Identification of Novel Candidate Genes for Type 2 Diabetes From a Genome-Wide Association Scan in the Old Order Amish
Abstract
OBJECTIVE: We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS: DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians. RESULTS: The strongest association (P = 1.07 x 10(-5)) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population. CONCLUSIONS: Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.
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Polymorphisms at the ERRγ locus were found to be associated with increased glucose area under the curve in a genetic analysis of Old Order Amish subjects.
“Although the physiological effects of the related gene ERR␥ remain unclear, it interacts with PGC-1 to regulate expression of ERR␣ (278), and polymorphisms at this locus were found to be associated with increased glucose area under the curve in a genetic analysis of Old Order Amish subjects (279).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [279]
Cites
Complement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492 · see citing works
Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees
Almasy, L. A., & Blangero, J. (1998) · The American Journal of Human Genetics · doi:10.1086/301844 · Cited by 3,007 · see citing works
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · see citing works
A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., et al. (2007) · Science · doi:10.1126/science.1142382 · Cited by 2,753 · see citing works
Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., et al. (2007) · Science · doi:10.1126/science.1142364 · Cited by 2,194 · see citing works
Purcell, S., Cherny, S. S., & Sham, P. C. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.1.149 · Cited by 2,057 · see citing works
A variant in CDKAL1 influences insulin response and risk of type 2 diabetes
Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Jonsdottir, T., Walters, G. B., Styrkarsdottir, U., Gretarsdottir, S., Emilsson, V., Ghosh, S., et al. (2007) · Nature Genetics · doi:10.1038/ng2043 · Cited by 1,072 · see citing works
Hanson, R. L., Ehm, M. G., Pettitt, D. J., Procházka, M., Thompson, D. B., Timberlake, D. S., Foroud, T., Kobes, S., Baier, L. J., Burns, D. K., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/302061 · Cited by 468 · see citing works
The use of measured genotype information in the analysis of quantitative phenotypes in man
Boerwinkle, E., Chakraborty, R., & Sing, C. F. (1986) · Annals of Human Genetics · doi:10.1111/j.1469-1809.1986.tb01037.x · Cited by 308 · see citing works
A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians.
Elbein, S. C., Hoffman, M., Teng, K., et al. (1999) · Diabetes · doi:10.2337/diabetes.48.5.1175 · Cited by 307 · see citing works
Wiltshire, S., Hattersley, A. T., Hitman, G. A., Walker, M., Lévy, J., Sampson, M., O’Rahilly, S., Frayling, T. M., Bell, J. I., Lathrop, M. G., et al. (2001) · The American Journal of Human Genetics · doi:10.1086/323249 · Cited by 305 · see citing works
Damcott, C., Pollin, T. I., Reinhart, L. J., Ott, S. H., Shen, H., Silver, K. D., Mitchell, B. D., & Shuldiner, A. R. (2006) · Diabetes · doi:10.2337/db06-0338 · Cited by 276 · see citing works
Self-citationMeigs, J. B., Panhuysen, C. I. M., Myers, R. H., Wilson, P. W. F., & Cupples, L. A. (2002) · Diabetes · doi:10.2337/diabetes.51.3.833 · Cited by 185 · see citing works
Hsueh, W.-C., Mitchell, B. D., Aburomia, R., Pollin, T. I., Sakul, H., Ehm, M. G., Michelsen, B. K., Wagner, M. J., Jean, P. L. S., Knowler, W. C., et al. (2000) · Diabetes Care · doi:10.2337/diacare.23.5.595 · Cited by 173 · see citing works
Self-citationHsueh, W., Jean, P. L. S., Mitchell, B. D., Pollin, T. I., Knowler, W. C., Ehm, M. G., Bell, C. J., Sakul, H., Wagner, M. J., Burns, D. K., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.2.550 · Cited by 146 · see citing works
Self-citationIdentification of Type 2 Diabetes Genes in Mexican Americans Through Genome-Wide Association Studies
Hayes, M. G., Pluzhnikov, A., Miyake, K., Sun, Y., Ng, M. C. Y., Roe, C. A., Below, J. E., Nicolae, R. I., Konkashbaev, A. I., Bell, G. I., et al. (2007) · Diabetes · doi:10.2337/db07-0482 · Cited by 129 · see citing works
Growing evidence for diabetes susceptibility genes from genome scan data
McCarthy, M. I. (2003) · Current Diabetes Reports · doi:10.1007/s11892-003-0040-y · Cited by 119 · see citing works
Application of Genome-Wide Single Nucleotide Polymorphism Typing: Simple Association and Beyond
Gibbs, J. R., & Singleton, A. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020150 · Cited by 103 · see citing works
Hanson, R. L., Bogardus, C., Duggan, D. J., Kobes, S., Knowlton, M., Infante, A. M., Marovich, L., Benitez, D. S., Baier, L. J., & Knowler, W. C. (2007) · Diabetes · doi:10.2337/db07-0462 · Cited by 98 · see citing works
A 100K Genome-Wide Association Scan for Diabetes and Related Traits in the Framingham Heart Study
Florez, J. C., Manning, A. K., Dupuis, J., McAteer, J. B., Irenze, K., Gianniny, L., Mirel, D. B., Fox, C. S., Cupples, L. A., & Meigs, J. B. (2007) · Diabetes · doi:10.2337/db07-0451 · Cited by 95 · see citing works
Owen, K. R., & McCarthy, M. I. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.04.003 · Cited by 81 · see citing works
