Metabolic MAGIC

Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) reveal new genetic regions influencing blood glucose traits

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DOI: 10.1038/ng.2385
Associations between glycemic loci and T2D, HDL-cholesterol and triglycerides24, BMI22 and WHR23. Loci associated with the above traits (P<0.05) are highlighted. Those with positively correlated effect directions are coloured yellow, and negative correlations blue. Those which did not reach a q-value < 0.05 in FDR analyses are also marked.

Researchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.

The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.

“We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed. Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.”

Dr Claudia Langenberg Co-lead author from the Medical Research Council Epidemiology Unit, Cambridge

The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.

“Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits. We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.”

Dr Inga Prokopenko Co-lead author from the University of Oxford

The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.

“In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them. Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.

“What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.”

Dr Inês Barroso Co-lead author from the Wellcome Trust Sanger Institute

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Funding

A full list of funding can be found in the paper.

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