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. 1997 Jan;60(1):166–173.

Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Pima Diabetes Gene Group.

R A Norman 1, D B Thompson 1, T Foroud 1, W T Garvey 1, P H Bennett 1, C Bogardus 1, E Ravussin 1
PMCID: PMC1712570  PMID: 8981960

Abstract

On the basis of accumulating evidence that obesity has a substantial genetic component, a genomewide search for linkages of DNA markers to percent body fat is ongoing in Pima Indians, a population with a very high prevalence of obesity. An initial screen of the genome (>600 markers in 874 individuals) has been completed using highly polymorphic markers (mean heterozygosity = .67). Reported here are the sib-pair linkage results for percent body fat (277 siblings), the best available indicator of overall obesity. Single-marker linkages to percent body fat were evaluated by sib-pair analysis for quantitative traits. From these analyses, the best evidence of genes influencing body fat came from markers at chromosome 11q21-q22 and 3p24.2-p22 (P = .001; LOD = 2.0). Regions flanking these markers were further investigated by multipoint linkage. The evidence for linkage at 11q21-q22 increased to P = .0002 (LOD = 2.8), peaking between markers D11S2000 and D11S2366. Evidence for linkage at 3p24.2-p22 did not change. No association was detected for any marker in the region. Although several genes are known in the 11q21-q22 region, none have been implicated as candidate genes for obesity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett P. H. Diabetes mellitus in Pima Indians. Lancet. 1971 Aug 28;2(7722):488–489. doi: 10.1016/s0140-6736(71)92651-1. [DOI] [PubMed] [Google Scholar]
  2. Borecki I. B., Bonney G. E., Rice T., Bouchard C., Rao D. C. Influence of genotype-dependent effects of covariates on the outcome of segregation analysis of the body mass index. Am J Hum Genet. 1993 Sep;53(3):676–687. [PMC free article] [PubMed] [Google Scholar]
  3. Borecki I. B., Rice T., Pérusse L., Bouchard C., Rao D. C. Major gene influence on the propensity to store fat in trunk versus extremity depots: evidence from the Québec Family Study. Obes Res. 1995 Jan;3(1):1–8. doi: 10.1002/j.1550-8528.1995.tb00115.x. [DOI] [PubMed] [Google Scholar]
  4. Bouchard C. Current understanding of the etiology of obesity: genetic and nongenetic factors. Am J Clin Nutr. 1991 Jun;53(6 Suppl):1561S–1565S. doi: 10.1093/ajcn/53.6.1561S. [DOI] [PubMed] [Google Scholar]
  5. Bouchard C., Pérusse L., Leblanc C., Tremblay A., Thériault G. Inheritance of the amount and distribution of human body fat. Int J Obes. 1988;12(3):205–215. [PubMed] [Google Scholar]
  6. Bunyan J., Murrell E. A., Shah P. P. The induction of obesity in rodents by means of monosodium glutamate. Br J Nutr. 1976 Jan;35(1):25–39. doi: 10.1079/bjn19760005. [DOI] [PubMed] [Google Scholar]
  7. Carmelli D., Cardon L. R., Fabsitz R. Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments? Am J Hum Genet. 1994 Sep;55(3):566–573. [PMC free article] [PubMed] [Google Scholar]
  8. Comings D. E., Flanagan S. D., Dietz G., Muhleman D., Knell E., Gysin R. The dopamine D2 receptor (DRD2) as a major gene in obesity and height. Biochem Med Metab Biol. 1993 Oct;50(2):176–185. doi: 10.1006/bmmb.1993.1059. [DOI] [PubMed] [Google Scholar]
  9. Comuzzie A. G., Blangero J., Mahaney M. C., Mitchell B. D., Hixson J. E., Samollow P. B., Stern M. P., MacCluer J. W. Major gene with sex-specific effects influences fat mass in Mexican Americans. Genet Epidemiol. 1995;12(5):475–488. doi: 10.1002/gepi.1370120505. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Fabsitz R. R., Sholinsky P., Carmelli D. Genetic influences on adult weight gain and maximum body mass index in male twins. Am J Epidemiol. 1994 Oct 15;140(8):711–720. doi: 10.1093/oxfordjournals.aje.a117319. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Garn S. M., Leonard W. R., Hawthorne V. M. Three limitations of the body mass index. Am J Clin Nutr. 1986 Dec;44(6):996–997. doi: 10.1093/ajcn/44.6.996. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Herskind A. M., McGue M., Sørensen T. I., Harvald B. Sex and age specific assessment of genetic and environmental influences on body mass index in twins. Int J Obes Relat Metab Disord. 1996 Feb;20(2):106–113. [PubMed] [Google Scholar]
  16. Johansson A. G., Forslund A., Sjödin A., Mallmin H., Hambraeus L., Ljunghall S. Determination of body composition--a comparison of dual-energy x-ray absorptiometry and hydrodensitometry. Am J Clin Nutr. 1993 Mar;57(3):323–326. doi: 10.1093/ajcn/57.3.323. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Kuczmarski R. J., Flegal K. M., Campbell S. M., Johnson C. L. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994 Jul 20;272(3):205–211. doi: 10.1001/jama.272.3.205. [DOI] [PubMed] [Google Scholar]
  20. Kuskowska-Wolk A., Bergström R. Trends in body mass index and prevalence of obesity in Swedish men 1980-89. J Epidemiol Community Health. 1993 Apr;47(2):103–108. doi: 10.1136/jech.47.2.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Lillioja S., Mott D. M., Spraul M., Ferraro R., Foley J. E., Ravussin E., Knowler W. C., Bennett P. H., Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993 Dec 30;329(27):1988–1992. doi: 10.1056/NEJM199312303292703. [DOI] [PubMed] [Google Scholar]
  24. NEEL J. V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet. 1962 Dec;14:353–362. [PMC free article] [PubMed] [Google Scholar]
  25. Olney J. W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science. 1969 May 9;164(3880):719–721. doi: 10.1126/science.164.3880.719. [DOI] [PubMed] [Google Scholar]
  26. Olson J. M. Robust multipoint linkage analysis: an extension of the Haseman-Elston method. Genet Epidemiol. 1995;12(2):177–193. doi: 10.1002/gepi.1370120206. [DOI] [PubMed] [Google Scholar]
  27. Rice T., Borecki I. B., Bouchard C., Rao D. C. Segregation analysis of fat mass and other body composition measures derived from underwater weighing. Am J Hum Genet. 1993 May;52(5):967–973. [PMC free article] [PubMed] [Google Scholar]
  28. Savitsky K., Bar-Shira A., Gilad S., Rotman G., Ziv Y., Vanagaite L., Tagle D. A., Smith S., Uziel T., Sfez S. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995 Jun 23;268(5218):1749–1753. doi: 10.1126/science.7792600. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Seidell J. C., Verschuren W. M., Kromhout D. Prevalence and trends of obesity in The Netherlands 1987-1991. Int J Obes Relat Metab Disord. 1995 Dec;19(12):924–927. [PubMed] [Google Scholar]
  31. Stunkard A. J., Harris J. R., Pedersen N. L., McClearn G. E. The body-mass index of twins who have been reared apart. N Engl J Med. 1990 May 24;322(21):1483–1487. doi: 10.1056/NEJM199005243222102. [DOI] [PubMed] [Google Scholar]
  32. Svendsen O. L., Haarbo J., Hassager C., Christiansen C. Accuracy of measurements of body composition by dual-energy x-ray absorptiometry in vivo. Am J Clin Nutr. 1993 May;57(5):605–608. doi: 10.1093/ajcn/57.5.605. [DOI] [PubMed] [Google Scholar]
  33. Thomson G. Identifying complex disease genes: progress and paradigms. Nat Genet. 1994 Oct;8(2):108–110. doi: 10.1038/ng1094-108. [DOI] [PubMed] [Google Scholar]
  34. Weber J. L., Wang Z., Hansen K., Stephenson M., Kappel C., Salzman S., Wilkie P. J., Keats B., Dracopoli N. C., Brandriff B. F. Evidence for human meiotic recombination interference obtained through construction of a short tandem repeat-polymorphism linkage map of chromosome 19. Am J Hum Genet. 1993 Nov;53(5):1079–1095. [PMC free article] [PubMed] [Google Scholar]
  35. Weber J. L., Wong C. Mutation of human short tandem repeats. Hum Mol Genet. 1993 Aug;2(8):1123–1128. doi: 10.1093/hmg/2.8.1123. [DOI] [PubMed] [Google Scholar]
  36. Weeks D. E., Lathrop G. M. Polygenic disease: methods for mapping complex disease traits. Trends Genet. 1995 Dec;11(12):513–519. doi: 10.1016/s0168-9525(00)89163-5. [DOI] [PubMed] [Google Scholar]
  37. West D. B., Goudey-Lefevre J., York B., Truett G. E. Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model. J Clin Invest. 1994 Oct;94(4):1410–1416. doi: 10.1172/JCI117477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. van Heyningen V., Little P. F. Report of the fourth international workshop on human chromosome 11 mapping 1994. Cytogenet Cell Genet. 1995;69(3-4):127–158. doi: 10.1159/000133953. [DOI] [PubMed] [Google Scholar]

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