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Bivariate genome linkage analysis suggests pleiotropic effects on chromosomes 20p and 3p for body fat mass and lean mass

  • JIAN ZHAO (a1), PENG XIAO (a2), YAN GUO (a1), YONG-JUN LIU (a3), YU-FANG PEI (a1), TIE-LIN YANG (a1), FENG PAN (a1) (a2), YUAN CHEN (a1), HUI SHEN (a3), LAN-JUAN ZHAO (a3), CHRISTOPHER J. PAPASIAN (a3), BETTY M. DREES (a3), JAMES J. HAMILTON (a3), HONG-YI DENG (a3), ROBERT R. RECKER (a2) and HONG-WEN DENG (a1) (a3) (a4)...


Total body fat mass (TBFM) and total body lean mass (TBLM) are the major components of the human body. Although these highly correlated phenotypic traits are frequently used to characterize obesity, the specific shared genetic factors that influence both traits remain largely unknown. Our study was aimed at identifying common quantitative trait loci (QTLs) contributing to both TBFM and TBLM. We performed a whole genome-linkage scan study in a large sample of 3255 subjects from 420 Caucasian pedigrees. Bivariate linkage analysis was carried out in both the entire sample and gender-specific subsamples. Several potentially important genomic regions that may harbour QTLs important for TBFM and TBLM were identified. For example, 20p12-11 achieved a LOD score of 2·04 in the entire sample and, in the male subsample, two genomic regions, 20p12 (LOD=2·08) and 3p26-25 (LOD=1·92), showed suggestive linkage. In addition, two-point linkage analyses for chromosome X showed suggestive linkages on Xp22 in the entire sample (LOD=2·14) and significant linkage on Xp22 in the female subsample (LOD=3·05). Complete pleiotropy was suggested for 20p12 and 3p26-25 in males. Our results suggest that QTLs on chromosomes 20p12, 3p26-25 and Xp22 may jointly influence TBFM and TBLM. Further fine mapping and gene identification studies for these pleiotropic effects are needed.

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Corresponding author

Corresponding author. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China, 710049. Tel: 0086-29-82667148. Fax: 0086-29-82665836. e-mail:


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Abecasis, G. R., Cherny, S. S., Cookson, W. O. & Cardon, L. R. (2002). Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genetics 30, 97101.
Agarwal, A. K. & Garg, A. (2002). A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. The Journal of Clinical Endocrinology and Metabolism 87, 408411.
Ahmad, W., De Fusco, M., ul Haque, M. F., Aridon, P., Sarno, T., Sohail, M., ul Haque, S., Ahmad, M., Ballabio, A., Franco, B. & Casari, G. (1999). Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity. European Journal of Human Genetics 7, 828832.
Almasy, L. & Blangero, J. (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics 62, 11981211.
Almasy, L., Dyer, T. D. & Blangero, J. (1997). Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genetic Epidemiology 14, 953958.
Amos, C. I. (1994). Robust variance-components approach for assessing genetic linkage in pedigrees. American Journal of Human Genetics 54, 535543.
Andersen, K. L., Echwald, S. M., Larsen, L. H., Hamid, Y. H., Glumer, C., Jorgensen, T., Borch-Johnsen, K., Andersen, T., Sorensen, T. I., Hansen, T. & Pedersen, O. (2005). Variation of the McKusick–Kaufman gene and studies of relationships with common forms of obesity. The Journal of Clinical Endocrinology and Metabolism 90, 225230.
Arya, R., Duggirala, R., Jenkinson, C. P., Almasy, L., Blangero, J., O'Connell, P. & Stern, M. P. (2004). Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in Mexican Americans. American Journal of Human Genetics 74, 272282.
Barsh, G. S., Farooqi, I. S. & O'Rahilly, S. (2000). Genetics of body-weight regulation. Nature 404, 644651.
Boomsma, D. I. & Dolan, C. V. (1998). A comparison of power to detect a QTL in sib-pair data using multivariate phenotypes, mean phenotypes, and factor scores. Behavior Genetics 28, 329340.
