retina mitochondria morphology pilot study Collaboration with Dr Tannman (UCL) and Prof Guggenheim (Cardiff) using matched case-control chick retina from eyes with and without lens-induced myopia to test whether eye growth induces mitochondria morphological changes (which is a proxy for metabolic function). The EM imaging methods used will test the feasibility of future studies using the same methods in relation to other traits such as T2D and Parkinson's disease.
Impact On hold. This is a pilot study & may not lead to publication
Start Year 2009
 
Description Mitochondria research mentor 
Organisation University of Oxford
Department Nuffield Department of Obstetrics & Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution I am actively discussing research ideas with Joanna along with the mitochondria data i have generated
Collaborator Contribution The MRC review panel originally suggested i contact Joanna Poulton to advise me on the mitochondria DNA side of this project. I am now in regular discussions with Joanna and she is informally acting as my mentor for my mitochondrial research
Impact Work in progress & we plan to publish together
Start Year 2009
 
Description The Mother-Offspring Mitochondria Study (MOMs) 
Organisation Baylor College of Medicine
Department Department of Molecular and Human Genetics
Country United States 
Sector Academic/University 
PI Contribution 1) proposed the research questions to be addressed 2) created the study design 3) my group will lead the data analysis Hypotheses: 1) Population mitochondrial DNA heteroplasmy rates for germline and somatic mutations are influenced by heritable factors (i.e. shared nuclear and cytoplasmic DNA). 2) Type 2 diabetes is causally associated with mitochondrial mutational load
Collaborator Contribution Drs Lee-Jun Wong and Victor Zhang (Baylor College of Medicine) are providing me with high quality mtDNA deep sequence data for up to 400 selected individuals to call heteroplasmy across the mtDNA molecule. The proposed hypotheses are currently being tested using blood DNA samples collected for 200 Mother-Offspring pairs (TwinsUK, Dr T Andrew and Prof Spector) and 100 mother-offspring pairs (French pedigree samples, Lille, Dr T Andrew and Prof Froguel)
Impact Outputs: 1) currently generating NGS data for the mitochondria genome with a minimum of x1000 read depth for 100 families 50 MZ and 50 DZ mother-offspring pairs 2) utilising positive heteroplasmy sequence control protocols using synthetic DNA strand assays in collaboration with Dr Zhang (Baylor College of Medicine, Texas)
Start Year 2010
 
Description The impact of aberrant methylation on Inter-individual variability of one-carbon metabolism 
Organisation University of Surrey
Department Department of Nutritional Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated measurements of plasma concentrations of methionine, Hcy, SAM, choline, betaine, and vitamins B2, B6, B9, and B12 for 350 identical and non-identical, post-menopausal (age: 55-90) twin pairs from the TwinsUK registry. In conjunction with already available Illumina 450 array data, we are currently testing the following research question: We hypothesise that perturbations in normal OCM function - through changes in physiological levels of methionine, Hcy, SAM, choline, betaine, and vitamins B2 (riboflavin), B6, folate (B9), and B12 (cobalamin) - acquired either through dietary deficiency and/or inter-individual variation in OCM nutrients disposition (i.e. absorption, distribution, elimination, and transport), can lead to aberrant DNA methylation. Hyper or hypomethylation of DNA, which is known to play a pivotal regulatory role in gene expression in response to both endogenous and exogenous stimuli, can impact a variety of processes pertaining to normal development, ageing, as well as susceptibility to a number of common, multifactorial diseases.
Collaborator Contribution 1) Design of the study 2) provided funds for the OCM phenotyping of the twins 3) will lead on the analysis and joint write-up with my collaborator
Impact We have generated measurements of plasma one carbon metabolites for 350 middle-aged twins from the TwinsUK registry in order to test our hypothesis.
Start Year 2013
 
