Family-based investigation of the genetics and epigenetics of obesity in Qatar

Abstract

Single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and DNA methylation patterns play a role in the susceptibility to obesity. Despite the alarming figures of obesity in the Arab world, the genetics of obesity remain understudied in Arabs. Here, I recruited ten multigenerational Qatari families segregating obesity, and generated genome-wide SNP genotyping, whole genome sequencing and genome-wide methylation profiling data using Illumina platforms to investigate the role of rare mutations, CNVs, and DNA methylation patterns in the susceptibility to obesity. For the identification of obesity mutations, I first identified candidate obesity regions through linkage and run of homozygosity analyses, and then investigated these regions to detect potential deleterious mutations. These analyses highlighted putative rare variants for obesity risk at PCSK1, NMUR2, CLOCK and RETSAT. The functional impact of the PCSK1 mutation on obesity was previously demonstrated while for the other candidates further work is needed to confirm their impact. For the identification of common obesity CNVs, I performed a genome-wide CNV association analysis with BMI and identified a common duplication of ~5.6kb on 19p13.3 that associates with higher BMI. Moreover, I investigated large (≥500kb) rare CNVs and identified a ~618kb deletion on 16p11.2 in the most extremely obese subject in my samples, which confirms the contribution of the previously reported 16p11.2 deletions to severe obesity beyond European populations. For the identification of DNA methylation changes in obesity, I attempted to replicate known associations with BMI from large EWASs. I replicated the associations at ABCG1 (P-value=6.3X10-3) and CPT1A (P-value=8.7X10-5) and compared the effects observed to the TwinsUK cohort through a meta-analysis. I observed low heterogeneity between the two studies, and that increased the associations at ABCG1 (P-value=2.5x10-13) and CPT1A (P-value=1.9x10-15). In conclusion, the work represents the first genetic and epigenetic study of obesity in an Arab population. I replicated known genetic and epigenetic obesity susceptibility loci and also discovered novel potential loci.