Burr, D. B. (1997). Muscle strength, bone mass, and age-related bone loss. Journal of Bone and Mineral Research 12, 15471551.
Carroll, K. K. (1998). Obesity as a risk factor for certain types of cancer. Lipids 33, 10551059.
Chen, A. S., Marsh, D. J., Trumbauer, M. E., Frazier, E. G., Guan, X. M., Yu, H., Rosenblum, C. I., Vongs, A., Feng, Y., Cao, L., Metzger, J. M., Strack, A. M., Camacho, R. E., Mellin, T. N., Nunes, C. N., Min, W., Fisher, J., Gopal-Truter, S., MacIntyre, D. E., Chen, H. Y. & Van der Ploeg, L. H. (2000). Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genetics 26, 97102.
Deng, H. W., Deng, H., Liu, Y. J., Liu, Y. Z., Xu, F. H., Shen, H., Conway, T., Li, J. L., Huang, Q. Y., Davies, K. M. & Recker, R. R. (2002). A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. American Journal of Human Genetics 70, 11381151.
Deng, H. W., Shen, H., Xu, F. H., Deng, H., Conway, T., Liu, Y. J., Liu, Y. Z., Li, J. L., Huang, Q. Y., Davies, K. M. & Recker, R. R. (2003). Several genomic regions potentially containing QTLs for bone size variation were identified in a whole-genome linkage scan. American Journal of Medical Genetics. Part A 119, 121131.
Durand, E., Boutin, P., Meyre, D., Charles, M. A., Clement, K., Dina, C. & Froguel, P. (2004). Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians. Diabetes 53, 24832486.
El Haschimi, K., Dufresne, S. D., Hirshman, M. F., Flier, J. S., Goodyear, L. J. & Bjorbaek, C. (2003). Insulin resistance and lipodystrophy in mice lacking ribosomal S6 kinase 2. Diabetes 52, 13401346.
Fischer, T. M. & Van der Werf, J. H. J. (2006). Genetic analysis of weight, fat and muscle depth in growing lambs using random regression models. Animal Science 82, 1322.
Frayn, K. N. & Coppack, S. W. (1992). Insulin resistance, adipose tissue and coronary heart disease. Clinical Science (London) 82, 18.
Gray, D. S. & Bauer, M. (1991). The relationship between body fat mass and fat-free mass. Journal of the American College of Nutrition 10, 6368.
Green, J. S., Parfrey, P. S., Harnett, J. D., Farid, N. R., Cramer, B. C., Johnson, G., Heath, O., McManamon, P. J., O'Leary, E. & Pryse-Phillips, W. (1989). The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence–Moon–Biedl syndrome. The New England Journal of Medicine 321, 10021009.
Hanisch, D., Dittmar, M., Hohler, T. & Alt, K. W. (2004). Contribution of genetic and environmental factors to variation in body compartments – a twin study in adults. Anthropologischer Anzeiger 62, 5160.
Hayashi, T., Huang, J. & Deeb, S. S. (2000). RINX(VSX1), a novel homeobox gene expressed in the inner nuclear layer of the adult retina. Genomics 67, 128139.
Hegele, R. A., Cao, H., Frankowski, C., Mathews, S. T. & Leff, T. (2002). PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 51, 35863590.
Hsu, F. C., Lenchik, L., Nicklas, B. J., Lohman, K., Register, T. C., Mychaleckyj, J., Langefeld, C. D., Freedman, B. I., Bowden, D. W. & Carr, J. J. (2005). Heritability of body composition measured by DXA in the diabetes heart study. Obesity Research 13, 312319.
Katsanis, N., Beales, P. L., Woods, M. O., Lewis, R. A., Green, J. S., Parfrey, P. S., Ansley, S. J., Davidson, W. S. & Lupski, J. R. (2000). Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nature Genetics 26, 6770.
