Genome-wide Linkage Analysis for Severe Obesity in French Caucasians Finds Significant Susceptibility Locus on Chromosome 19q

Abstract

To ascertain whether distinct chromosomal loci existed that were linked to severe obesity, as well as to utilize the increased heritability of this excessive phenotype, we performed a genome-wide scan in severely obese French Caucasians. The 109 selected pedigrees, totaling 447 individuals, required both the proband and a sibling to be severely obese (BMI ≥35 kg/m²), and 84.8% of the nuclear families possessed ≥1 morbidly obese sibling (BMI ≥40). Severe and morbid obesity are still relatively rare in France, with rates of 2.5 and 0.6%, respectively. The initial genome scan consisted of 395 evenly spaced microsatellite markers. Six regions were found to have suggestive linkage on 4q, 6cen-q, 17q, and 19q for a BMI ≥35 phenotypic subset, and 5q and 10q for an inclusive BMI ≥27 group. The highest peak on chromosome 19q (logarithm of odds [LOD] = 3.59) was significant by genome scan simulation testing (P = 0.042). These regions then underwent second-stage mapping with an additional set of 42 markers. BMI ≥35 analysis defined regions on 17q23.3–25.1 and 19q13.33–13.43 with an maximum likelihood score LOD of 3.16 and 3.21, respectively. Subsequent pooled data analysis with an additional previous population of 66 BMI ≥35 sib-pairs led to a significant LOD score of 3.8 at the 19q locus (empirical P = 0.023). For more moderate obesity and overweight susceptibility loci, BMI ≥27 analysis confirmed suggestive linkage to chromosome regions 5q14.3–q21.3 (LOD = 2.68) and 10q24.32–26.2 (LOD = 2.47). Plausible positional candidate genes include NR1H2 and TULP2.