BADERC-David Altshuler

David Altshuler, M.D., Ph.D.

Human genetic variation and the genetic basis of type 2 diabetes in humans

Research in the Altshuler Lab focuses on two intertwined goals: (a) to characterize and catalogue patterns of human genetic variation, and (b) using this information, to dissect the genetic contribution to common human diseases. These studies have contributed to the creation of a publicly available, genome-wide collection of common variants to fuel association studies, understanding of haplotype patterns and their role in human genetic research, and knowledge of genes and pathways involved in common endocrine disorders such as type 2 diabetes.

To characterize and catalogue patterns of human genetic variation: We performed the first large-scale study of common sequence variation in the coding regions of human genomes (Cargil, Altshuler et al, Nature Genetics, 1999), and developed methods to discover and characterize genome-wide patterns of human genetic variation (Altshuler et al, Nature, 2000). We helped lead an international effort to create and analyze the first genome-wide map of single nucleotide polymorphisms in the human genome, we published in the “Human Genome” issue of Nature (February, 2001).

We performed one of the first large-scale characterizations of haplotype structure in the human genome, finding that the human genome can be parsed into haplotype “blocks”, regions over which there has been limited recombination in the history of the current population (Gabriel et al, Science, 2001). Within each such block, only a few ancestral alleles explain most of the genetic variation in the population.

We developed a novel population genetic framework, and using data generated in the course of building the SNP map, characterized the genealogical and biological forces shaping human genetic variation (Reich et al, Nat. Genet., 2001). This work indicated that hotspots of recombination are likely a general feature shaping human genetic variation. In October 2002 we received an $8.9 million grant from the NIH for construction and analysis of the Haplotype Map of the Human Genome.

Identify genes for common human diseases: The other main focus of the laboratory is to develop and perform association studies to understand the inherited contribution to disease risk. (Many of these studies are in collaboration with Joel Hirschhorn, Assistant Professor of Genetics at HMS and Children’s Hospital.)

Through a longstanding collaboration with Leif Groop (Lund U.), we study genetic risk factors in over 5,000 DNA well characterized samples collected from patients with type 2 diabetes and related metabolic disorders. We are performing genetic association studies, with candidates based on (a) biological pathway, (b) family-based linkage studies, and (c) expression profiling.

We were among the first to demonstrate that PPARG Pro12Ala is the first reproducible genetic risk factor for type 2 diabetes (Altshuler et al, Nature Genetics, 2000), and have followed this by creating a comprehensive haplotype map of this gene. Based on PPARG’s role as a drug target for hypoglycemic medication, we have confirmed and extended the previously described association of genetic variation in the sulfonylurea receptor/Kir6.2 complex and AMPKinase in type 2 diabetes (Florez et al, in preparation).

We are studying genes previously identified as playing a role in monogenic forms of type 2 diabetes, and biological and expression candidates that underlie linkage peaks for type 2 diabetes. We have performed expression analysis of biopsies from patients with type 2 DM, developing a novel method for analysis of microarray data (Mootha et al,, Nature Genetics, 2003). This recent study has highlighted the possible role of disorders of mitochondrial respiration on type 2 DM, and we are performing association studies with members of this biochemical and regulatory pathway.

References:

1. Cargill, M., Altshuler, D, et. al. (1999) “Characterization of Single Nucleotide Polymorphisms in Coding Regions of Human Genes." Nature Genetics 22, 231-238.

*These authors contributed equally to this work.

2. Altshuler, D., Hirschhorn, J., et al. (2000)“The common PPAR gamma Pro12Ala polymorphism is associated with decreased risk of type II diabetes." Nature Genetics 26:76-80. These authors contributed equally to this work. Altshuler, D., et al. (2000)“An SNP map of the human genome generated by reduced representation shotgun sequencing.” Nature 407:513-516

3. The International SNP Map Working Group: Sachidanandam, R, Weissman, D, Schmidt, SC, Kakol, JK, Stein, LD, Marth G Sherry, D, Mullikin, JC, Mortimore, BJ, Willey, D, Hunt, SE, Cole, CG, Coggill, PC, Rice, CM, Ning, Z, Rogers, J, Bentley, DR, Kwok, P-Y, Mardis, ER, Yeh, RT, Schultz, B, Cook, L, Davenport, R, Dante, R, Fulton, L, Waterston, RH, McPherson, JD, Gilman, B, Schaffner, SF, Van Etten, WJ, Reich, DE, Higgins, J, Blumenstiel, B, Baldwin, J, Stange-Thomann, N, Zody, MC, Linton, LM, Lander, ES, and Altshuler, D, (2001)“A map of human genome sequence variation containing 1.4 million SNPs,” Nature 409:928-933.

