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Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi455
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 21, 2005
Revised December 9, 2005
Accepted December 9, 2005

Article

A PYY Q62P variant linked to human obesity

Nadav Ahituv 1, Nihan Kavaslar 2, Wendy Schackwitz 1, Anna Ustaszewska 3, John Michael Collier 3, Sybil Hébert 2, Heather Doelle 2, Robert Dent 2, Len A. Pennacchio 4 *, and Ruth McPherson 2

1 Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720 USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598 USA
2 Division of Cardiology and Lipoprotein & Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Canada, K1Y 4W7
3 U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598 USA
4 Genomics Division, One Cyclotron Road, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720 USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598 USA

* To whom correspondence should be addressed.
Len A. Pennacchio, E-mail: LAPennacchio{at}lbl.gov


  Abstract

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI) 49.0 kg/m2] and lean (n = 378; average BMI 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous cell culture based studies revealed this precise variant to have altered receptor binding selectivity in vitro. We further show using mouse peptide injection experiments that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.


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