2nd Genetics Conference: Genetics in developing countries unique challenges and opportunities

摘要

The global disease pattern has shifted, with a more dominant prevalence of chronic disease such as type 2 diabetes, metabolic syndrome, cancer and cardiovascular diseases. The inter-population differences in the prevalence of these diseases support the role of genetics and biological factors in the aetiology of these diseases. Most of the candidate gene and genome-wide association studies are conducted on large cohorts of unrelated individuals. This has a major limitation due to the population subdivision and admixture that may lead to disease association even in the absence of linkage. Recent studies have focused on the use of extended family pedigrees in the study of heritability and genetic associations of complex traits like metabolic syndrome. Rapid developments in recent years with statistical methods have used family-based association designs to infer allelic association and linkage. In Oman, each individual is traditionally genealogically well-defined within their family tribe. In addition, Omani families have maintained homogeneity with extremely high levels of inbreeding due to the tradition of encouraging consanguineous marriages, mostly between first cousins. Therefore, Omani families in geographically-isolated regions like Nizwa provide a unique ideal population to provide the statistical power required to study complex diseases with confidence. The Oman Family Study consists of multigenerational pedigree subjects, descended from a small number of founders just a few generations ago, and with environmental homogeneity, restricted geographical distribution, detailed records, well-ascertained and validated pedigrees and a history of inbreeding. These families are used as a model to study the traits of metabolic syndrome: adiposity, hyperglycaemia, dyslipidaemia and hypertension. We have studied the heritability of these traits and the attributions of genetic loci for the adiponectin gene. Further analysis was done on genetic and familial clustering in non-alcoholic fatty liver disease as a complication of metabolic syndrome. With the emerging roles of exome sequencing and dark inheritance from rare variants, we identified clusters of inheritance units within one family, in which there were different segregations of type 2 diabetes. These units provide an excellent model to identify rare variants that contribute to the genetics of type 2 diabetes.