4. Engert JC, Vohl MC, Williams SM, Lepage P, Loredo-Osti JC, Faith J, Dore C, Renaud Y, Burtt NP, Villeneuve A, Hirschhorn JN, Altshuler D, Groop LC, Despres JP, Gaudet D, Hudson TJ. (2002) “5' flanking variants of resistin are associated with obesity.” Diabetes. 51,1629-34.

5. Gabriel1 SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel1 B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, and Altshuler, D. (2002) “The structure of haplotypes in the human genome,” Science 296, 2225-2229 (doi;10.1126/science.1069424)

6. Schaffner, S.F., Daly, M.J., McVean, G., Mullikin, J.C., Higgins, J.M, Richter, D.J., Lander, E.S., Altshuler, D. (2002) “Human genome sequence variation and the influence of gene history, mutation and recombination.” Nature Genetics 32(1),135-42.

7. Sabeti, P., Reich,D., Higgins,J., Levine,H., Richter,D., Schaffner,S., Gabriel,S., Platko,J., Patterson,N., McDonald,G., Ackerman,H., Campbell,S., Altshuler,D., Cooper,R., Kwiatkowski,D., Ward,R. and Lander,E.S. (2002) “Detecting recent positive selection in the human genome from haplotype structure” Nature 419:832–837 (doi:10.1038/nature01140)

8. Cowles, C., Hirschhorn,J.N., Altshuler,D., and Lander,E.S. (2002) “Detection of regulatory polymorphism in mouse genes”. Nature Genetics 32:432–437 (doi:10.1038/ng992)

9. Reich, DE, Gabriel, SB, and Altshuler, D, (2003) “Quality and Completeness of SNP Databases” (2003), Nature Genetics 33 457-458 (doi:10.1038/ng1133)

10. Mootha, VK, Lindgren, CM, Eriksson, KF, Subramanian, A., Sihag, M, Lehar, J Puigserver, P., Carlsson, E, Ridderstråle, M, Laurila, E, Daly, MJ, Patterson, P, Mesirov, JP, Golub, TR, Tamayo, P., Spiegelman, B. Lander, ES, Hirschhorn, JN, Altshuler, D., and Groop, LC (2003) “PGC-1a Responsive Genes Involved in Oxidative Phosphorylation are Coordinately Downregulated in Human Diabetes”, Nature Genetics 2003 34:267-273.

11. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004 May;53(5):1360-8.

12. Altshuler JS, Altshuler D. Organizational challenges in clinical genomic research. Nature. 2004 May 27;429(6990):478-81.






