Nature; auth:Group Reymond

Nature. 2011 Aug 31. doi: 10.1038/nature10406. [Epub ahead of print]

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Jacquemont SReymond AZufferey FHarewood LWalters RGKutalik ZMartinet DShen YValsesia ABeckmann ND,Thorleifsson GBelfiore MBouquillon SCampion Dde Leeuw Nde Vries BBEsko TFernandez BAFernández-Aranda F,Fernández-Real JMGratacòs MGuilmatre AHoyer JJarvelin MRFrank Kooy RKurg ALe Caignec CMännik KPlatt OS,Sanlaville DVan Haelst MMVillatoro Gomez SWalha FWu BLYu YAboura AAddor MCAlembik YAntonarakis SEArveiler B,Barth MBednarek NBéna FBergmann SBeri MBernardini LBlaumeiser BBonneau DBottani ABoute OBrunner HGCailley DCallier PChiesa JChrast JCoin LCoutton CCuisset JMCuvellier JCDavid Ade Freminville BDelobel BDelrue MA,Demeer BDescamps DDidelot GDieterich KDisciglio VDoco-Fenzy MDrunat SDuban-Bedu BDubourg CEl-Sayed Moustafa JSElliott PFaas BHFaivre LFaudet AFellmann FFerrarini AFisher RFlori EForer LGaillard DGerard MGieger CGimelli SGimelli GGrabe HJGuichet AGuillin OHartikainen ALHeron DHippolyte LHolder MHomuth GIsidor BJaillard SJaros ZJiménez-Murcia SJoly Helas GJonveaux PKaksonen SKeren BKloss-Brandstätter AKnoers NVKoolen DA,Kroisel PMKronenberg FLabalme ALandais ELapi ELayet VLegallic SLeheup BLeube BLewis SLucas JMacdermot KD,Magnusson PMarshall CMathieu-Dramard MMcCarthy MIMeitinger TAntonietta Mencarelli MMerla GMoerman AMooser V,Morice-Picard FMucciolo MNauck MCoumba Ndiaye NNordgren APasquier LPetit FPfundt RPlessis GRajcan-Separovic EPaolo Ramelli GRauch ARavazzolo RReis ARenieri ARichart CRied JSRieubland CRoberts WRoetzer KMRooryck C,Rossi MSaemundsen ESatre VSchurmann CSigurdsson EStavropoulos DJStefansson HTengström CThorsteinsdóttir U,Tinahones FJTouraine RVallée Lvan Binsbergen EVan der Aa NVincent-Delorme CVisvikis-Siest SVollenweider PVölzke HVulto-van Silfhout ATWaeber GWallgren-Pettersson CWitwicki RMZwolinksi SAndrieux JEstivill XGusella JFGustafsson OMetspalu AScherer SWStefansson KBlakemore AIBeckmann JSFroguel P.

Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.


Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinicallyreferred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.





[PubMed – as supplied by publisher]

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