A Major Predisposition Locus for Severe Obesity, at 4p15-p14

Abstract

Although the predisposition to morbid obesity is heritable, the identities of the disease-causing genes are largely unknown. Therefore, we have conducted a genomewide search with 628 markers, using multigenerational Utah pedigrees to identify genes involved in predisposition to obesity. In the genomewide search, we identified a highly significant linkage to high body-mass index in female patients, at D4S2632, with a multipoint heterogeneity LOD (HLOD) score of 6.1 and a nonparametric linkage (NPL) score of 5.3. To further delineate the linkage, we increased both the marker density around D4S2632 and the size of our pedigree data set. As a result, the linkage evidence increased to a multipoint HLOD score of 9.2 (at D4S3350) and an NPL score of 11.3. Evidence from almost half of the families in this analysis support this linkage, and therefore the gene in this region might account for a significant percentage of the genetic predisposition to severe obesity in females. However, further studies are necessary to clarify the effect that this gene has in males and in the general population.

Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon

“…QTLs has been reported in this same human chromosomal region for the related phenotypes of body mass index, fat mass and severe obesity (Mitchell et al, 1999;Stone et al, 2002;Perusse et al, 2005). This chromosomal region harbors the b-3 adrenergic receptor, which has been associated with obesity-related phenotypes including body mass index, fat mass, waist circumference and D19S591 D19S1034 D19S586 D19S840 D19S714 D19S410 D19S925 D19S433 D19S75 D19S587 D19S178 D19S246 D19S601 D19S589 D19S418 D19S254 0 10 20 30 40 50 60 Cross-species replication of a resistin mRNA QTL ME Tejero et al body weight in human populations (Mitchell et al, 1999;Perusse et al, 2005).…”

Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Polymorphism Is Not Associated with Essential Hypertension and Type 2 Diabetes Mellitus in Chinese Population

“…PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α. fatty acid levels in Dutch dyslipidemic families (13) and to high BMI in Utah pedigrees (33). Amino acids 338-403 of PGC-1α contain a major domain of interaction with PPARγ, and thereby impact the ability of cells to uptake fatty acids and store them in adipocytes, while residues 403-570 of PGC-1α interact with myocyte enhancer factor 2C (MEF2C), which is responsible for activation of the GLUT4 gene (6,8).…”

A genome scan for loci influencing anti-atherogenic serum bilirubin levels

“…The main differences between these two methods were discussed recently. 30 NPL statistics can detect genes with causal mutations that segregate among individuals with either low or high bilirubin values. It not only circumvents the problem of model mis-specifications but also has the ability to recognize the effects of multiple mutations, even if their penetrances, phenotypic effects, and modes of inheritance are quite different.…”

“…An asymptotic formula was derived to adjust NPL scores, such that equal LOD and NPL scores translated to the same P values. 30 Other statistical methods We compared age and HDL cholesterol concentrations between CAD patients and controls by unpaired t-tests. Wilcoxon rank sum tests were used for bilirubin concentrations.…”