Human Molecular Genetics Advance Access originally published online on June 24, 2009
Human Molecular Genetics 2009 18(18):3502-3507; doi:10.1093/hmg/ddp292
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Common body mass index-associated variants confer risk of extreme obesity
1 Center for Human Genetic Research and 2 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA, 3 Department of Medicine, Harvard Medical School, Boston, MA, USA, 4 Medical and Population Genetics Program and 5 Metabolism Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA, 6 MGH Weight Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 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 and 9 Program in Genomics and Divisions of Endocrinology and Genetics, Children's Hospital, Boston, MA, USA
* To whom correspondence should be addressed at: Massachusetts General Hospital, Blake 4, 55 Fruit St., Boston, MA 02114, USA. Tel: +1 617 726-3768; Fax: +1 617 724-6832; Email: kaplan{at}helix.mgh.harvard.edu (L.M.K.) and Center for Human Genetic Research, Massachusetts General Hospital, CPZN 6818, 185 Cambridge Street, Boston, MA 02114, USA. Tel: +1 6176433290; Fax: +1 6176433293; Email: mjdaly{at}chgr.mgh.harvard.edu (M.J.D.)
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 
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 12 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. 
See appendix for list of participants.