OBJECTIVE: To investigate linkage and association between the leptin receptor (LEPR) gene and body composition variables in the Que  bec Family Study (QFS). DESIGN: Single-point linkage analysis using families, and covariance and chi-square analyses using normal weight and obese unrelated subjects from QFS. SUBJECTS: 169 nuclear families were used for linkage study. 308 unrelated subjects (146 males; 162 females) from these families were used for chi-square testing of genotype and allele distributions between subjects with body mass index (BMI)`27 kgam 2 (n 167) and those with BMI ! 27 kgam 2 (n 141), and for a series of covariance analyses using age, plus height for fat mass (FM) and fat free mass (FFM), as covariates. A corrected P value (P*) for multiple tests has been calculated according to P* 1-(1-P) number of phenotypes . MEASUREMENTS: Variables were BMI (in kgam 2 ), sum of six skinfolds (SF6 in mm), FM (in kg), percent body fat (%FAT) and FFM (in kg). Polymerase chain react restricted fragment length polymorphisms PCR-RFLP) was used to identi®ed a K109R substitution in exon 4, a Q223R in exon 6, a K656N in exon 14 and an automatic DNA sequencer for a CA microsatellite repeat in intron 3, and heteroduplex pattern on non-denaturing gel for a CTTT repeat in intron 16. RESULTS: Good evidence of linkage was observed for Q223R with FM (P 0.005; P* 0.02), and for the CTTT repeat with FFM (P 0.007; P* 0.03). Weaker linkages (0.02 P 0.05) were also observed between Q223R and BMI, SF6 and FFM, between the CA repeat and BMI, SF6 and FM, and between the CTTT repeat and FM. Moreover, FFM values were found to be different among genotypes for the CTTT repeat polymorphism with heavier females, carriers of the 123* allele at the CTTT repeat, showing 4 kg less of FFM (43.6 AE 1.0, n 21 vs 47.7 AE 0.8, n 30; P 0.005; P* 0.02) than non-carriers. Also, at the Q223R polymorphism, in lower BMI males, carriers of the Q223 allele were 4 kg lighter in FFM (53.4 AE 0.6, n 47 vs 56.6 AE 0.9, n 18; P 0.005; P* 0.02) than non-carriers. No signi®cant differences were observed between lower and higher BMI subjects in genotype and allele frequency distributions for any of the polymorphisms. CONCLUSIONS: These results indicate that the LEPR gene is involved in the regulation of the body composition in human particularly of FFM in the QFS.

This report constitutes the sixth update of the human obesity gene map incorporating published results up to the end of October 1999. Evidence from the rodent and human obesity cases caused by single gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTL) uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, pig and chicken models, association and linkage studies with candidate genes and other markers is reviewed. Twenty-five human cases of obesity can now be explained by variation in five genes. Twenty Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models reaches now 98. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 89 reports of positive associations pertaining to 40 candidate genes. Finally, 44 loci have linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes can be found on all autosomes, with chromosomes 14 and 21 showing each one locus only. The number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes continues to increase and is now well above 200.

OBJECTIVE:To investigate whether interactions between glucocorticoid receptor (GRL), lipoprotein lipase (LPL) and adrenergic receptor (ADR) gene markers contribute to individual differences in indicators of adiposity and abdominal obesity, including visceral fat level. DESIGN AND SUBJECTS: Cross-sectional study; 742 individuals from the phase 2 of the Québec Family Study cohort. MEASUREMENTS: Total body fat assessed by hydrodensitometry and the sum of six skinfolds. Abdominal fat areas measured by computed tomography and adjusted for age, sex and total fat mass in all analyses. GRL Bcl I, a2A-ADR Dra I and b2-ADR Ban I markers were typed by Southern blot, and other markers by polymerase chain reaction technique. RESULTS: It is confirmed that the 4.5 kb allele of the GRL BclI polymorphism is associated with a higher amount of abdominal visceral fat (AVF) depot (P for trend < 0.001) independent of the level of total body fat. Furthermore, the a2-ADR Dra I variant is associated with lower cross-sectional areas of abdominal total (P ¼ 0.003) and subcutaneous (P ¼ 0.012) adipose tissue. Genegene interactions between GRL and a2-ADR genes affecting overall adiposity (P ¼ 0.016) as well as between GRL and b2-ADR genes (P ¼ 0.049) having influence on total abdominal fat levels were observed. When the three genes were considered together in the same analysis, significant interactions having influence on overall adiposity (P ¼ 0.017), abdominal total (P ¼ 0.032) and visceral fat (P ¼ 0.002) were observed. About 1 -2% of the total variation in total fatness and abdominal fat was explained by these gene -gene interactions. CONCLUSION: There is an association between the GRL BclI polymorphism and increased AVF levels independent of the level of total body fat. The a2-ADR DraI variant is associated with a lower cross-sectional area of abdominal total fat. Numerous interactions between GRL and ADR markers on overall adiposity and total abdominal fat as well as between GRL, LPL and ADR genes on overall adiposity, abdominal total and visceral fat suggest that the genetic architecture of body fat content and adipose tissue distribution is complex although some genes, like GRL, may have ubiquitous effects.

