Areas of Focus

One of the fundamental challenges in biomedicine is to discover, understand and ultimately address the root causes underlying common diseases. To address this challenge, the Altshuler laboratory at the Broad Institute of Harvard and MIT and Massachusetts General Hospital uses genetic mapping in human populations. At the core of the Altshuler laboratory’s approach is the view that genetic mapping is a tool to uncover novel genes – and thereby biological processes — that play fundamental roles in the biology of human disease. The long term goal is that the discovery of such genes and biological processes will, in the long run, offer a foundation for fundamentally new approaches to diagnosis, treatment, and prevention.

The Altshuler laboratory focuses on two main goals: creating generally useful tools and methods needed to discover and study genes underlying risk of human disease, and to apply these methods to the study of Type 2 diabetes mellitus (T2D). An estimated 23.6 million people in the United States have T2D and that number is rising rapidly. Type 2 diabetes is characterized by hyperglycemia and associated with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular), and neuropathic (ie, autonomic, peripheral) complications – but the underlying pathways and even tissues responsible for human diabetes remain unclear.

Over its ten-year history, the Altshuler laboratory has developed the tools to make it possible to find genes for complex diseases, and apply those tools to diabetes and other diseases. These efforts have included leadership in the SNP Consortium, HapMap Project, and 1000 Genomes Projects. Looking forward, the next step is to develop methods to study the function of newly identified genes and SNPs related to type 2 diabetes and open new paths to disease therapeutics.

The laboratory is run as a close partnership with the laboratory of Mark Daly, also at Massachusetts General Hospital and Broad Institute. In addition, the lab has benefited from long-term and sustained collaboration with Leif Groop of Lund University in Sweden, as well as with Mark McCarthy (Oxford), Mike Boehnke (Michigan) and colleagues in the DIAGRAM Consortium.

Major research areas in the Altshuler lab include:

I. Developing methods for genetic mapping in complex human diseases: human population genetics, construction of the public database of common genetic variants, laboratory and analytical methods

The Altshuler laboratory has contributed to the world-wide effort to develop the understcaanding, data, laboratory tools and analytical methods required to systematically study the role of human genetic variation in disease. From 1999-2001 the SNP Consortium set out to discover common genetic variants and produce a public resource of single nucleotide polymorphisms (SNPs) in the human genome. Starting in 2002, the International HapMap Project characterized SNP frequencies in 1,300 samples across the human genome in 11 global populations. Whereas the SNP Consortium focused on individual SNPs, the HapMap Project searches for SNP combinations called haplotypes that are inherited together. Most recently, the 1000 Genomes Project, benefiting from rapid advances in sequencing technology, is on a path to sequence the genomes from 2,500 people representing 27 populations. All data from these projects is freely available in the public domain, and has been a foundation for human genetic research.

To accomplish these large-scale projects, members of the laboratory and collaborators at Broad have contributed to the development of the necessary tools and methods for gene discovery, including arrays for genotyping, methods for studying copy number variation, sequencing to discover variation, and analytical methods such as Birdsuite, HaploView and the Genome Analysis Tool Kit (GATK).

II. Finding Genes for Type 2 Diabetes

In 2000, Altshuler, Groop and colleagues published the first strong evidence for a reproducible association of a common variant associated with type 2 diabetes. From this early study, to recent meta-analysis of genome wide association studies reporting over three dozen such findings, the Altshuler laboratory is committed to discovering robust, reproducible associations with T2D as a key step towards gene discovery and new biological knowledge. With collaborators, Altshuler laboratory members have discovered over 35 different regions of the genome involved in T2D, and contributed to discovery of others associated with related traits such as fasting glucose, cholesterol levels, myocardial infarction, and others.

Today, the laboratory is both following up these genes localized by genome wide association studies, and discovering new genes by the study of rare variants yet to be identified. Examples of the former include large-scale sequencing of exons from T2D gene regions in large cohorts from the extremes of risk for T2D, and sequencing of such exons in multiethnic samples with T2D (in collaboration with the T2D-GENES Project of NIDDK). The lab is contributing to genome-wide resequencing and genotyping in 2,500 samples with T2D and controls as part of a Grand Opportunities award, with co-funding from the Wellcome Trust, in collaboration Groop, McCarthy, Boehnke and their colleagues in Lund, UK-T2D and the FUSION study, and in samples from Mexican and Mexcian American populations in collaboration with scientists in Mexico and USC as part of the SIGMA Project.

The hope is that in the next five years, as these and other projects reach fruition, researchers will gain from a much more complete understanding of the role that genetic variation plays in T2D – and, it is hoped, of the biological pathways that can lead to this common disease.

III. Functional Studies of Type 2 Diabetes Genes

The ultimate goal of the work being done at the Altshuler laboratory is to use human genetics to reveal novel biological mechanisms that inform understanding of T2D, and ultimately its diagnosis, prevention and treatment. Over the last three years, as GWAS studies have succeeded in gene localization, the lab has developed a new studying those genes for their molecular functions, roles in relevant cell models, and physiology in both mice and humans.

Over the past five years, the rate-limiting step in human genetics has moved from localizing genes for common disease to identifying the causal genes and mutations, and understanding their function. While three dozen new loci for T2D have been found, the functions of these genes remains unknown. Members of the Altshuler laboratory are dedicated to pursuing this new area of genetics research with the aim of contributing to improved medical care for those with or at risk of developing type 2 diabetes.