Altshuler, David M., MD, PhD
Testing low-frequency SNPs and private loss of function variants for contributions to the regulation of glucose and insulin in humans
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Epidemiology, Genetics, Genetics\Type 2 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
Over the last decade, data from the Human Genome Project and advances in technology have made it possible for researchers to discover common genetic risk factors contributing to risk of type 2 diabetes (T2D) and the regulation of glucose and insulin. While these studies have been successful in providing new clues about the biological basis of T2D, two current limitations are: (1) it remains difficult to pinpoint the specific genes and mutations responsible, and (2) that much of the inherited risk of T2D remains to be found. To move beyond these limitations human geneticists are now probing the roles of lower frequency genetic variation that was too rare to have been identified in the first such wave of studies.
The current proposal aims to develop statistical methods, and then to apply these methods to DNA sequencing data and clinical data collected in human populations. Specifically, we will apply these new methods to study two different study designs, comparing and contrasting the results. One study is a population-based design of unrelated individuals selected based on extremes of risk for diabetes. The second study involves DNA sequencing in large families, allowing individual rare mutations to be traced (for their effect on glucose and insulin) across the generations. If successful, the proposed research will provide new methods for genetic studies of T2D, pinpoint specific genes influencing insulin and glucose, and increase the proportion of the inheritance of T2D that has been explained.
Mentor: David M. Altshuler Postdoctoral Fellow: Alisa Knodle Manning, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Over the last five years studies of genome sequence variation in large cohorts has resulted in the discovery of many common genetic variants that are associated with the risk of type 2 diabetes (T2D) and diabetes-related traits such as fasting glucose levels. While these studies have been successful in localizing genomic regions that contribute to the biological basis of T2D, two current limitations are: (1) it remains difficult to pinpoint the specific genes and mutations responsible for each common variant association, and (2) a substantial fraction of the inherited risk of T2D remains as yet unexplained. The study of rare genetic variants offers great promise in attempting to overcome these limitations. Advances in technology for DNA sequencing now allow the comprehensive interrogation of the genetic variation underlying susceptibility to T2D. Characterizing the entire DNA sequence of a large number of individuals allows the study of all genetic mutations, not only those that are common, but also those that are rare in the population, and even private to an individual or their immediate family members. However, many scientific and analytical challenges need to be solved before the potential of this new data can be realized.
This project aims to develop new statistical methods, and to apply these methods to DNA sequencing data and clinical data collected in human populations with T2D. Specifically, we will apply these new methods to study two different study designs, comparing and contrasting the results. One study is a population-based design of unrelated individuals selected based on extremes of risk for T2D. The second involves DNA sequencing in large families, allowing individual rare mutations to be traced (for their effect on glucose and insulin) across the generations. If successful, this project will provide new methods for genetic studies of T2D, pinpoint specific genes and mutations influencing T2D, insulin and glucose levels, and increase the proportion of the inheritance of T2D that has been explained.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The effort to discover new and improved methods for diagnosis, prevention and treatment of diabetes requires a deep understanding of the biological underpinnings that lead to the disease, and its complications. Thanks to international efforts such as the Human Genome, HapMap and 1000 Genomes Projects, we know in great detail the landscape of human genetic variation, i.e. the common genetic changes that are present in all the human populations. Studies have been performed to investigate how these common genetic changes increase risk for T2D and modify glucose and insulin regulation. These studies have provided many new clues about the biology of T2D. However, in order to understand these clues, we need more detailed data than studies of common variants provide. Sequencing technology has undergone a remarkable advancement, such that it is now practical to measure DNA sequence variants that exist at a very low frequency in the population, and even those that are private to an individual or her family.
Statistical methods need to be developed for us to understand the extent to which these low frequency and private variations influence the risk of diabetes. We will apply these methods to study individuals who have multiple risk factors for T2D (they are obese, and elderly), but whose blood sugar remains normal. Such genetic variants could inform strategies to protect "at risk" individuals from diabetes. We will also apply these methods to a collection of multigenerational families in whom we can observe private genetic changes in multiple people in the same family. We will use these data to ask whether there exist private genetic changes that will have a strong effect on diabetes-related traits. If successful, our project will provide new statistical methods that can be generally useful in the field of diabetes research, and insights that could guide design and interpretation of future diabetes genetic studies. More importantly, if we succeed in identifying low frequency and private genetic variants, we will contribute to understanding the pathophysiology of T2D, with the potential to inform the design of new approaches to diagnose, prevent and treat T2D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My clinical specialty is diabetes and endocrinology, and the vast majority of patients I cared for suffered with the challenges of type 2 diabetes (T2D). It was impossible not to be struck by the fact that many of their family members were burdened with the same disease — and careful epidemiological studies have shown that the risk of having T2D is two to four fold higher in the relatives of patients with T2D than in the general population. When we started this research, in only a tiny fraction of cases could science explain the specific genes and mutations that explain why the disease runs in families. More importantly, our current approaches to prevent and treat diabetes are inadequate. While they no doubt help patients with T2D, we lack treatments that arrest, or even better reverse, the progression of T2D. It is my conviction that the effort to develop new approaches to prevention and treatment must be based upon a deep and solid foundation of understanding of the biological processes that underlie T2D risk in human populations.
Human genetic research offers one approach to discovering those biological processes, and how their altered function puts one at increased or decreased risk of T2D. The specific research award will have three main goals. First, it will support the development of a promising young researcher (Alisa Manning) who has already made important contributions to diabetes genetics research. Second, it will allow Alisa to develop new statistical methods that will advance diabetes research, making it possible to benefit from advances in the technologies for DNA sequencing. Third, it has the potential to discover new genes that contribute to T2D.
In what direction do you see the future of diabetes research going?
One of the major unmet needs in diabetes research is to understand the biological processes that underlie T2D susceptibility and resistance in the human population. Efforts to develop new approaches to prevention and treatments are fundamentally limited until we obtain a deep understanding of these systems, how they function in health and how they go wrong in disease. Human genetics is one method that can be applied to advance these goals, identifying underlying biological processes in patients through the study of "experiments of nature" – DNA variants that arose at random, and influence an individual’s risk and pattern of disease.
In the coming years, thanks to new technologies and methods, we will develop a systematic and extensive "genetic anatomy" of T2D. Just as the anatomy of the body is a foundation for medicine and surgery, so the "genetic anatomy" will be a foundation for the molecular understanding and treatment of disease. In the long run, this holds much promise. However, many challenges remain. We must develop methods to understand the function of new genes found through genetics as playing a role in diabetes, and methods to understand how the mutations in these genes lead to diabetes risk. We must develop new animal and cell models that faithfully represent these observations made in patients, and yet provide more tractable systems for experimental research. And, finally, we must develop new approaches to diagnosis, prevention and therapy that restore normal function to these systems, and protect patients and their families from the burden of T2D.
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