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Significant Linkage of BMI to Chromosome 10p in the U.K. Population and Evaluation of GAD2 as a Positional Candidate

¹ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
³ School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K
⁴ Department of Diabetes and Metabolic Medicine, Bart’s and The London Queen Mary’s School of Medicine and Dentistry, London, U.K
⁵ Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, U.K
⁶ Centre for Molecular Genetics, Peninsula Medical School, Exeter, U.K

Address correspondence and reprint requests to Prof. Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, EndocrinologyMetabolism, Churchill Hospital, Old Road, Oxford, OX3 7LJ, U.K. E-mail: mark.mccarthy{at}drl.ox.ac.uk

Abbreviations: LD, linkage disequilibrium; LOD, logarithm of odds; QTDT, quantitative transmission-disequilibrium test; QTL, quantitative trait locus; SNP, single nucleotide polymorphism

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genome-wide P = 0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01 < P < 0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity.

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