An integrated atlas of adiposity traits in Mexican adults

In recent decades, the prevalence of obesity and diabetes has increased substantially in Latin-America, and the worldwide risks of death due to overweight and obesity have doubled. Obesity and various adiposity traits are of clinical interest due to their causal link to cardiometabolic diseases and premature death. However, abdominal and gluteofemoral fat have opposing associations with cardiometabolic disease risk, as do fat and lean mass. Whether these inverse associations of different adiposity traits with favourable cardio-metabolic risk factors and cause-specific mortality share common genetically determined pathways is unclear. Furthermore, populations with dominant Indigenous ancestry may have a more hazardous metabolic risk profile compared with European populations. However, there is limited evidence on the genetic architecture of various adiposity traits and pathways related to disease-specific risk in such populations.  

The Mexico City Prospective Study (MCPS) is a prospective cohort study of 150,000 participants with socio-demographic and lifestyle characteristics, medication and disease history, biological characteristics (including genetics and NMR-metabolomics), and 20 years of follow-up for cause-specific mortality. It provides a unique platform for genetic discovery studies of adipose traits in a contemporary admixed Hispanic population with a high degree of relatedness. 

This key aims of the project are to:

1. Characterize the genetic architecture of adiposity traits (e.g. BMI, fat and lean mass, WHR, hip and waist circumferences) in an admixed Mexican cohort through genome-wide association analyses. This would include resolving conditionally independent associations, identifying novel variants that may be segregating at higher frequencies in Indigenous American populations, and genetic fine mapping.
2. Characterise the full-spectrum of metabolomic features of the observed adiposity traits through phenome-wide association analyses.
3. Incorporate tissue- and cell-specific epigenomic annotations to resolve the molecular basis of genetic associations with adiposity through genome-wide enrichment analyses and molecular QTL colocalization analyses at trait-associated loci in order to distinguish different physiological and pathological characteristics of adiposity.