Katsanis, N., Ansley, S. J., Badano, J. L., Eichers, E. R., Lewis, R. A., Hoskins, B. E., Scambler, P. J., Davidson, W. S., Beales, P. L. & Lupski, J. R. (2001). Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science 293, 22562259.
Kelley, D. E. (2005). Skeletal muscle fat oxidation: timing and flexibility are everything. The Journal of Clinical Investigation 115, 16991702.
Kopelman, P. G. (2000). Obesity as a medical problem. Nature 404, 635643.
Korbonits, M., Gueorguiev, M., O'Grady, E., Lecoeur, C., Swan, D. C., Mein, C. A., Weill, J., Grossman, A. B. & Froguel, P. (2002). A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. The Journal of Clinical Endocrinology and Metabolism 87, 40054008.
Kruglyak, L., Daly, M. J., Reeve-Daly, M. P. & Lander, E. S. (1996). Parametric and nonparametric linkage analysis: a unified multipoint approach. American Journal of Human Genetics 58, 13471363.
Lander, E. & Kruglyak, L. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics 11, 241247.
Li, J. L., Deng, H., Lai, D. B., Xu, F., Chen, J., Gao, G., Recker, R. R. & Deng, H. W. (2001). Toward high-throughput genotyping: dynamic and automatic software for manipulating large-scale genotype data using fluorescently labeled dinucleotide markers. Genome Research 11, 13041314.
Lin, J., Wu, H., Tarr, P. T., Zhang, C. Y., Wu, Z., Boss, O., Michael, L. F., Puigserver, P., Isotani, E., Olson, E. N., Lowell, B. B., Bassel-Duby, R. & Spiegelman, B. M. (2002). Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418, 797801.
Marlow, A. J., Fisher, S. E., Francks, C., MacPhie, I. L., Cherny, S. S., Richardson, A. J., Talcott, J. B., Stein, J. F., Monaco, A. P. & Cardon, L. R. (2003). Use of multivariate linkage analysis for dissection of a complex cognitive trait. American Journal of Human Genetics 72, 561570.
Masaki, T., Chiba, S., Yasuda, T., Noguchi, H., Kakuma, T., Watanabe, T., Sakata, T. & Yoshimatsu, H. (2004). Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 53, 22502260.
Miraglia del Giudice, E., Cirillo, G., Santoro, N., D'Urso, L., Carbone, M. T., Di Toro, R. & Perrone, L. (2001). Molecular screening of the proopiomelanocortin (POMC) gene in Italian obese children: report of three new mutations. International Journal of Obesity and Related Metabolic Disorders 25, 6167.
Nguyen, T. V., Sambrook, P. N. & Eisman, J. A. (1998). Bone loss, physical activity, and weight change in elderly women: the Dubbo Osteoporosis Epidemiology Study. Journal of Bone and Mineral Research 13, 14581467.
Nonogaki, K., Abdallah, L., Goulding, E. H., Bonasera, S. J. & Tecott, L. H. (2003) Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT(2C) receptor mutant mice. Diabetes 52, 315320.
O'Connell, J. R. & Weeks, D. E. (1998). PedCheck: a program for identification of genotype incompatibilities in linkage analysis. American Journal of Human Genetics 63, 259266.
Petit, M. A., Beck, T. J., Shults, J., Zemel, B. S., Foster, B. J. & Leonard, M. B. (2005). Proximal femur bone geometry is appropriately adapted to lean mass in overweight children and adolescents. Bone 36, 568576.
Platte, P., Papanicolaou, G. J., Johnston, J., Klein, C. M., Doheny, K. F., Pugh, E. W., Roy-Gagnon, M. H., Stunkard, A. J., Francomano, C. A. & Wilson, A. F. (2003). A study of linkage and association of body mass index in the Old Order Amish. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 121, 7180.
Price, R. A. (2002). Genetics and common obesities: background, current status, strategies and future prospects. In Obesity, Theory and Therapy (ed. Wadden, T.). pp. 7394. New York: Guilford Publications.