			David Altshuler, M.D., Ph.D. Human genetic variation and the genetic basis of type 2 diabetes in humans Research in the Altshuler Lab focuses on two intertwined goals: (a) to characterize and catalogue patterns of human genetic variation, and (b) using this information, to dissect the genetic contribution to common human diseases. These studies have contributed to the creation of a publicly available, genome-wide collection of common variants to fuel association studies, understanding of haplotype patterns and their role in human genetic research, and knowledge of genes and pathways involved in common endocrine disorders such as type 2 diabetes. To characterize and catalogue patterns of human genetic variation: We performed the first large-scale study of common sequence variation in the coding regions of human genomes (Cargil, Altshuler et al, Nature Genetics, 1999), and developed methods to discover and characterize genome-wide patterns of human genetic variation (Altshuler et al, Nature, 2000). We helped lead an international effort to create and analyze the first genome-wide map of single nucleotide polymorphisms in the human genome, we published in the “Human Genome” issue of Nature (February, 2001). We performed one of the first large-scale characterizations of haplotype structure in the human genome, finding that the human genome can be parsed into haplotype “blocks”, regions over which there has been limited recombination in the history of the current population (Gabriel et al, Science, 2001). Within each such block, only a few ancestral alleles explain most of the genetic variation in the population. We developed a novel population genetic framework, and using data generated in the course of building the SNP map, characterized the genealogical and biological forces shaping human genetic variation (Reich et al, Nat. Genet., 2001). This work indicated that hotspots of recombination are likely a general feature shaping human genetic variation. In October 2002 we received an $8.9 million grant from the NIH for construction and analysis of the Haplotype Map of the Human Genome. Identify genes for common human diseases: The other main focus of the laboratory is to develop and perform association studies to understand the inherited contribution to disease risk. (Many of these studies are in collaboration with Joel Hirschhorn, Assistant Professor of Genetics at HMS and Children’s Hospital.) Through a longstanding collaboration with Leif Groop (Lund U.), we study genetic risk factors in over 5,000 DNA well characterized samples collected from patients with type 2 diabetes and related metabolic disorders. We are performing genetic association studies, with candidates based on (a) biological pathway, (b) family-based linkage studies, and (c) expression profiling. We were among the first to demonstrate that PPARG Pro12Ala is the first reproducible genetic risk factor for type 2 diabetes (Altshuler et al, Nature Genetics, 2000), and have followed this by creating a comprehensive haplotype map of this gene. Based on PPARG’s role as a drug target for hypoglycemic medication, we have confirmed and extended the previously described association of genetic variation in the sulfonylurea receptor/Kir6.2 complex and AMPKinase in type 2 diabetes (Florez et al, in preparation). We are studying genes previously identified as playing a role in monogenic forms of type 2 diabetes, and biological and expression candidates that underlie linkage peaks for type 2 diabetes. We have performed expression analysis of biopsies from patients with type 2 DM, developing a novel method for analysis of microarray data (Mootha et al,, Nature Genetics, 2003). This recent study has highlighted the possible role of disorders of mitochondrial respiration on type 2 DM, and we are performing association studies with members of this biochemical and regulatory pathway. References: 1. Cargill, M., Altshuler, D, et. al. (1999) “Characterization of Single Nucleotide Polymorphisms in Coding Regions of Human Genes." Nature Genetics 22, 231-238. *These authors contributed equally to this work. 2. Altshuler, D., Hirschhorn, J., et al. (2000)“The common PPAR gamma Pro12Ala polymorphism is associated with decreased risk of type II diabetes." Nature Genetics 26:76-80. These authors contributed equally to this work. Altshuler, D., et al. (2000)“An SNP map of the human genome generated by reduced representation shotgun sequencing.” Nature 407:513-516 3. The International SNP Map Working Group: Sachidanandam, R, Weissman, D, Schmidt, SC, Kakol, JK, Stein, LD, Marth G Sherry, D, Mullikin, JC, Mortimore, BJ, Willey, D, Hunt, SE, Cole, CG, Coggill, PC, Rice, CM, Ning, Z, Rogers, J, Bentley, DR, Kwok, P-Y, Mardis, ER, Yeh, RT, Schultz, B, Cook, L, Davenport, R, Dante, R, Fulton, L, Waterston, RH, McPherson, JD, Gilman, B, Schaffner, SF, Van Etten, WJ, Reich, DE, Higgins, J, Blumenstiel, B, Baldwin, J, Stange-Thomann, N, Zody, MC, Linton, LM, Lander, ES, and Altshuler, D, (2001)“A map of human genome sequence variation containing 1.4 million SNPs,” Nature 409:928-933. 4. Engert JC, Vohl MC, Williams SM, Lepage P, Loredo-Osti JC, Faith J, Dore C, Renaud Y, Burtt NP, Villeneuve A, Hirschhorn JN, Altshuler D, Groop LC, Despres JP, Gaudet D, Hudson TJ. (2002) “5' flanking variants of resistin are associated with obesity.” Diabetes. 51,1629-34. 5. Gabriel1 SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel1 B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, and Altshuler, D. (2002) “The structure of haplotypes in the human genome,” Science 296, 2225-2229 (doi;10.1126/science.1069424) 6. Schaffner, S.F., Daly, M.J., McVean, G., Mullikin, J.C., Higgins, J.M, Richter, D.J., Lander, E.S., Altshuler, D. (2002) “Human genome sequence variation and the influence of gene history, mutation and recombination.” Nature Genetics 32(1),135-42. 7. Sabeti, P., Reich,D., Higgins,J., Levine,H., Richter,D., Schaffner,S., Gabriel,S., Platko,J., Patterson,N., McDonald,G., Ackerman,H., Campbell,S., Altshuler,D., Cooper,R., Kwiatkowski,D., Ward,R. and Lander,E.S. (2002) “Detecting recent positive selection in the human genome from haplotype structure” Nature 419:832–837 (doi:10.1038/nature01140) 8. Cowles, C., Hirschhorn,J.N., Altshuler,D., and Lander,E.S. (2002) “Detection of regulatory polymorphism in mouse genes”. Nature Genetics 32:432–437 (doi:10.1038/ng992) 9. Reich, DE, Gabriel, SB, and Altshuler, D, (2003) “Quality and Completeness of SNP Databases” (2003), Nature Genetics 33 457-458 (doi:10.1038/ng1133) 10. Mootha, VK, Lindgren, CM, Eriksson, KF, Subramanian, A., Sihag, M, Lehar, J Puigserver, P., Carlsson, E, Ridderstråle, M, Laurila, E, Daly, MJ, Patterson, P, Mesirov, JP, Golub, TR, Tamayo, P., Spiegelman, B. Lander, ES, Hirschhorn, JN, Altshuler, D., and Groop, LC (2003) “PGC-1a Responsive Genes Involved in Oxidative Phosphorylation are Coordinately Downregulated in Human Diabetes”, Nature Genetics 2003 34:267-273. 11. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004 May;53(5):1360-8. 12. Altshuler JS, Altshuler D. Organizational challenges in clinical genomic research. Nature. 2004 May 27;429(6990):478-81.