Abstract
Although obesity is more prevalent in Hispanics than non-Hispanic whites in the United States, little is known about the genetic etiology of the related traits in this population. To identify genetic loci influencing obesity in non-Mexican Hispanics, we performed a genome-wide linkage scan in 1,390 subjects from 100 Caribbean Hispanic families on six obesity-related quantitative traits: body mass index (BMI), body weight, waist circumference, waist-to-hip ratio, abdominal and average triceps skinfold thickness after adjusting for significant demographic and lifestyle factors. We then carried out an association analysis of the linkage peaks and the FTO gene in an independent community-based Hispanic subcohort (N = 652, 64% Caribbean Hispanics) from the Northern Manhattan Study. Evidence of linkage was strongest on 1q43 with multipoint LOD score of 2.45 (p = 0.0004) for body weight. Suggestive linkage evidence of LOD > 2.0 was also identified on 1q43 for BMI (LOD = 2.03), 14q32 for abdominal skinfold thickness (LOD = 2.17), 16p12 for BMI (LOD = 2.27) and weight (LOD = 2.26), and 16q23–24 for average triceps skinfold thickness (LOD = 2.32). In the association analysis of 6,440 single nucleotide polymorphisms (SNPs) under 1-LOD unit down regions of our linkage peaks on chromosome 1q43 and 16p12 as well as in the FTO gene, we found that two SNPs (rs6665519 and rs669231) on 1q43 and one FTO SNP (rs12447427) were significantly associated with BMI or body weight after adjustment for multiple testing. Our results suggest that in addition to FTO, multiple genetic loci, particularly those on 1q43 region, may contribute to the variations in obesity-related quantitative traits in Caribbean Hispanics.
Similar content being viewed by others
References
Aissani B, Perusse L, Lapointe G, Chagnon YC, Bouchard L, Walts B, Bouchard C (2006) A quantitative trait locus for body fat on chromosome 1q43 in French Canadians: linkage and association studies. Obesity (Silver Spring) 14:1605–1615
Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211
Amos CI, Krushkal J, Thiel TJ, Young A, Zhu DK, Boerwinkle E, de Andrade M (1997) Comparison of model-free linkage mapping strategies for the study of a complex trait. Genet Epidemiol 14:743–748
Arya R, Duggirala R, Jenkinson CP, Almasy L, Blangero J, O’Connell P, Stern MP (2004) Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in Mexican Americans. Am J Hum Genet 74:272–282
Bosse Y, Chagnon YC, Despres JP, Rice T, Rao DC, Bouchard C, Perusse L, Vohl MC (2004) Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study. J Lipid Res 45:419–426
CDC (2009) Differences in prevalence of obesity among black, white, and Hispanic adults - United States, 2006–2008. MMWR Morb Mortal Wkly Rep 58:740–744
Chagnon YC, Borecki IB, Perusse L, Roy S, Lacaille M, Chagnon M, Ho-Kim MA, Rice T, Province MA, Rao DC, Bouchard C (2000) Genome-wide search for genes related to the fat-free body mass in the Quebec family study. Metabolism 49:203–207
Chagnon YC, Rice T, Perusse L, Borecki IB, Ho-Kim MA, Lacaille M, Pare C, Bouchard L, Gagnon J, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C (2001) Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE. J Appl Physiol 90:1777–1787
Chagnon YC, Merette C, Bouchard RH, Emond C, Roy MA, Maziade M (2004) A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses. Mol Psychiatry 9:1067–1074
Chen W, Li S, Cook NR, Rosner BA, Srinivasan SR, Boerwinkle E, Berenson GS (2004) An autosomal genome scan for loci influencing longitudinal burden of body mass index from childhood to young adulthood in white sibships: The Bogalusa Heart Study. Int J Obes Relat Metab Disord 28:462–469
Collaku A, Rankinen T, Rice T, Leon AS, Rao DC, Skinner JS, Wilmore JH, Bouchard C (2004) A genome-wide linkage scan for dietary energy and nutrient intakes: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. Am J Clin Nutr 79:881–886
Deng HW, Deng H, Liu YJ, Liu YZ, Xu FH, Shen H, Conway T, Li JL, Huang QY, Davies KM, Recker RR (2002) A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. Am J Hum Genet 70:1138–1151