Description The role of nuclear-encoded mitochondrial genes in the genetic susceptibility to type 2 diabetes 
Organisation University of Lille
Department CNRS-UMR-8199
Country France 
Sector Academic/University 
PI Contribution Evidence indicates that nuclear-encoded "mitochondria morphology" genes that control the rate of fusion and fission between mitochondria provide a quality-control turnover mechanism to maintain mitochondrial metabolic function and dispose of damaged organelles. Hypothesis: Defects in the functional efficiency of fusion/fission genes will impact upon mitochondrial mutational load and increase susceptibility to type 2 diabetes.
Collaborator Contribution In collaboration with Dr Bonnefond (CNRS UMR8199); Institut de Biologie de Lille) and RainDance, I am testing the mitochondrial "fusion/fission" hypothesis by the targeted NGS re-sequencing of 5 key mitochondria morphology genes to identify common and intermediate frequency variants for 2000 T2D cases and 2000 controls.
Impact Work in progress - advanced targeted re-sequencing methods using the RainDance platform are being modified and improved. Once this is complete, the sequence data for this project will be generated.
Start Year 2013
 
Description The role of one carbon metabolism (OCM) in gestational (GDM) and type 2 diabetes (T2D) 
Organisation Imperial College London
Department School of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I am investigating the hypothesis that mild maternal deficiencies in methyl donors and modulatory cofactors during pregnancy disrupt normal OCM function leading to aberrant changes in the methylome of the mother. To do this we will be using four existing data sets (TwinsUK; NFBC; FinnGEDI and NSU South Korea samples). We are currently generating methylation pilot data for NFBC, FinnGEDI and NSU South Korea samples using department laboratory facilities and department funds.
Collaborator Contribution Professor Philippe Froguel (Imperial), Professor Jarvelin (Imperial) and Dr Kwak (SNU, Seoul) are collecting GDM cohort data as part of a broader programme of research. Drs Eero Kajante (National Institute for Health & Welfare, Helsinki) and Marja Vaarasmaki (University Hospital, Olulu) are providing samples from the Finnish FinnGeDI cohort. Dr Ahmadi's (Surrey University) will be phenotyping the blood samples for one carbon metabolism and providing Nutritional Genomic expertise.
Impact 1) Vitamin B12 BJN article (PMID: 23628113) 2) Rank prize PhD studentship application (Nov 2013) 3) Methods for methylome analysis * Methylation pipeline: developed a QC & data analysis pipeline for genome-wide methylation, using serum OCM and Illumina 27k and 450k data * Mixed linear models for multivariate analysis OCM pathway phenotypes in relation to methylation 4) Grant application to Diabetes UK (PI T.Andrew, £401,490): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus" 5) Grant application to European Foundation for the Study of Diabetes (EFSD, PI T.Andrew, € 99994): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus"
Start Year 2013
 
Description The role of one carbon metabolism (OCM) in gestational (GDM) and type 2 diabetes (T2D) 
Organisation National Institute for Health and Welfare
Country Finland 
Sector Public 
PI Contribution I am investigating the hypothesis that mild maternal deficiencies in methyl donors and modulatory cofactors during pregnancy disrupt normal OCM function leading to aberrant changes in the methylome of the mother. To do this we will be using four existing data sets (TwinsUK; NFBC; FinnGEDI and NSU South Korea samples). We are currently generating methylation pilot data for NFBC, FinnGEDI and NSU South Korea samples using department laboratory facilities and department funds.
Collaborator Contribution Professor Philippe Froguel (Imperial), Professor Jarvelin (Imperial) and Dr Kwak (SNU, Seoul) are collecting GDM cohort data as part of a broader programme of research. Drs Eero Kajante (National Institute for Health & Welfare, Helsinki) and Marja Vaarasmaki (University Hospital, Olulu) are providing samples from the Finnish FinnGeDI cohort. Dr Ahmadi's (Surrey University) will be phenotyping the blood samples for one carbon metabolism and providing Nutritional Genomic expertise.
Impact 1) Vitamin B12 BJN article (PMID: 23628113) 2) Rank prize PhD studentship application (Nov 2013) 3) Methods for methylome analysis * Methylation pipeline: developed a QC & data analysis pipeline for genome-wide methylation, using serum OCM and Illumina 27k and 450k data * Mixed linear models for multivariate analysis OCM pathway phenotypes in relation to methylation 4) Grant application to Diabetes UK (PI T.Andrew, £401,490): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus" 5) Grant application to European Foundation for the Study of Diabetes (EFSD, PI T.Andrew, € 99994): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus"
Start Year 2013
 
