Journal
NATURE
Volume 478, Issue 7367, Pages 97-U111Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10406
Keywords
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Categories
Funding
- Leenaards Foundation
- Jerome Lejeune Foundation
- Telethon Action Suisse Foundation
- Swiss National Science Foundation
- European Commission [037627, QLG1-CT-2000-01643]
- Ludwig Institute for Cancer Research
- Swiss Institute of Bioinformatics
- Imperial College Department of Medicine
- Comprehensive Biomedical Research Centre
- Imperial College Healthcare NHS Trust
- National Institute for Health Research
- Wellcome Trust
- Medical Research Council
- Instituto de Salud Carlos III (ISCIII)-FIS
- German Mental Retardation Network
- German Federal Ministry of Education and Research [NGFNplus 01GS08160]
- European Union [PI081714, PS09/01778, 201413, 245536, HEALTH-2007-2.2.1-10-223423]
- Belgian National Fund for Scientific Research, Flanders
- Dutch Organisation for Health Research and Development (ZON-MW) [917-86-319]
- Hersenstichting Nederland (B.B.A.d.V.)
- Chinese National Natural Science Foundation [81000346]
- Simons Foundation Autism Research Initiative
- Autism Speaks
- NIH [GM061354, MH071425]
- Oesterreichische Nationalbank (OENB) [13059]
- Children's Tumor Foundation
- Harvard Medical School
- Fudan University
- Chinese National '973' project on Population and Health [2010CB529601]
- Science and Technology Council of Shanghai [09JC1402400]
- Michael Smith Foundation for Health
- CIHR [MOP 74502]
- Estonian Government [SF0180142s08, SF0180026s09, SF0180027s10]
- Helmholtz Zentrum Munich
- State of Bavaria
- German National Genome Research Network [01GS0823]
- German Federal Ministry of Education and Research (BMBF)
- Munich Center of Health Sciences (MC Health, LMUinnovativ)
- Genome Canada
- McLaughlin Centre
- Academy of Finland [104781, 120315, 129269, 1114194]
- University Hospital Oulu
- Biocenter
- University of Oulu, Finland [75617]
- NHLBI [5R01HL087679-02, 1RL1MH083268-01]
- NIH/NIMH [5R01MH63706:02]
- ENGAGE project
- Medical Research Council, UK [G0500539, G0600705]
- Academy of Finland
- Biocentrum Helsinki
- [SAF2008-02278]
- [HEALTH-F4-2007-201413]
- Diabetes UK [08/0003775] Funding Source: researchfish
- Medical Research Council [G0600705, G0801056B, G0801056] Funding Source: researchfish
- MRC [G0801056, G0600705] Funding Source: UKRI
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Both obesity and being underweight have been associated with increased mortality(1,2). 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(3-5), feeding and eating disorder and/or anorexia nervosa(6,7). In contrast to obesity, few genetic variants underlying these clinical conditions have been reported(8,9). We previously showed that hemizygosity of a similar to 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(10). 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 clinically referred 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.
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