Feitosa MF, Borecki IB, Rich SS, Arnett DK, Sholinsky P, Myers RH, Leppert M, Province MA (2002) Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 70:72–82
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894
Gao X, Starmer J, Martin ER (2008) A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet Epidemiol 32:361–369
Gautam D, Gavrilova O, Jeon J, Pack S, Jou W, Cui Y, Li JH, Wess J (2006) Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency. Cell Metab 4:363–375
Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, Cui Y, Jeon J, Wess J (2007) Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes Metab 9(Suppl 2):158–169
Gautam D, Jeon J, Li JH, Han SJ, Hamdan FF, Cui Y, Lu H, Deng C, Gavrilova O, Wess J (2008) Metabolic roles of the M3 muscarinic acetylcholine receptor studied with M3 receptor mutant mice: a review. J Recept Signal Transduct Res 28:93–108
Guo Y, Traurig M, Ma L, Kobes S, Harper I, Infante AM, Bogardus C, Baier LJ, Prochazka M (2006) CHRM3 gene variation is associated with decreased acute insulin secretion and increased risk for early-onset type 2 diabetes in Pima Indians. Diabetes 55:3625–3629
Hsueh WC, Mitchell BD, Schneider JL, St Jean PL, Pollin TI, Ehm MG, Wagner MJ, Burns DK, Sakul H, Bell CJ, Shuldiner AR (2001) Genome-wide scan of obesity in the Old Order Amish. J Clin Endocrinol Metab 86:1199–1205
Ingelsson E, Larson MG, Vasan RS, O’Donnell CJ, Yin X, Hirschhorn JN, Newton-Cheh C, Drake JA, Musone SL, Heard-Costa NL, Benjamin EJ, Levy D, Atwood LD, Wang TJ, Kathiresan S (2007) Heritability, linkage, and genetic associations of exercise treadmill test responses. Circulation 115:2917–2924
Kraja AT, Rao DC, Weder AB, Cooper R, Curb JD, Hanis CL, Turner ST, de Andrade M, Hsiung CA, Quertermous T, Zhu X, Province MA (2005) Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program. Hypertension 46:751–757
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247
Lima-Leopoldo AP, Sugizaki MM, Leopoldo AS, Carvalho RF, Nogueira CR, Nascimento AF, Martinez PF, Luvizotto RA, Padovani CR, Cicogna AC (2008) Obesity induces upregulation of genes involved in myocardial Ca2+ handling. Braz J Med Biol Res 41:615–620
Lindsay RS, Kobes S, Knowler WC, Bennett PH, Hanson RL (2001) Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians. Diabetes 50:2850–2857
Liu YJ, Xu FH, Shen H, Liu YZ, Deng HY, Zhao LJ, Huang QY, Dvornyk V, Conway T, Davies KM, Li JL, Recker RR, Deng HW (2004) A follow-up linkage study for quantitative trait loci contributing to obesity-related phenotypes. J Clin Endocrinol Metab 89:875–882
Maresca A, Supuran CT (2008) Muscarinic acetylcholine receptors as therapeutic targets for obesity. Expert Opin Ther Targets 12:1167–1175
Marteau JB, Samara A, Dedoussis G, Pfister M, Visvikis-Siest S (2009) Candidate gene microarray analysis in peripheral blood cells for studying hypertension/obesity. Per Med 6:22
Moslehi R, Goldstein AM, Beerman M, Goldin L, Bergen AW (2003) A genome-wide linkage scan for body mass index on Framingham Heart Study families. BMC Genet 4(Suppl 1):S9
O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266
Perusse L, Rice T, Chagnon YC, Despres JP, Lemieux S, Roy S, Lacaille M, Ho-Kim MA, Chagnon M, Province MA, Rao DC, Bouchard C (2001) A genome-wide scan for abdominal fat assessed by computed tomography in the Quebec Family Study. Diabetes 50:614–621
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L, Bouchard C (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14:529–644
Sacco RL, Anand K, Lee HS, Boden-Albala B, Stabler S, Allen R, Paik MC (2004) Homocysteine and the risk of ischemic stroke in a triethnic cohort: the Northern Manhattan Study. Stroke 35:2263–2269
Sacco RL, Sabala EA, Rundek T, Juo SH, Huang JS, DiTullio M, Homma S, Almonte K, Lithgow CG, Boden-Albala B (2007) Design of a family study among high-risk Caribbean Hispanics: the Northern Manhattan Family Study. Ethn Dis 17:351–357