Price, R. A., Cadoret, R. J., Stunkard, A. J. & Troughton, E. (1987). Genetic contributions to human fatness: an adoption study. The American Journal of Psychiatry 144, 10031008.
Savage, D. B., Tan, G. D., Acerini, C. L., Jebb, S. A., Agostini, M., Gurnell, M., Williams, R. L., Umpleby, A. M., Thomas, E. L., Bell, J. D., Dixon, A. K., Dunne, F., Boiani, R., Cinti, S., Vidal-Puig, A., Karpe, F., Chatterjee, V. K. & O'Rahilly, S. (2003). Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 52, 910917.
Self, S. G. & Liang, K.-Y. (1987). Asymptotic properties of maximum likelihood estimators and likelihood ratio tests under nonstandard conditions. Journal of the American Statistical Association 82, 605609.
Semina, E. V., Mintz-Hittner, H. A. & Murray, J. C. (2000). Isolation and characterization of a novel human paired-like homeodomain-containing transcription factor gene, VSX1, expressed in ocular tissues. Genomics 63, 289293.
Shibata, R., Sato, K., Pimentel, D. R., Takemura, Y., Kihara, S., Ohashi, K., Funahashi, T., Ouchi, N. & Walsh, K. (2005). Adiponectin protects against myocardial ischemia–reperfusion injury through. Nature Medicine 11, 10961103.
Shimabukuro, M., Koyama, K., Chen, G., Wang, M. Y., Trieu, F., Lee, Y., Newgard, C. B. & Unger, R. H. (1997). Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proceedings of the National Academy of Sciences of the USA 94, 46374641.
Slavotinek, A. M., Stone, E. M., Mykytyn, K., Heckenlively, J. R., Green, J. S., Heon, E., Musarella, M. A., Parfrey, P. S., Sheffield, V. C. & Biesecker, L. G. (2000). Mutations in MKKS cause Bardet–Biedl syndrome. Nature Genetics 26, 1516.
Suviolahti, E., Oksanen, L. J., Ohman, M., Cantor, R. M., Ridderstrale, M., Tuomi, T., Kaprio, J., Rissanen, A., Mustajoki, P., Jousilahti, P., Vartiainen, E., Silander, K., Kilpikari, R., Salomaa, V., Groop, L., Kontula, K., Peltonen, L. & Pajukanta, P. (2003). The SLC6A14 gene shows evidence of association with obesity. The Journal of Clinical Investigation 112, 17621772.
Ukkola, O., Ravussin, E., Jacobson, P., Snyder, E. E., Chagnon, M., Sjostrom, L. & Bouchard, C. (2001). Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. The Journal of Clinical Endocrinology and Metabolism 86, 39963999.
Van der Meulen, M. C., Moro, M., Kiratli, B. J., Marcus, R. & Bachrach, L. K. (2000). Mechanobiology of femoral neck structure during adolescence. Journal of Rehabilitation Research and Development 37, 201208.
Williams, J. T., Van Eerdewegh, P., Almasy, L. & Blangero, J. (1999). Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results. American Journal of Human Genetics 65, 11341147.
Wolfrum, C., Shih, D. Q., Kuwajima, S., Norris, A. W., Kahn, C. R. & Stoffel, M. (2003). Role of Foxa-2 in adipocyte metabolism and differentiation. The Journal of Clinical Investigation 112, 345356.
Zhao, L. J., Guo, Y. F., Xiong, D. H., Xiao, P., Recker, R. R. & Deng, H. W. (2006). Is a gene important for bone resorption a candidate for obesity? An association and linkage study on the RANK (receptor activator of nuclear factor-kappaB) gene in a large Caucasian sample. Human Genetics 120, 561570.
Zhao, L. J., Xiao, P., Liu, Y. J., Xiong, D. H., Shen, H., Recker, R. R. & Deng, H. W. (2007). A genome-wide linkage scan for quantitative trait loci underlying obesity related phenotypes in 434 Caucasian families. Human Genetics 121, 145148.


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