Identification of four chromosomal loci determining obesity in a multifactorial mouse model.

We previously described a new mouse model for multigenic obesity, designated BSB. We now report the use of a complete linkage map approach to identify loci contributing to body fat and other traits associated with obesity in this model. Four loci exhibiting linkage with body fat, or with the weights of four different fat depots, residing on mouse chromosomes 6, 7, 12, and 15, were identified and confirmed by analysis of additional BSB mice. Each of the four loci differed with respect to their effects on the percent of body fat, specific fat depots and plasma lipoproteins. The loci exhibited allele-specific, non-additive interactions. A locus for hepatic lipase activity was co-incident with the body fat and total cholesterol loci on chromosome 7, providing a possible mechanism linking plasma lipoproteins and obesity. The chromosome 7 locus affecting body fat, total cholesterol and hepatic lipase activity was isolated in congenic strains whose donor strain regions overlap with the chromosome 7 BSB locus. These results provide candidate genes and candidate loci for the analysis of human obesity.

[1]  J. Witte,et al.  Genetic dissection of complex traits , 1996, Nature Genetics.

[2]  D. West,et al.  Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model. , 1994, The Journal of clinical investigation.

[3]  Eric S. Lander,et al.  A genetic map of the mouse with 4,006 simple sequence length polymorphisms , 1994, Nature Genetics.

[4]  B. Paigen,et al.  Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. , 1994, Metabolism: clinical and experimental.

[5]  C. Bouchard,et al.  An exploratory investigation of genetic linkage with body composition and fatness phenotypes: the Québec Family Study. , 1994, Obesity research.

[6]  P. Björntorp,et al.  Growth hormone secretion after testosterone administration to men with visceral obesity. , 1994, Obesity research.

[7]  E. Lander,et al.  Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse , 1993, Cell.

[8]  K. Svenson,et al.  Linkage mapping of 40 randomly isolated liver cDNA clones in the mouse. , 1993, Genomics.

[9]  E. Lander,et al.  A genetic linkage map of the mouse: current applications and future prospects. , 1993, Science.

[10]  N. Risch,et al.  Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[11]  R. Niaura,et al.  Stress and lipoprotein metabolism: modulators and mechanisms. , 1993, Metabolism: clinical and experimental.

[12]  K. Svenson,et al.  Coincidence of genetic loci for plasma cholesterol levels and obesity in a multifactorial mouse model. , 1993, The Journal of clinical investigation.

[13]  J. Todd,et al.  Polygenic control of autoimmune diabetes in nonobese diabetic mice , 1993, Nature Genetics.

[14]  A. Lusis,et al.  Chromosomal localization of lipolytic enzymes in the mouse: pancreatic lipase, colipase, hormone-sensitive lipase, hepatic lipase, and carboxyl ester lipase. , 1993, Journal of lipid research.

[15]  A. Lusis,et al.  BSB: a new mouse model of multigenic obesity. , 1993, Obesity research.

[16]  Nancy A. Jenkins,et al.  Anchored reference loci for comparative genome mapping in mammals , 1993, Nature Genetics.

[17]  Uta Francke,et al.  Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader–Willi syndrome region , 1992, Nature Genetics.

[18]  M. Meisler,et al.  Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7. , 1992, Genomics.

[19]  R. Krauss,et al.  Reduced HDL2 cholesterol subspecies and elevated postheparin hepatic lipase activity in older men with abdominal obesity and asymptomatic myocardial ischemia. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[20]  E S Lander,et al.  A genetic map of the mouse suitable for typing intraspecific crosses. , 1992, Genetics.

[21]  C N Boozer,et al.  Dietary obesity in nine inbred mouse strains. , 1992, The American journal of physiology.

[22]  P. Björntorp,et al.  Is abdominal body fat distribution a major explanation for the sex difference in the incidence of myocardial infarction? The study of men born in 1913 and the study of women, Göteborg, Sweden. , 1992, American journal of epidemiology.

[23]  P. Björntorp.  Visceral fat accumulation: the missing link between psychosocial factors and cardiovascular disease? , 1991, Journal of internal medicine.

[24]  C. Bouchard,et al.  Genetics of obesity and human energy metabolism , 1991, Proceedings of the Nutrition Society.

[25]  C. Bouchard,et al.  Current understanding of the etiology of obesity: genetic and nongenetic factors. , 1991, The American journal of clinical nutrition.

[26]  P. Björntorp,et al.  Fat distribution and gender differences in serum lipids in men and women from four European communities. , 1991, Atherosclerosis.

[27]  D. Coleman,et al.  Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. , 1990, The Journal of heredity.

[28]  J. Love,et al.  Towards construction of a high resolution map of the mouse genome using PCR-analysed microsatellites. , 1990, Nucleic acids research.

[29]  A Tremblay,et al.  Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. , 1990, Arteriosclerosis.

[30]  P. Björntorp.  "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. , 1990, Arteriosclerosis.

[31]  D. Brindley,et al.  Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis. , 1989, Clinical science.

[32]  C. Bouchard,et al.  Role of hepatic-triglyceride lipase activity in the association between intra-abdominal fat and plasma HDL cholesterol in obese women. , 1989, Arteriosclerosis.

[33]  E. Skamene,et al.  ATH-3, a new gene for atherosclerosis in the mouse. , 1989, Clinical and investigative medicine. Medecine clinique et experimentale.

[34]  M. Braga,et al.  Exploratory Data Analysis , 2018, Encyclopedia of Social Network Analysis and Mining. 2nd Ed..

[35]  M. Daly,et al.  MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. , 1987, Genomics.

[36]  A. Lusis,et al.  Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. J. Forrest,et al.  IMPAIRED GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING FACTOR AND INSULIN‐HYPOGLYCAEMIA IN OBESITY , 1985, Clinical endocrinology.

[38]  M. Schotz,et al.  Hepatic lipase. Purification and characterization. , 1984, Biochimica et biophysica acta.

[39]  J. Canary,et al.  Growth hormone response in the thinned obese. , 1972, The Journal of clinical endocrinology and metabolism.

[40]  P. Crockford,et al.  Hormones and obesity: changes in insulin and growth hormone secretion following surgically induced weight loss. , 1970, Canadian Medical Association journal.

[41]  G. Snell,et al.  Histocompatibility genes of mce. 8. The alleles of the H-1 locus. , 1968, Transplantation.

[42]  G. Snell,et al.  HISTOCOMPATIBILITY GENES OF MICE VIII. THE ALLELES OF THE H‐1 LOCUS , 1968 .

[43]  J. Qiao,et al.  Influence of the apoA-II gene locus on HDL levels and fatty streak development in mice. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[44]  Z. Hochberg,et al.  The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa. , 1992, Metabolism: clinical and experimental.

[45]  E. Lander,et al.  Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. , 1989, Genetics.

[46]  A N Peiris,et al.  Health risks of obesity. , 1989, The Medical clinics of North America.

[47]  C. Bouchard,et al.  Heredity and body fat. , 1988, Annual review of nutrition.

[48]  C. Bouchard,et al.  Inheritance of the amount and distribution of human body fat. , 1988, International journal of obesity.

[49]  P. Björntorp,et al.  The health consequences of moderate obesity. , 1981, International journal of obesity.

[50]  W. Dahms,et al.  Endocrine function in human obesity. , 1981, Metabolism: clinical and experimental.

[51]  L. Garfinkel,et al.  Variations in mortality by weight among 750,000 men and women. , 1979, Journal of chronic diseases.