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Obesity and diabetes risk variants affect chromatin and gene regulation in the human brain


Obesity and type 2 diabetes (T2D) are complex diseases that are major public health concerns. Genetic variation contributes substantially to risk of developing obesity and T2D. Many previous studies on genetic factors influencing obesity (as measured by body mass index, or BMI) and T2D have focused on the effects of insulin resistance and glucose homeostasis in the pancreas and adipose tissue. A recent study demonstrated that genetic loci associated with BMI are enriched near genes expressed in the brain, but the effects of specific BMI variants on brain function is unknown. Furthermore, despite being a key regulator of energy intake as well as glucose homeostasis, the brain has not been a focus in the molecular genetics of T2D risk. In this work, we aimed to determine the effects of BMI and T2D variants on regulatory processes in the brain through computational analyses integrating genetic association data and brain epigenome data. We determined the enrichment of enhancers in various regions of the brain for BMI and T2D risk signals, identified BMI and T2D risk signals affecting gene expression in the brain, predicted the allelic effects of variants based on brain chromatin features, and prioritized specific BMI and T2D variants likely affecting brain regulation. These data together suggest that variants associated with BMI and T2D risk are broadly enriched for effects on regulatory processes in the brain. Together with pancreatic and adipose tissue, the brain should be considered when studying the molecular mechanisms of genetic variants affecting obesity and diabetes pathogenesis.

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