title: 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 >or=35 kg/m(2)), and 84.8% of the nuclear families possessed >or=1 morbidly obese sibling (BMI >or=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 >or=35 phenotypic subset, and 5q and 10q for an inclusive BMI >or=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 >or=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 >or=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 >or=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.
authors.affiliation: Hammersmith Genome Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College Faculty of Medicine, London, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.forename: Michael
authors.initials: M
authors.lastname: Benzinou
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lemainque
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.forename: Arnaud
authors.initials: A
authors.lastname: Basdevant
authors.forename: Bernard
authors.initials: B
authors.lastname: Guy-Grand
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D015992:Body Mass Index; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D044465:White People / Q000235:genetics*