David Altshuler

Department of Genetics and of Medicine, MGH
Program in Medical and Population Genetics, Broad Institute
Department of Molecular Biology
Center for Human Genetic Research
Massachusetts General Hospital
Richard B. Simches Research Center
185 Cambridge St., Room 6806
Boston, MA 02114
Tel: (617) 726-5940
Email: altshuler@molbio.mgh.harvard.edu
Web Page: The Altshuler Lab Page
Additional Page: http://www.broad.mit.edu/mpg
10 postdoctoral fellows, 4 graduate students, 1 medical student, 7 technicians

Despite remarkable progress in biomedical research, relatively little is known about the root causes that underlie individual risk of common diseases. Disease is typically caused by the combination of multiple genes and non-genetic factors; in this setting, traditional approaches of human genetics historically met with limited success. By combining information from human and population genetics, genomics and epidemiology we are searching for mutations contributing to common, polygenic diseases, and applying these tools to discover root causes of type 2 diabetes and other disorders in the human population.

One major focus of the lab is to characterize human genome sequence variation. Most human genetic diversity is attributable to common single nucleotide polymorphisms (SNPs), and we have helped create a map that now contains the vast majority of common SNPs in human populations. We have characterized how these SNPs are distributed across the genome and among population, and the origin of these patterns in human history and recombination. We have been deeply involved in the SNP Consortium, International HapMap Project, and 1000 Genomes Projects, and have contributed to study of copy number variation, tools and methods for genome-wide genotyping and statistical genetics methodologies to relate genotype and phenotype.

A second major focus is to apply these methods to understand type 2 diabetes and other diseases. Until recently such studies met with limited success, because the tools were not available to comprehensively search the genome. In the past year we and others have undertaken genome wide association studies that have resulted in the identification of over 150 novel genetic contributors to common diseases, with our group contributing to discover of 30 novel loci influencing risk of type 2 diabetes, cholesterol levels, rheumatoid arthritis, lupus, autism and other diseases.

Our long-term goal is to define the causal genes and mutations responsible for these genetic influences on type 2 diabetes, how they contribute to pathophysiology, and to apply this information to improve diagnosis, prevention, and treatment of disease.

References:

• Diabetes Genetics Initiative of Broad, Lund and Novartis. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (2007) vol. 316 (5829) pp. 1331-6.
  (Consortium publication, DA PI and senior, corresponding author)
• Zeggini et al. Meta-analysis of genome-wide association data and large- scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genetics (2008) pp.
  (Consortium publication, DA senior and corresponding author)
• Kathiresan et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature Genetics (2008) vol. 40 (2) pp. 189-97.
• Lyssenko et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. New England Journal of Medicine (2008) vol. 359 (21) pp. 2220-32.