Human Molecular Genetics Advance Access published online on June 24, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp292
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Common BMI-associated variants confer risk of extreme obesity
1 Center for Human Genetic Research, Massachusetts General Hospital, Boston MA, USA 2 Dept of Medicine, Harvard Medical School, Boston MA, USA 3 Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge MA, USA 4 Metabolism Initiative, Broad Institute of MIT and Harvard, Cambridge MA, USA 5 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA 6 MGH Weight Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 7 Genetics, Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc. Seattle, WA 98109, USA 8 Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA 9 Program in Genomics and Divisions of Endocrinology and Genetics, Children's Hospital, Boston MA USA
* Correspondence to Mark J Daly PhD, Center for Human Genetic Research, Massachusetts General Hospital, CPZN 6818, 185 Cambridge St, Boston MA, 02114 USA Tel: +1 617 643 3290, Fax: +1 617 643 3293, email: mjdaly{at}chgr.mgh.harvard.edu
Received February 23, 2009; Revised June 10, 2009; Accepted June 17, 2009
To investigate the genetic architecture of severe obesity we performed a genome-wide association study of 775 cases and 3197 unascertained controls at approximately 550,000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of twelve other loci previously reported to influence body-mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity, and that cases have a higher proportion of risk-conferring alleles than controls.. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.
# These authors contributed equally