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region. Keywords: schizophrenia; bipolar disorder; melanin-concentrating hormone Adverse metabolic effects of antipsychotics such as weight gain may contribute to noncompliance with treatment and may lead to medical morbidity when obesity is reached.1 Indeed, obesity, as defined by a body mass index (BMI) of 30 kg/m 2 and greater 2 is associated with higher risks of developing cardiovascular diseases, hypertension, type II diabetes, dyslipidemia, arthritis, and some forms of cancer. The estimate of the proportion of schizophrenic (SZ)-or bipolar disorder (BP)-treated patients experiencing significant weight gain for a given antipsychotic varies between 10 and 50%, according to the population studied, and the dose and the duration of the follow-up. For example, 25% of the patients treated with fluphenazine experienced significant weight gain after 1 month, and this proportion reaches 50% in 1 year.3 In patients treated with olanzapine for up to 3 years, weight gain tended toward a plateau at approximately 36 weeks. 4 The proportion of patients experiencing weight gain also varies according to the antipsychotic used, the greatest proportion being observed with olanzapine and clozapine, followed by chlorpromazine and thioridazine/ mesoridazine, and the lowest with ziprasidone and molindone, the latter even inducing a weight loss. 5Antipsychotics can also induce other metabolic perturbations such as hyperglycemia,...

An update of the human obesity gene map up to October 1996 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature, single-gene mutation rodent models, quantitative trait loci uncovered in crossbreeding experiments with mouse, rat, and pig models, association and case-control studies with candidate genes, and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all these loci reveals that only 4 of the 24 human chromosomes are not yet represented, i.e., 9, 18, 21, and Y. Several chromosome arms are characterized by the presence of several putative loci. The following arms include at least three such loci: 1p, 1q, 3p, 4q, 6p, 7q, 8p, 8q, 11p, 11q, 15q, 20q, and Xq. Studies with negative association and linkage results are also reviewed.

Suggestive linkages between markers on human lp32-p22 and body fat and insulin levels in the Quebec family study. Obes Res. 1997;5:115-121. A single-gene rodent mutation (diabetes) and a quantitative trait locus (dietary obese I) mapped to the mid portion of mouse chromosome 4 have been related to obesity and/or insulin levels. Synteny relationships place their putative human homologs on lp31 and 1~3 5~3 1 , respectively. In 137 sibships of adult brothers and sisters from the Quebec Family Study, genetic linkages between seven microsatellite markers from lp32-p22 and various obesity-and diabetes-related quantitative phenotypes were examined using single locus sibpair linkage analysis. Suggestive linkages were observed between markers DlS476 and body mass index (p=0.05), fat mass (p=0.02), the sum of six skinfolds (p=0.02), the insulin area after an oral glucose tolerance test (p=0.02), and between the neighboring marker DlS200 and body mass index (p=0.03), and fat mass (p=0.009). Suggestive linkages were also observed between the more telomeric markers DlS193 and body mass index (p=0.03), and between the neighboring marker DlS197 and fasting insulin level extremity skinfolds ratio. These linkages suggest that human homologs of the mouse diabetes or dietary obese I and/or other genes in this interval on chromosome 1 play a role in the regulation of body mass, body composition, and insulin levels, but not of subcutaneous fat distribution.

OBJECTIVE:To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study. SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects. MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO 2max (FFA60%); and fasting insulin (INS). STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene. RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P ¼ 0.0005), FAT (P ¼ 0.0007), %FAT (P ¼ 0.0003), SF8 (P ¼ 0.0001), ASF (P ¼ 0.03) and ATF (P ¼ 0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P ¼ 0.005) and SF8 (P ¼ 0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P ¼ 0.004), FAT (P ¼ 0.009), %FAT (P ¼ 0.01) and SF8 (P ¼ 0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%. CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race-and insulin-dependent.

A deficient dopamine D 2 receptor (DA2) formation or action may contribute to hypertension via an increase of catecholamine release. In addition, Axis II personality disorders that appears odd or eccentric (cluster A) is associated with a low density of DA2. This study sought to examine if a NcoI restriction fragment length polymorphism (C to T transition) in exon 6 of the dopamine D 2 receptor gene (DRD2) was associated with these characteristics. The genotypes (CC, CT and TT) were compared in anthropometric, endocrine, metabolic and haemodynamic variables as well as estimates of personality disorders in 284 randomly selected 51-year-old men. Homozygotes for the C allele constituted 49% of the men and homozygotes for the T allele 9%, while heterozygotes were 41%. The TT genotype was associated with elevated systolic and diastolic blood pressure,