Abstract
Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.
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- Almasy L., Dyer T. D., Blangero J. Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet Epidemiol. 1997;14(6):953–958. doi: 10.1002/(SICI)1098-2272(1997)14:6<953::AID-GEPI65>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
- Amos C. I. Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet. 1994 Mar;54(3):535–543. [PMC free article] [PubMed] [Google Scholar]
- Amos C. I., Zhu D. K., Boerwinkle E. Assessing genetic linkage and association with robust components of variance approaches. Ann Hum Genet. 1996 Mar;60(Pt 2):143–160. doi: 10.1111/j.1469-1809.1996.tb01184.x. [DOI] [PubMed] [Google Scholar]
- Barnett A. H., Eff C., Leslie R. D., Pyke D. A. Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981 Feb;20(2):87–93. doi: 10.1007/BF00262007. [DOI] [PubMed] [Google Scholar]
- Beaty T. H., Self S. G., Liang K. Y., Connolly M. A., Chase G. A., Kwiterovich P. O. Use of robust variance components models to analyse triglyceride data in families. Ann Hum Genet. 1985 Oct;49(Pt 4):315–328. doi: 10.1111/j.1469-1809.1985.tb01707.x. [DOI] [PubMed] [Google Scholar]
- Bell G. I., Xiang K. S., Newman M. V., Wu S. H., Wright L. G., Fajans S. S., Spielman R. S., Cox N. J. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1484–1488. doi: 10.1073/pnas.88.4.1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bennett P. H., Burch T. A., Miller M. Diabetes mellitus in American (Pima) Indians. Lancet. 1971 Jul 17;2(7716):125–128. doi: 10.1016/s0140-6736(71)92303-8. [DOI] [PubMed] [Google Scholar]
- Bogardus C., Lillioja S. Pima Indians as a model to study the genetics of NIDDM. J Cell Biochem. 1992 Apr;48(4):337–343. doi: 10.1002/jcb.240480402. [DOI] [PubMed] [Google Scholar]
- Chotai J. On the lod score method in linkage analysis. Ann Hum Genet. 1984 Oct;48(Pt 4):359–378. doi: 10.1111/j.1469-1809.1984.tb00849.x. [DOI] [PubMed] [Google Scholar]
- Davies J. L., Kawaguchi Y., Bennett S. T., Copeman J. B., Cordell H. J., Pritchard L. E., Reed P. W., Gough S. C., Jenkins S. C., Palmer S. M. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994 Sep 8;371(6493):130–136. doi: 10.1038/371130a0. [DOI] [PubMed] [Google Scholar]
- Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
- Dubovsky J., Sheffield V. C., Duyk G. M., Weber J. L. Sets of short tandem repeat polymorphisms for efficient linkage screening of the human genome. Hum Mol Genet. 1995 Mar;4(3):449–452. doi: 10.1093/hmg/4.3.449. [DOI] [PubMed] [Google Scholar]
- Ehm M., Wagner M. A test statistic to detect errors in sib-pair relationships. Am J Hum Genet. 1998 Jan;62(1):181–188. doi: 10.1086/301668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elston R. C. Genetic Analysis Workshop II: sib pair screening tests for linkage. Genet Epidemiol. 1984;1(2):175–178. doi: 10.1002/gepi.1370010210. [DOI] [PubMed] [Google Scholar]
- Froguel P., Vaxillaire M., Sun F., Velho G., Zouali H., Butel M. O., Lesage S., Vionnet N., Clément K., Fougerousse F. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature. 1992 Mar 12;356(6365):162–164. doi: 10.1038/356162a0. [DOI] [PubMed] [Google Scholar]
- Fulker D. W., Cardon L. R. A sib-pair approach to interval mapping of quantitative trait loci. Am J Hum Genet. 1994 Jun;54(6):1092–1103. [PMC free article] [PubMed] [Google Scholar]
- Fulker D. W., Cherny S. S. An improved multipoint sib-pair analysis of quantitative traits. Behav Genet. 1996 Sep;26(5):527–532. doi: 10.1007/BF02359758. [DOI] [PubMed] [Google Scholar]
- Fulker D. W., Cherny S. S., Cardon L. R. Multipoint interval mapping of quantitative trait loci, using sib pairs. Am J Hum Genet. 1995 May;56(5):1224–1233. [PMC free article] [PubMed] [Google Scholar]
- Ghosh S., Schork N. J. Genetic analysis of NIDDM. The study of quantitative traits. Diabetes. 1996 Jan;45(1):1–14. doi: 10.2337/diab.45.1.1. [DOI] [PubMed] [Google Scholar]
- Hanis C. L., Boerwinkle E., Chakraborty R., Ellsworth D. L., Concannon P., Stirling B., Morrison V. A., Wapelhorst B., Spielman R. S., Gogolin-Ewens K. J. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161–166. doi: 10.1038/ng0696-161. [DOI] [PubMed] [Google Scholar]
- Hanson R. L., Elston R. C., Pettitt D. J., Bennett P. H., Knowler W. C. Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am J Hum Genet. 1995 Jul;57(1):160–170. [PMC free article] [PubMed] [Google Scholar]
- Hanson R. L., Knowler W. C. Analytic strategies to detect linkage to a common disorder with genetically determined age of onset: diabetes mellitus in Pima Indians. Genet Epidemiol. 1998;15(3):299–315. doi: 10.1002/(SICI)1098-2272(1998)15:3<299::AID-GEPI7>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
- Hanson R. L., Pettitt D. J., Bennett P. H., Narayan K. M., Fernandes R., de Courten M., Knowler W. C. Familial relationships between obesity and NIDDM. Diabetes. 1995 Apr;44(4):418–422. doi: 10.2337/diab.44.4.418. [DOI] [PubMed] [Google Scholar]
- Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
- Hopper J. L., Mathews J. D. Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet. 1982 Oct;46(Pt 4):373–383. doi: 10.1111/j.1469-1809.1982.tb01588.x. [DOI] [PubMed] [Google Scholar]
- Knowler W. C., Bennett P. H., Hamman R. F., Miller M. Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol. 1978 Dec;108(6):497–505. doi: 10.1093/oxfordjournals.aje.a112648. [DOI] [PubMed] [Google Scholar]
- Knowler W. C., Pettitt D. J., Saad M. F., Charles M. A., Nelson R. G., Howard B. V., Bogardus C., Bennett P. H. Obesity in the Pima Indians: its magnitude and relationship with diabetes. Am J Clin Nutr. 1991 Jun;53(6 Suppl):1543S–1551S. doi: 10.1093/ajcn/53.6.1543S. [DOI] [PubMed] [Google Scholar]
- Knowler W. C., Pettitt D. J., Savage P. J., Bennett P. H. Diabetes incidence in Pima indians: contributions of obesity and parental diabetes. Am J Epidemiol. 1981 Feb;113(2):144–156. doi: 10.1093/oxfordjournals.aje.a113079. [DOI] [PubMed] [Google Scholar]
- Kruglyak L., Lander E. S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995 Aug;57(2):439–454. [PMC free article] [PubMed] [Google Scholar]
- Lander E. S., Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363–2367. doi: 10.1073/pnas.84.8.2363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
- Lange K., Boehnke M. Extensions to pedigree analysis. IV. Covariance components models for multivariate traits. Am J Med Genet. 1983 Mar;14(3):513–524. doi: 10.1002/ajmg.1320140315. [DOI] [PubMed] [Google Scholar]
- Mahtani M. M., Widén E., Lehto M., Thomas J., McCarthy M., Brayer J., Bryant B., Chan G., Daly M., Forsblom C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90–94. doi: 10.1038/ng0996-90. [DOI] [PubMed] [Google Scholar]
- Morton N. E. Significance levels in complex inheritance. Am J Hum Genet. 1998 Mar;62(3):690–697. doi: 10.1086/301741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray J. C., Buetow K. H., Weber J. L., Ludwigsen S., Scherpbier-Heddema T., Manion F., Quillen J., Sheffield V. C., Sunden S., Duyk G. M. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science. 1994 Sep 30;265(5181):2049–2054. doi: 10.1126/science.8091227. [DOI] [PubMed] [Google Scholar]
- Norman R. A., Tataranni P. A., Pratley R., Thompson D. B., Hanson R. L., Prochazka M., Baier L., Ehm M. G., Sakul H., Foroud T. Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. Am J Hum Genet. 1998 Mar;62(3):659–668. doi: 10.1086/301758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Norman R. A., Thompson D. B., Foroud T., Garvey W. T., Bennett P. H., Bogardus C., Ravussin E. Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Pima Diabetes Gene Group. Am J Hum Genet. 1997 Jan;60(1):166–173. [PMC free article] [PubMed] [Google Scholar]
- Pratley R. E., Thompson D. B., Prochazka M., Baier L., Mott D., Ravussin E., Sakul H., Ehm M. G., Burns D. K., Foroud T. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest. 1998 Apr 15;101(8):1757–1764. doi: 10.1172/JCI1850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Price R. A., Charles M. A., Pettitt D. J., Knowler W. C. Obesity in Pima Indians: genetic segregation analyses of body mass index complicated by temporal increases in obesity. Hum Biol. 1994 Apr;66(2):251–274. [PubMed] [Google Scholar]
- Pugh E. W., Jaquish C. E., Sorant A. J., Doetsch J. P., Bailey-Wilson J. E., Wilson A. F. Comparison of sib-pair and variance-components methods for genomic screening. Genet Epidemiol. 1997;14(6):867–872. doi: 10.1002/(SICI)1098-2272(1997)14:6<867::AID-GEPI51>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
- Schwengel D. A., Jedlicka A. E., Nanthakumar E. J., Weber J. L., Levitt R. C. Comparison of fluorescence-based semi-automated genotyping of multiple microsatellite loci with autoradiographic techniques. Genomics. 1994 Jul 1;22(1):46–54. doi: 10.1006/geno.1994.1344. [DOI] [PubMed] [Google Scholar]
- Stoffers D. A., Ferrer J., Clarke W. L., Habener J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997 Oct;17(2):138–139. doi: 10.1038/ng1097-138. [DOI] [PubMed] [Google Scholar]
- Tuomilehto-Wolf E., Tuomilehto J., Hitman G. A., Nissinen A., Stengård J., Pekkanen J., Kivinen P., Kaarsalo E., Karvonen M. J. Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region. BMJ. 1993 Jul 17;307(6897):155–159. doi: 10.1136/bmj.307.6897.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vaxillaire M., Boccio V., Philippi A., Vigouroux C., Terwilliger J., Passa P., Beckmann J. S., Velho G., Lathrop G. M., Froguel P. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet. 1995 Apr;9(4):418–423. doi: 10.1038/ng0495-418. [DOI] [PubMed] [Google Scholar]
- Wilson A. F., Elston R. C. Statistical validity of the Haseman-Elston sib-pair test in small samples. Genet Epidemiol. 1993;10(6):593–598. doi: 10.1002/gepi.1370100644. [DOI] [PubMed] [Google Scholar]
- Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]
- Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]