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Diabetes 53:1857-1865, 2004
© 2004 by the American Diabetes Association, Inc.

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

Christopher G. Bell1, Michael Benzinou1, Afshan Siddiq1, Cécile Lecoeur1, Christian Dina2, Arnaud Lemainque3, Karine Clément4, Arnaud Basdevant4, Bernard Guy-Grand4, Charles A. Mein5, David Meyre2, and Philippe Froguel1,2

1 Hammersmith Genome Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College Faculty of Medicine, London, U.K
2 Centre National de la Recherche Scientifique, UMR 8090, Pasteur Institute, Lille, France
3 Centre National de Genotypage, Evry, France
4 Hôtel-Dieu Hospital, Assistance Publique Hôpitaux de Paris, and INSERM Avenir, Paris, France
5 Bart’s and the London Genome Centre, Queen Mary’s School of Medicine, London, U.K

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.

Address correspondence and reprint requests to Philippe Froguel, Professor of Genomic Medicine, Director of the Hammersmith Genome Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.ukandphilippe.froguel{at}mail-good.pasteur-lille.fr

Abbreviations: IBD, identity-by-descent; LOD, logarithm of odds; LXR, liver X receptor; MLS, maximum likelihood score


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