ABSTRACT
Introduction ............................................................................................................................................................................. 833 Rationale and Scope of Human Genetic Studies of Obesity ................................................................................................... 834
Evidence of Genetic Contributions in Human Obesity ...................................................................................................... 834 Genetic Architecture of Obesity ......................................................................................................................................... 834 Searching for Novel Genes of Small Effect ....................................................................................................................... 834
Current Findings of Human Genetic Studies .......................................................................................................................... 835 Monogenic Obesity and Obesity Syndromes ..................................................................................................................... 835 Common Obesity ............................................................................................................................................................... 835
Linkage Studies ............................................................................................................................................................. 835 QTLs Supported by Independent Replications ....................................................................................................................... 835
From QTLs to Genes .......................................................................................................................................................... 836 Follow-up and Fine Mapping Studies ........................................................................................................................... 836 Candidate Gene Studies................................................................................................................................................. 836 Association Studies ....................................................................................................................................................... 837 Genes Regulating Energy Intake ................................................................................................................................... 838 Melanocortin 4 Receptor ............................................................................................................................................... 838 Genes Regulating Energy Expenditure ......................................................................................................................... 838 Other Candidate Genes .................................................................................................................................................. 839
Nonreplication in Genetic Studies of Obesity ........................................................................................................................ 839 Potential Factors Accounting for Nonreplication ............................................................................................................... 839 Constructive Replication .................................................................................................................................................... 840
Future Directions .................................................................................................................................................................... 840 Nonmammalian Animal Models ........................................................................................................................................ 840 Pooling Data ....................................................................................................................................................................... 840 Meta-Analysis .................................................................................................................................................................... 840 Integration of Data within and Across Domains ................................................................................................................ 841
References ............................................................................................................................................................................... 841
Obesity has substantially increased in prevalence1 to the point where many believe the label “epidemic” is appropriate today.2 It is also among the leading causes of disability3 and a source of premature death.4 It is an established risk factor for cardiovascular disease, hypertension, diabetes, and certain types of cancer.5 Although the increase in the prevalence of obesity during the past two decades strongly suggests that environmental causes are involved,6 considerable variation exists both within and between populations in susceptibility to obesity that is likely to be genetic in origin. Populations also differ on the associations of obesity with disease risk, indicating genetic susceptibility to the effects of obesity. Thus, research on genetic susceptibility to obesity is important for a better understanding of the etiology and pathophysiology of obesity and associated diseases, for developing more effective means as well as for preventing and treating obesity.
