Human Genetics of Obesity and Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2D) and obesity already represent 2 of the most prominent risk factors for cardiovascular disease, and are destined to increase in importance given the global changes in lifestyle. Ten years have passed since the first round of genome-wide association studies for T2D and obesity. During this decade, we have witnessed remarkable developments in human genetics. We have graduated from the despair of candidate gene-based studies that generated few consistently replicated genotype-phenotype associations, to the excitement of an exponential harvest of loci robustly associated with medical outcomes through ever larger genome-wide association study meta-analyses. As well as discovering hundreds of loci, genome-wide association studies have provided transformative insights into the genetic architecture of T2D and other complex traits, highlighting the extent of polygenicity and the tiny effect sizes of many common risk alleles. Genome-wide association studies have also provided a critical starting point for discovering new biology relevant to these traits. Expectations are high that these discoveries will foster development of more effective strategies for intervention, through optimization of precision medicine approaches. In this article, we review current knowledge and provide suggestions for the next steps in genetic research for T2D and obesity. We focus on four areas relevant to precision medicine: genetic architecture, pharmacogenetics and other gene-environment interactions, mechanistic inference, and drug development. As we describe, the genetic architecture of complex traits has major implications for the prospects of precision medicine, rendering some anticipated approaches decidedly unrealistic. We highlight obstacles to the translation of human genetic findings into mechanism inference but are optimistic that, as these are overcome, there is untapped potential for novel drugs and more effective strategies for treating and preventing T2D and obesity.

Interplay of an Obesity-Based Genetic Risk Score with Dietary and Endocrine Factors on Insulin Resistance

“…Also, multiprotein network analyses revealed partial, but significant interactions between these proteins. These results support a link between genetics, obesity and glucose homeostasis, as reviewed elsewhere [35,36].…”

Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: a narrative review with emphasis on data from Europe

“…It is also noteworthy that, the Botnia Study in Finland (5810 individuals from 942 families) reported that the strongest T2DM heritability was identified in patients with onset age between 35 and 60 years [64]. Overall, there is now compelling evidence from studies with family and twin cohorts that genetic factors strongly impact on the T2DM risk, whilst a rapidly increasing body of large genomewide association studies (GWAS) has identified over 300 genetic variants which are strongly associated with T2DM [1,65]. However, due to the highly complex and polygenic T2DM nature, these explain only a fraction of the T2DM heritability, while the rest could be attributed to other factors (e.g.…”

Genetic architecture of cardiometabolic risks in people living with HIV

“…Genetic variants have been identified as significant predictors of traditional CVD risk factors including cardiometabolic traits and diseases, such as dyslipidemia and lipid levels (low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides) [ 9 , 10 ], obesity [ 11 , 12 ], type 2 diabetes mellitus (T2D) [ 13 ], and myocardial infarction (MI) [ 14 ] in the general population. CVD and related disorders have been demonstrated to have polygenic modes of inheritance, meaning that common genetic variants with small effect sizes located in multiple genes contribute to variability in disease or trait risk [ 15 , 16 ].…”