Description The role of one carbon metabolism (OCM) in gestational (GDM) and type 2 diabetes (T2D) 
Organisation Seoul National University Hospital
Country Korea, Republic of 
Sector Hospitals 
PI Contribution I am investigating the hypothesis that mild maternal deficiencies in methyl donors and modulatory cofactors during pregnancy disrupt normal OCM function leading to aberrant changes in the methylome of the mother. To do this we will be using four existing data sets (TwinsUK; NFBC; FinnGEDI and NSU South Korea samples). We are currently generating methylation pilot data for NFBC, FinnGEDI and NSU South Korea samples using department laboratory facilities and department funds.
Collaborator Contribution Professor Philippe Froguel (Imperial), Professor Jarvelin (Imperial) and Dr Kwak (SNU, Seoul) are collecting GDM cohort data as part of a broader programme of research. Drs Eero Kajante (National Institute for Health & Welfare, Helsinki) and Marja Vaarasmaki (University Hospital, Olulu) are providing samples from the Finnish FinnGeDI cohort. Dr Ahmadi's (Surrey University) will be phenotyping the blood samples for one carbon metabolism and providing Nutritional Genomic expertise.
Impact 1) Vitamin B12 BJN article (PMID: 23628113) 2) Rank prize PhD studentship application (Nov 2013) 3) Methods for methylome analysis * Methylation pipeline: developed a QC & data analysis pipeline for genome-wide methylation, using serum OCM and Illumina 27k and 450k data * Mixed linear models for multivariate analysis OCM pathway phenotypes in relation to methylation 4) Grant application to Diabetes UK (PI T.Andrew, £401,490): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus" 5) Grant application to European Foundation for the Study of Diabetes (EFSD, PI T.Andrew, € 99994): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus"
Start Year 2013
 
Description The role of one carbon metabolism (OCM) in gestational (GDM) and type 2 diabetes (T2D) 
Organisation University of Surrey
Department Department of Nutritional Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I am investigating the hypothesis that mild maternal deficiencies in methyl donors and modulatory cofactors during pregnancy disrupt normal OCM function leading to aberrant changes in the methylome of the mother. To do this we will be using four existing data sets (TwinsUK; NFBC; FinnGEDI and NSU South Korea samples). We are currently generating methylation pilot data for NFBC, FinnGEDI and NSU South Korea samples using department laboratory facilities and department funds.
Collaborator Contribution Professor Philippe Froguel (Imperial), Professor Jarvelin (Imperial) and Dr Kwak (SNU, Seoul) are collecting GDM cohort data as part of a broader programme of research. Drs Eero Kajante (National Institute for Health & Welfare, Helsinki) and Marja Vaarasmaki (University Hospital, Olulu) are providing samples from the Finnish FinnGeDI cohort. Dr Ahmadi's (Surrey University) will be phenotyping the blood samples for one carbon metabolism and providing Nutritional Genomic expertise.
Impact 1) Vitamin B12 BJN article (PMID: 23628113) 2) Rank prize PhD studentship application (Nov 2013) 3) Methods for methylome analysis * Methylation pipeline: developed a QC & data analysis pipeline for genome-wide methylation, using serum OCM and Illumina 27k and 450k data * Mixed linear models for multivariate analysis OCM pathway phenotypes in relation to methylation 4) Grant application to Diabetes UK (PI T.Andrew, £401,490): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus" 5) Grant application to European Foundation for the Study of Diabetes (EFSD, PI T.Andrew, € 99994): Rejected "The role of one-carbon metabolism and epigenetics in the development of gestational diabetes mellitus"
Start Year 2013
 
Description Speaker, Gyllenberg Conference 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gyllenberg Conference 2017: "Childbearing, parenthood and outcomes of children - an interplay between psychological and biological factors"

Session: "Pregnancy and epigenetic programming". Talk title: "Epigenetic programming in gestational diabetes"
Toby Andrew, ICL
Year(s) Of Engagement Activity 2017
URL http://gyllenbergs.fi/stipendier-och-symposier/symposium/program
 
Description Twin Research Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Newsletter article explaining the aims of the new Mother-Offspring Mitochondria study launched in 2010 to recruit female twins and their children

Positive feedback and great interest in the study
Year(s) Of Engagement Activity 2010