Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Mar;62(3):659–668. doi: 10.1086/301758

Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians.

R A Norman 1, P A Tataranni 1, R Pratley 1, D B Thompson 1, R L Hanson 1, M Prochazka 1, L Baier 1, M G Ehm 1, H Sakul 1, T Foroud 1, W T Garvey 1, D Burns 1, W C Knowler 1, P H Bennett 1, C Bogardus 1, E Ravussin 1
PMCID: PMC1376952  PMID: 9497255

Abstract

An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.

Full Text

The Full Text of this article is available as a PDF (315.9 KB).

Selected References

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

  1. Allison D. B., Kaprio J., Korkeila M., Koskenvuo M., Neale M. C., Hayakawa K. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord. 1996 Jun;20(6):501–506. [PubMed] [Google Scholar]
  2. Amos C. I., Elston R. C., Wilson A. F., Bailey-Wilson J. E. A more powerful robust sib-pair test of linkage for quantitative traits. Genet Epidemiol. 1989;6(3):435–449. doi: 10.1002/gepi.1370060306. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Bogardus C., Lillioja S., Ravussin E., Abbott W., Zawadzki J. K., Young A., Knowler W. C., Jacobowitz R., Moll P. P. Familial dependence of the resting metabolic rate. N Engl J Med. 1986 Jul 10;315(2):96–100. doi: 10.1056/NEJM198607103150205. [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. Bouchard C., Tremblay A., Nadeau A., Després J. P., Thériault G., Boulay M. R., Lortie G., Leblanc C., Fournier G. Genetic effect in resting and exercise metabolic rates. Metabolism. 1989 Apr;38(4):364–370. doi: 10.1016/0026-0495(89)90126-1. [DOI] [PubMed] [Google Scholar]
  7. Churchill G. A., Doerge R. W. Empirical threshold values for quantitative trait mapping. Genetics. 1994 Nov;138(3):963–971. doi: 10.1093/genetics/138.3.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clement K., Garner C., Hager J., Philippi A., LeDuc C., Carey A., Harris T. J., Jury C., Cardon L. R., Basdevant A. Indication for linkage of the human OB gene region with extreme obesity. Diabetes. 1996 May;45(5):687–690. doi: 10.2337/diab.45.5.687. [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. Comuzzie A. G., Hixson J. E., Almasy L., Mitchell B. D., Mahaney M. C., Dyer T. D., Stern M. P., MacCluer J. W., Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet. 1997 Mar;15(3):273–276. doi: 10.1038/ng0397-273. [DOI] [PubMed] [Google Scholar]
  11. Curtis D. Genetic dissection of complex traits. Nat Genet. 1996 Apr;12(4):356–358. doi: 10.1038/ng0496-356. [DOI] [PubMed] [Google Scholar]
  12. Daly M. J., Lander E. S. The importance of being independent: sib pair analysis in diabetes. Nat Genet. 1996 Oct;14(2):131–132. doi: 10.1038/ng1096-131. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Duggirala R., Stern M. P., Mitchell B. D., Reinhart L. J., Shipman P. A., Uresandi O. C., Chung W. K., Leibel R. L., Hales C. N., O'Connell P. Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7. Am J Hum Genet. 1996 Sep;59(3):694–703. [PMC free article] [PubMed] [Google Scholar]
  15. Edwards D. R., Beaudry P. P., Laing T. D., Kowal V., Leco K. J., Leco P. A., Lim M. S. The roles of tissue inhibitors of metalloproteinases in tissue remodelling and cell growth. Int J Obes Relat Metab Disord. 1996 Mar;20 (Suppl 3):S9–15. [PubMed] [Google Scholar]
  16. Elbein S. C., Hoffman M., Barrett K., Wegner K., Miles C., Bachman K., Berkowitz D., Shuldiner A. R., Leppert M. F., Hasstedt S. Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. J Clin Endocrinol Metab. 1996 Dec;81(12):4422–4427. doi: 10.1210/jcem.81.12.8954053. [DOI] [PubMed] [Google Scholar]