Sacco RL, Blanton SH, Slifer S, Beecham A, Glover K, Gardener H, Wang L, Sabala E, Juo SH, Rundek T (2009a) Heritability and linkage analysis for carotid intima-media thickness: the family study of stroke risk and carotid atherosclerosis. Stroke 40:2307–2312
Sacco RL, Khatri M, Rundek T, Xu Q, Gardener H, Boden-Albala B, Di Tullio MR, Homma S, Elkind MS, Paik MC (2009b) Improving global vascular risk prediction with behavioral and anthropometric factors. The multiethnic NOMAS (Northern Manhattan Cohort Study). J Am Coll Cardiol 54:2303–2311
Saunders CL, Chiodini BD, Sham P, Lewis CM, Abkevich V, Adeyemo AA, de Andrade M, Arya R, Berenson GS, Blangero J, Boehnke M, Borecki IB, Chagnon YC, Chen W, Comuzzie AG, Deng HW, Duggirala R, Feitosa MF, Froguel P, Hanson RL, Hebebrand J, Huezo-Dias P, Kissebah AH, Li W, Luke A, Martin LJ, Nash M, Ohman M, Palmer LJ, Peltonen L, Perola M, Price RA, Redline S, Srinivasan SR, Stern MP, Stone S, Stringham H, Turner S, Wijmenga C, Collier DA (2007) Meta-analysis of genome-wide linkage studies in BMI and obesity. Obesity (Silver Spring) 15:2263–2275
Schelling JR, Abboud HE, Nicholas SB, Pahl MV, Sedor JR, Adler SG, Arar NH, Bowden DW, Elston RC, Freedman BI, Goddard KA, Guo X, Hanson RL, Ipp E, Iyengar SK, Jun G, Kao WH, Kasinath BS, Kimmel PL, Klag MJ, Knowler WC, Nelson RG, Parekh RS, Quade SR, Rich SS, Saad MF, Scavini M, Smith MW, Taylor K, Winkler CA, Zager PG, Shah VO (2008) Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 57:235–243
Shao CH, Wehrens XH, Wyatt TA, Parbhu S, Rozanski GJ, Patel KP, Bidasee KR (2009) Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol 106:1280–1292
Shugart YY, O’Connell JR, Wilson AF (2002) An evaluation of the variance components approach: type I error, power and size of the estimated effect. Eur J Hum Genet 10:133–136
Stone S, Abkevich V, Hunt SC, Gutin A, Russell DL, Neff CD, Riley R, Frech GC, Hensel CH, Jammulapati S, Potter J, Sexton D, Tran T, Gibbs D, Iliev D, Gress R, Bloomquist B, Amatruda J, Rae PM, Adams TD, Skolnick MH, Shattuck D (2002) A major predisposition locus for severe obesity, at 4p15–p14. Am J Hum Genet 70:1459–1468
Sun L, Wilder K, McPeek MS (2002) Enhanced pedigree error detection. Hum Hered 54:99–110
Tobin MD, Tomaszewski M, Braund PS, Hajat C, Raleigh SM, Palmer TM, Caulfield M, Burton PR, Samani NJ (2008) Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population. Hypertension 51:1658–1664
Wess J (1996) Molecular biology of muscarinic acetylcholine receptors. Crit Rev Neurobiol 10:69–99
Wess J, Eglen RM, Gautam D (2007) Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 6:721–733
WTCCC (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678
Wu X, Cooper RS, Borecki I, Hanis C, Bray M, Lewis CE, Zhu X, Kan D, Luke A, Curb D (2002) A combined analysis of genomewide linkage scans for body mass index from the National Heart, Lung, and Blood Institute Family Blood Pressure Program. Am J Hum Genet 70:1247–1256
Yamada M, Miyakawa T, Duttaroy A, Yamanaka A, Moriguchi T, Makita R, Ogawa M, Chou CJ, Xia B, Crawley JN, Felder CC, Deng CX, Wess J (2001) Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410:207–212
Yang W, Kelly T, He J (2007) Genetic epidemiology of obesity. Epidemiol Rev 29:49–61
Acknowledgments
This work was supported by the National Institute of Neurologic Disorders and Stroke [R01NS40807 to R.L.S., R01NS047655 and K24 NS 062737 to T.R., R37NS29993 to R.L.S]; and Evelyn F. McKnight Center for Age-related Memory Loss. We are thankful to the study participants for their collaboration and to all staff of the Northern Manhattan Study and Family Study for their energetic efforts to this study, and in particular Edison Sabala and Janet DeRosa.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dong, C., Beecham, A., Slifer, S. et al. Genome-wide linkage and peak-wide association study of obesity-related quantitative traits in Caribbean Hispanics. Hum Genet 129, 209–219 (2011). https://doi.org/10.1007/s00439-010-0916-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-010-0916-2