Excessive weight can have a severe impact on health as well as creating a significant economic burden. Obesity is reaching epidemic proportions, but the mode of inheritance of obesity and its underlying complexity remains largely unresolved. Thus, the aim of this research project was to provide a further understanding of this condition in an Australian adolescent and adult population. Qualitative and quantitative differences in genetic and environmental influences affecting body mass index (BMI) in males and females, during development were examined. Structural equation models were fitted to longitudinal data collected at ages twelve, fourteen and sixteen from 470 monozygotic (MZ) twin pairs and 673 dizygotic (DZ) twin pairs. In addition, it is generally known that some genetic differences are only exposed in the presence of certain environmental stressors, such as the effects of parity and age on post-partum obesity. Therefore, models were fitted to data from 11, 915 female twins and their sisters from whom reproductive history was available in order to assess the changes in magnitude of genetic and environmental variation in female BMI due to these variables. To detect quantitative trait loci (QTLs) influencing adolescent BMI, up to 1133 highly polymorphic microsatellite markers were typed across the genome in a sub-sample of adolescent twins, their parents and siblings. Because gene mutations for some genetic disorders affecting body weight may manifest during childhood, univariate linkage analysis were applied to test for linkage between marker loci and BMI at twelve, fourteen and sixteen across the genome. Additionally, genes involved in pathways regulating body weight may operate differently in men and women. Therefore, a genome-wide linkage analysis allowing for sex difference in linkage patterns was performed in order to identify QTLs influencing BMI which may differ between adult males and females. Genetic factors contributed strongly to BMI in adolescent twins, accounting for approximately ninety percent of phenotypic variation at twelve, fourteen and sixteen years of age. In addition, the majority of this genetic variance was transmitted from age twelve to ages fourteen and sixteen. Sex differences in the size of genetic innovations at ages fourteen and sixteen suggest that the genetic variation in weight regulation is different in males and females. The presence of environmental influences in males and females may reflect the effects of lifestyle activities during adolescents such as severe exercise and diet regimes. Structural equation models exploring the effects of parity and age on female BMI revealed that genes become more important in the variation in BMI as parity increases. The ability to retain weight for lactation and support for foetal growth possibly reflects an evolutionary advantage in times when it was a necessary condition of survival. Unique environmental influences were also important in the variation female BMI across parity and age, possibly reflecting lifestyle factors and individual responses to social attitudes towards weight gain. Genome-wide linkage analysis in adolescent twins revealed strong evidence for linkage on chromosome 14q12-q13 at age fourteen (logarithm of odds (LOD) = 3.71, p = 0.000018) and suggestive linkage in the same region in sixteen year old twins (LOD = 2.46, p = 0.00038) which has been previously implicated in adiponectin in Northern Europeans. Chromosome 6p12 yielded a suggestive LOD = 2.95 (p = 0.00012) which harboured a known gene responsible for rebound weight gain. Evidence for replication (LOD = 1) at other areas of the genome was also observed, including 1, 4, 10, 11, 13 and 20, which have been previously associated with obesity in other studies, being LEPR, UCP1, OB10P, BMIQ3 and BMIQ6, respectively, although we did not have time to genotype these to test for association in our samples. The use of a genome-wide linkage analysis allowing for sex difference in linkage patterns identified areas on chromosome 8 and 20, providing us with evidence that some of the genes responsible for BMI may have different effects in adult men and women. Results revealed a suggestive linkage peak (-log10p = 3.13; equivalent to LOD = 2.19, p = 0.000741) at 12q24 (-log10p = 3.02; equivalent to LOD = 2.08, p = 0.000955), that has been implicated in weight in a wide range of populations and where non-insulin-dependent diabetes mellitus, a consequence of obesity, has also been mapped. We also identified many peaks near the threshold for replicating an existing finding (-log10p = 2; equivalent to LOD = 1.18, p = 0.01) in many areas across the genome that are within regions previously identified by other studies, as well as in locations that harbour genes known to influence weight regulation. Finally, the significances of these results are discussed and future directions are considered including association analysis on single nucleotide polymorphisms (SNPs) across six candidate genes: LEPR, GNβ3, UCP2, UCP3, FTO and INSIG2 which have previously been associated with obesity or BMI. We typed seventeen SNPs and performed analyses in a sample of 4494 MZ and DZ twins. Significant association was found for rs9939609 (A/T polymorphism) of the FTO gene. In our data, each additional copy of the rs9939609 A allele increased mean BMI by approximately 0.14kg/m2 in an apparent additive manner, comparable with recent published results from population-based studies in white European children and adults.
| Identifer | oai:union.ndltd.org:ADTP/252441 |
| Creators | Belinda Cornes |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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