Obesity is a highly heritable and genetically heterogeneous disorder. Reports have shown that the number of obese individuals will project to worldwide high levels in the next couple of years. In this study I tried to identify missing heritability in obesity by looking at extreme phenotypes that are likely to be enriched with rare variants. This will improve the power of their discovery by identifying the loci that may reveal more rare variants. I employed the strategy of using 'extreme' sub-groups of obese patients to identify known and novel loci for obesity in the population of Saudi Arabia. Two different approaches were used. The first was to investigate the contribution of copy number variation (CNV) to obesity in Saudi adults/children that have mental retardation, dysmorphic features and obesity or morbid obesity: for adults, this was defined as body mass index (BMI) ≥ 30 and ≥ 40 kg.m-2 respectively; for children, BMI respectively above the 90th and 97th percentiles. The second was to look for known and new Mendelian forms of obesity in multiplex consanguineous families in children that have extreme obesity (z-BMI above 97th centile). Genome-wide genotyping was performed using the Affymetrix SNP 6.0 Chip platform (AFFYMETRIX, Santa Clara, CA) to discover novel copy number variants using PennCNV. I also used a whole exome sequencing in combination with the detection of runs of homozygosity (ROH) and linkage analysis to screen for known monogenic and possibly novel obesity genes in multiplex Saudi consanguineous families. Two rare obesity causing CNVs were identified from this study. The first was the known chromosome 16p11.2 heterozygous deletion that has been previously shown to be associated with obesity. The second is a novel rare homozygous CNV deletion that encompasses TRIB3 gene that has been previously associated with diabetes. A chromosome 16p11.2 duplication was also found within the known chromosome 16p11.2 deletion. This duplication helped in narrowing down the obesity-causing region within the chromosome 16p11.2 deletion region. Additionally, rare CNV duplication with a size above 500kb were found to be slightly enriched (P=0.017) in cases versus controls. In this study we have also shown the presence of a novel homozygous missense MC4R mutation in combination with a heterozygous missense LPIN3 mutation within the same family. The carriers of MC4R mutation have developed an extreme obesity phenotype on the other hand the carriers of LPIN3 mutation also carried a heterozygous MC4R mutation and were found to be lean suggesting a reverse effect of the LPIN3 gene on the development of obesity. In another family a heterozygous deletion was found in a possibly novel obesity-causing gene CHRNA7. This gene mainly mediates fast signalling transmission at synapses and is found particularly in the lateral hypothalamus that regulates food appetite. In summary, this thesis presents multiple novel CNVs and genes that are found as promising obesity causing variants. It is hoped that the work from this thesis may contribute towards elucidation of the role of CNVs and novel genes in the development of obesity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:666472 |
| Date | January 2013 |
| Creators | Al-Saud, Haya |
| Contributors | Froguel, Philippe; Falchi, Mario |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/25989 |
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