Genome-wide association studies (GWAS) have recently shown their potential in the discovery of genetic factors associated with common diseases. Genetic association studies including GWAS can be used to explore the role of genetic variation underlying the associations between birth size, growth and metabolic phenotypes such as adiposity, lipid and glucose levels and hypertension. The aim of this thesis was to 1) review methods for genetic association analyses, 2) fit models for growth measurements, and to investigate prenatal predictors of early growth and associations between early growth and adult metabolic phenotypes, and 3) to examine genetic variation underlying birth size, postnatal growth and adult metabolic phenotypes. The primary study population comprised Northern Finland Birth Cohort 1966 (NFBC1966) members with DNA (N=5,753). Phenotypes included height/weight throughout childhood and adult metabolic phenotypes. Parametric growth curves were fitted to obtain peak growth velocities and timings of peaks and nadirs. These growth parameters were analysed in relation to birth and adult metabolic phenotypes and genetic variation. Meta-analyses of GWAS included samples with similar data. Shorter babies grew faster in length immediately after birth. Faster postnatal growth was associated with higher adult blood pressure and adiposity, independently of birth weight. Risk alleles at type 2 diabetes locus (ADCY5) were inversely associated with birth weight in a GWAS meta-analysis. Variants near BMI candidate genes LEPR and PCSK1 were associated with infant BMI. The established obesity locus (FTO) had a strong association with BMI after age 5 years. A GWAS meta-analysis of metabolic phenotypes suggested distinct pathways leading to the development of a metabolic syndrome. Adult height variants were associated with infant and/or pubertal height growth. The results suggest that foetal programming, growth acceleration and genetic susceptibility contribute to the associations between growth and metabolic phenotypes, and that some of the genetic effects are age-dependent.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:530233 |
| Date | January 2011 |
| Creators | Sovio, Ulla Maarit Hannele |
| Contributors | Järvelin, Marjo-Riitta ; Whittaker, John ; Molitor, John |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/6396 |
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