Telomeres, the protective caps at the end of chromosomes, shorten with every cell division. Dysfunction of the maternally inherited mitochondrial genome leads to oxidative stress, and the genome is copy-number variable, with more copies in tissues with higher energy requirements. Damage to both telomeric and mitochondrial DNA contributes to cell signalling via p53-mediated pathways, leading to cellular senescence and apoptosis (programmed cell death). Telomere shortening, and mitochondrial dysfunction are therefore known mechanisms of cellular ageing, and recent studies have suggested that mtDNA copy number and leucocyte telomere length (LTL) may be related (Passos et al., Sahin et al.). Telomere length is related to diseases involving accelerated ageing, including those in which inflammation, oxidative stress and disordered cell turnover have been proposed as important: such diseases are cardiovascular disease (Haycock et al.), respiratory disease (Albrecht et al.), and putatively, psychosis (Nieratschker et al). Whilst classical risk factors related to these diseases may also associate with LTL/mtDNA copy number, inflammation may act as a global risk factor for them all, and LTL/mtDNA copy number may mediate these associations (Masi et al.).

We propose to measure average LTL in ALSPAC mothers and children using qPCR, and to perform downstream analyses on the dataset generated. By studying young people, we may analyse telomere length and mtDNA copy number as mediators of associations between early risk factors of chronic disease (e.g. growth trajectories (Barker, 2003), and inflammation) and outcomes, before a large burden of classical risk factors are accrued. Genomic control of these traits, including imprinting effects, will be assessed using mother-child pairs. As well as assessing prior hypotheses, we propose to perform phenome scans of LTL and mtDNA copy number. Ultimately, this proposal aims to understand the relationships between LTL and mtDNA copy number, and their contribution, individual or combined, to senescence.

Hypotheses:

1.Average telomere length will be shorter in ALSPAC mothers compared to offspring, and children's average telomere length will decrease with age.

2.SNPs that may be associated with telomere length may have small effect sizes. Controlling for parent-of-origin effects may unmask these effects.

3.LTL will correlate with phenotypes of accelerated ageing, inflammation or oxidative stress.

4.Telomere length will be related to foetal and childhood growth, biomarkers of growth (GHBP/IGF1) and pubertal stage (as measured by Tanner stage/testosterone).

5.Telomere length will correlate positively with mtDNA copy number.

6.Given the fundamental role of telomeric and mitochondrial dysfunction in senescence, as-of-yet unidentified phenotypes will be associated with these 'genetic phenotypes'.

Aims:

1.To assess average LTL in the Avon Longitudinal Study of Parents and Children.

2.To perform a genome-wide association study of LTL/mtDNA copy number in children, and to assess mother-offspring pairs for parent-of-origin effects.

3.To study telomere length and mtDNA copy number in relation to diseases involving accelerated ageing processes (cardiovascular disease, COPD/asthma, and putatively, psychosis/depression), risk factors for these diseases (e.g. classical CVD risk factors, smoking, inflammation), and intermediate disease phenotypes (e.g. spirometry, psychosis-like symptoms).

a.To refine these associations in individuals with extreme phenotypes.

4.To investigate LTL changes in relation to foetal and childhood growth and puberty.

5.To study the association between telomere length and mtDNA copy number.

6.To undertake phenome scans of LTL/mtDNA copy number (and genetic variants determining them) to determine novel associations.