  17. Evans J. L., Honer C. M., Womelsdorf B. E., Kaplan E. L., Bell P. A. The effects of wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, on insulin-stimulated glucose transport, GLUT4 translocation, antilipolysis, and DNA synthesis. Cell Signal. 1995 May;7(4):365–376. doi: 10.1016/0898-6568(95)00007-c. [DOI] [PubMed] [Google Scholar]
  18. Fleury C., Neverova M., Collins S., Raimbault S., Champigny O., Levi-Meyrueis C., Bouillaud F., Seldin M. F., Surwit R. S., Ricquier D. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997 Mar;15(3):269–272. doi: 10.1038/ng0397-269. [DOI] [PubMed] [Google Scholar]
  19. Fontaine E., Savard R., Tremblay A., Després J. P., Poehlman E., Bouchard C. Resting metabolic rate in monozygotic and dizygotic twins. Acta Genet Med Gemellol (Roma) 1985;34(1-2):41–47. doi: 10.1017/s0001566000004906. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Heseltine L., Webster J. M., Taylor R. Adenosine effects upon insulin action on lipolysis and glucose transport in human adipocytes. Mol Cell Biochem. 1995 Mar 23;144(2):147–151. doi: 10.1007/BF00944394. [DOI] [PubMed] [Google Scholar]
  22. Hotamisligil G. S., Shargill N. S., Spiegelman B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87–91. doi: 10.1126/science.7678183. [DOI] [PubMed] [Google Scholar]
  23. Knowler W. C., Pettitt D. J., Saad M. F., Bennett P. H. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab Rev. 1990 Feb;6(1):1–27. doi: 10.1002/dmr.5610060101. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Kwon H. Y., Bultman S. J., Löffler C., Chen W. J., Furdon P. J., Powell J. G., Usala A. L., Wilkison W., Hansmann I., Woychik R. P. Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9760–9764. doi: 10.1073/pnas.91.21.9760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. 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]
  30. Lu D., Willard D., Patel I. R., Kadwell S., Overton L., Kost T., Luther M., Chen W., Woychik R. P., Wilkison W. O. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature. 1994 Oct 27;371(6500):799–802. doi: 10.1038/371799a0. [DOI] [PubMed] [Google Scholar]
  31. Maffei M., Halaas J., Ravussin E., Pratley R. E., Lee G. H., Zhang Y., Fei H., Kim S., Lallone R., Ranganathan S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995 Nov;1(11):1155–1161. doi: 10.1038/nm1195-1155. [DOI] [PubMed] [Google Scholar]
  32. Norman R. A., Bogardus C., Ravussin E. Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians. J Clin Invest. 1995 Jul;96(1):158–162. doi: 10.1172/JCI118016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Norman R. A., Leibel R. L., Chung W. K., Power-Kehoe L., Chua S. C., Jr, Knowler W. C., Thompson D. B., Bogardus C., Ravussin E. Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima Indians. Diabetes. 1996 Sep;45(9):1229–1232. doi: 10.2337/diab.45.9.1229. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Pi-Sunyer F. X. Health implications of obesity. Am J Clin Nutr. 1991 Jun;53(6 Suppl):1595S–1603S. doi: 10.1093/ajcn/53.6.1595S. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Ravussin E., Lillioja S., Anderson T. E., Christin L., Bogardus C. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest. 1986 Dec;78(6):1568–1578. doi: 10.1172/JCI112749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ravussin E., Lillioja S., Knowler W. C., Christin L., Freymond D., Abbott W. G., Boyce V., Howard B. V., Bogardus C. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med. 1988 Feb 25;318(8):467–472. doi: 10.1056/NEJM198802253180802. [DOI] [PubMed] [Google Scholar]