Shiura, H., Miyoshi, N., Konishi, A., Wakisaka‐Saito, N., Suzuki, R., Muguruma, K., Kohda, T., Wakana, S., Yokoyama, M., Ishino, F., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.02.047 · Cited by 76 · see citing works
Damcott, C., Hoppman, N. L., Ott, S. H., Reinhart, L. J., Wang, J., Pollin, T. I., O’Connell, J. R., Mitchell, B. D., & Shuldiner, A. R. (2004) · Diabetes · doi:10.2337/diabetes.53.12.3337 · Cited by 67 · see citing works
Self-citationNg, M. C. Y., So, W., Cox, N. J., Lam, V. K. L., Cockram, C. S., Critchley, J., Bell, G. I., & Chan, J. C. N. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1609 · Cited by 62 · see citing works
Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling By Grb10
Langlais, P. R., Dong, L., Ramos, F. J., Hu, D., Li, Y., Quon, M. J., & Liu, F. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0117 · Cited by 59 · see citing works
Deng, Y., Bhattacharya, S., Swamy, O. R., Tandon, R., Wang, Y., Janda, R., & Riedel, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304599200 · Cited by 52 · see citing works
Mounier, C., Lavoie, L., Dumas, V., Mohammad-Ali, K., Wu, J., Nantel, A., Bergeron, J. J. M., Thomas, D. Y., & Posner, B. I. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(00)00439-1 · Cited by 33 · see citing works
Du, W., Sun, H.-X., Wang, H., et al. (2001) · PubMed · Cited by 27 · see citing works
Association of hGrb10 Genetic Variations With Type 2 Diabetes in Caucasian Subjects
Paola, R. D. (2006) · Diabetes Care · doi:10.2337/diacare.2951181a · Cited by 19 · see citing works
Association of hGrb10 Genetic Variations With Type 2 Diabetes in Caucasian Subjects
Paola, R. D., Ciociola, E., Boonyasrisawat, W., et al. (2006) · Diabetes Care · doi:10.2337/dc05-2551 · Cited by 15 · see citing works
Transient Diabetes Associated With Withdrawal of Lithium Therapy
Okosieme, O. E. (2006) · Diabetes Care · doi:10.2337/diacare.2951181 · Cited by 9 · see citing works
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Wellcome Trust Case Control Consortium, Zeggini, E., Scott, L. J., Saxena, R., Voight, B. F., Marchini, J. L., Hu, T., de Bakker, P. I., Abecasis, G. R., Almgren, P., et al. (2008) · Nature Genetics · doi:10.1038/ng.120 · Cited by 1,864 · see citing works
Biochemical and cellular properties of insulin receptor signalling
Haeusler, R. A., McGraw, T. E., & Accili, D. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.89 · Cited by 739 · see citing works
The role of mitochondria in the pathogenesis of type 2 diabetes
Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551 · see citing works
Volkmar, M., Dedeurwaerder, S., Cunha, D. A., Ndlovu, M. N., Defrance, M., Deplus, R., Calonne, E., Volkmar, U., Igoillo‐Esteve, M., Naamane, N., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.503 · Cited by 420 · see citing works
“Figure 2, Supplementary Figure S4 and Supplementary Table S2), 181 had associated probes on the microarray, with a total of 320 matches between Infinium and expression assays (due to multiple methylation or expression probes affiliated to the same genes; Supplementary Table S4).”
Lesch, K.-P., Timmesfeld, N., Renner, T. J., Halperin, R., Röser, C., Nguyen, T. T., Craig, D. W., Romanos, J., Heine, M., Meyer, J., et al. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-008-0119-3 · Cited by 374 · see citing works
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Wang, Y., O'Connell, J. R., McArdle, P. F., Wade, J. B., Dorff, S. E., Shah, S. J., Shi, X., Pan, L., Rampersaud, E., Shen, H., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808358106 · Cited by 298 · see citing works
Self-citationJablonski, K. A., McAteer, J. B., de Bakker, P. I. W., Franks, P. W., Pollin, T. I., Hanson, R. L., Saxena, R., Fowler, S., Shuldiner, A. R., Knowler, W. C., et al. (2010) · Diabetes · doi:10.2337/db10-0543 · Cited by 271 · see citing works
Self-citationBespalova, I. N., Angelo, G. W., Ritter, B. P., Hunter, J., Reyes-Rabanillo, M. L., Siever, L. J., & Silverman, J. M. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8169-y · Cited by 14 · see citing works
- Authors
- Rampersaud, E., Damcott, C. M., Fu, M., Shen, H., McArdle, P., Shi, X., Shelton, J., Yin, J., Chang, Y.-P. C., Ott, S. H., Zhang, L., Zhao, Y., Mitchell, B. D., O'Connell, J., & Shuldiner, A. R.
- Affiliations
- University of Maryland, Baltimore (US)
- Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, Maryland
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2007-12-01
- Volume
- 56
- Issue
- 12
- Pages
- 3053-3062
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2130613040
- Cited by
- 170
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 11 · 2014: 10 · 2013: 14 · 2012: 15
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL072751)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK054261, R01-DK54261, P30DK072488)
- National Center for Research Resources (M01RR002719, M01RR016500, M0-1-RR-02719, M01RR 16500)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, genetic susceptibility, candidate genes, Old Order Amish, single nucleotide polymorphisms, Grb10, oral glucose tolerance test, insulin receptor signaling, BCAT1, FHIT
- MeSH terms
- Adult, Aged, Chromosome Mapping, Diabetes Mellitus, Type 2, DNA, Ethnicity, Female, Humans, Male, Maryland, Middle Aged, Genome, Human, Body Mass Index, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Overweight, GRB10 Adaptor Protein
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