Genome-wide linkage analysis for severe obesity in French Caucasians finds significant susceptibility locus on chromosome 19q

被引:54
作者
Bell, CG
Benzinou, M
Siddiq, A
Lecoeur, C
Dina, C
Lemainque, A
Clément, K
Basdevant, A
Guy-Grand, B
Mein, CA
Meyre, D
Froguel, P
机构
[1] Hammersmith Hosp, Imperial Coll, Fac Med, Hammersmith Genome Ctr, London W12 0NN, England
[2] Hammersmith Hosp, Imperial Coll, Fac Med, Dept Genom Med, London W12 0NN, England
[3] Inst Pasteur, UMR 8090, CNRS, Lille, France
[4] Ctr Natl Genotypage, Evry, France
[5] Assistance Publ Hop, Hotel Dieu Hosp, Paris, France
[6] INSERM Avenir, Paris, France
[7] Queen Marys Sch Med, Barts & London Genome Ctr, London, England
基金
英国医学研究理事会;
关键词
D O I
10.2337/diabetes.53.7.1857
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 greater than or equal to 35 kg/m(2)), and 84.8% of the nuclear families possessed greater than or equal to1 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 greater than or equal to35 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 2:35 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 greater than or equal to27 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.
引用
收藏
页码:1857 / 1865
页数:9
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