  39. Ravussin E., Swinburn B. A. Metabolic predictors of obesity: cross-sectional versus longitudinal data. Int J Obes Relat Metab Disord. 1993 Dec;17 (Suppl 3):S28–S42. [PubMed] [Google Scholar]
  40. Reed D. R., Ding Y., Xu W., Cather C., Green E. D., Price R. A. Extreme obesity may be linked to markers flanking the human OB gene. Diabetes. 1996 May;45(5):691–694. doi: 10.2337/diab.45.5.691. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Rice T., Tremblay A., Dériaz O., Pérusse L., Rao D. C., Bouchard C. Genetic pleiotropy for resting metabolic rate with fat-free mass and fat mass: the Québec Family Study. Obes Res. 1996 Mar;4(2):125–131. doi: 10.1002/j.1550-8528.1996.tb00524.x. [DOI] [PubMed] [Google Scholar]
  43. Rothschild C. B., Akots G., Hayworth R., Pettenati M. J., Rao P. N., Wood P., Stolz F. M., Hansmann I., Serino K., Keith T. P. A genetic map of chromosome 20q12-q13.1: multiple highly polymorphic microsatellite and RFLP markers linked to the maturity-onset diabetes of the young (MODY) locus. Am J Hum Genet. 1993 Jan;52(1):110–123. [PMC free article] [PubMed] [Google Scholar]
  44. Sakul H., Pratley R., Cardon L., Ravussin E., Mott D., Bogardus C. Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians. Am J Hum Genet. 1997 Mar;60(3):651–656. [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. Shimabukuro M., Koyama K., Chen G., Wang M. Y., Trieu F., Lee Y., Newgard C. B., Unger R. H. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637–4641. doi: 10.1073/pnas.94.9.4637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Tebar F., Soley M., Ramírez I. The antilipolytic effects of insulin and epidermal growth factor in rat adipocytes are mediated by different mechanisms. Endocrinology. 1996 Oct;137(10):4181–4188. doi: 10.1210/endo.137.10.8828475. [DOI] [PubMed] [Google Scholar]
  49. Thompson D. B., Sutherland J., Apel W., Ossowski V. A physical map at 1p31 encompassing the acute insulin response locus and the leptin receptor. Genomics. 1997 Jan 15;39(2):227–230. doi: 10.1006/geno.1996.4504. [DOI] [PubMed] [Google Scholar]
  50. Walston J., Silver K., Bogardus C., Knowler W. C., Celi F. S., Austin S., Manning B., Strosberg A. D., Stern M. P., Raben N. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. N Engl J Med. 1995 Aug 10;333(6):343–347. doi: 10.1056/NEJM199508103330603. [DOI] [PubMed] [Google Scholar]
  51. Wilson B. D., Ollmann M. M., Kang L., Stoffel M., Bell G. I., Barsh G. S. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet. 1995 Feb;4(2):223–230. doi: 10.1093/hmg/4.2.223. [DOI] [PubMed] [Google Scholar]
  52. Witte J. S., Elston R. C., Schork N. J. Genetic dissection of complex traits. Nat Genet. 1996 Apr;12(4):355–358. doi: 10.1038/ng0496-355. [DOI] [PubMed] [Google Scholar]
  53. 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]
  54. Zurlo F., Ferraro R. T., Fontvielle A. M., Rising R., Bogardus C., Ravussin E. Spontaneous physical activity and obesity: cross-sectional and longitudinal studies in Pima Indians. Am J Physiol. 1992 Aug;263(2 Pt 1):E296–E300. doi: 10.1152/ajpendo.1992.263.2.E296. [DOI] [PubMed] [Google Scholar]
  55. Zurlo F., Lillioja S., Esposito-Del Puente A., Nyomba B. L., Raz I., Saad M. F., Swinburn B. A., Knowler W. C., Bogardus C., Ravussin E. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol. 1990 Nov;259(5 Pt 1):E650–E657. doi: 10.1152/ajpendo.1990.259.5.E650. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES