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

Abstract

Both obesity and being underweight have been associated with increased mortality1,2. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m2 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 thrive3,4,5, feeding and eating disorder and/or anorexia nervosa6,7. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported8,9. 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 disabilities10. 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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Figure 1: Effect of the chromosome 16p11.2 duplication on BMI and head circumference.
Figure 2: Transcript levels for genes within and near to the 16p11.2 rearrangements.

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Acknowledgements

We thank the Vital-IT high-performance computing centre of the Swiss Institute of Bioinformatics. S.J. is recipient of a bourse de relève académique de la Faculté de Biologie et Médecine de l’Université de Lausanne. This work was supported by the Leenaards Foundation Prize (S.J., D.M. and A.Reymond), the Jérôme Lejeune Foundation (A.Reymond), the Telethon Action Suisse Foundation (A.Reymond), the Swiss National Science Foundation (A.Reymond, J.S.B., S.B. and S.E.A.), a Swiss National Science Foundation Sinergia grant (S.J., D.M., S.B., J.S.B. and A.Reymond), the European Commission anEUploidy Integrated Project grant 037627 (A.Reymond, S.B., X.E., H.G.B. and S.E.A.), the Ludwig Institute for Cancer Research (A.V.), the Swiss Institute of Bioinformatics (S.B. and Z.K.), an Imperial College Department of Medicine PhD studentship (J.S.E.-S.M), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (P.E.), the Wellcome Trust and the Medical Research Council (A.I.F.B. and P.F.), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) (A.Reis), European Union-FEDER (PI081714, PS09/01778) (F.F.A., M.G. and X.E.), SAF2008-02278 (C.R.), the Belgian National Fund for Scientific Research, Flanders (N.V.A. and R.F.K.), the Dutch Organisation for Health Research and Development (ZON-MW grant 917-86-319) and Hersenstichting Nederland (B.B.A.d.V.), grant 81000346 from the Chinese National Natural Science Foundation (Y.G.Y.), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (J.F.G.), and Oesterreichische Nationalbank (OENB) grant 13059 (A.K.-B.). Y.S. holds a Young Investigator Award from the Children’s Tumor Foundation and a Catalyst Award from Harvard Medical School. B.L.W. holds a Fudan Scholar Research Award from Fudan University, a grant from Chinese National ‘973’ project on Population and Health (2010CB529601) and a grant from the Science and Technology Council of Shanghai (09JC1402400). E.R.S. and S.L., recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. The Estonian Genome Center of the University of Tartu (EGCUT) received support from the EU Centre of Excellence in Genomics and FP7 grants 201413 and 245536, and from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (A.M., K.M. and A.K.). D.S. thanks the Direction Générale de l’Organisation des Soins from the French Ministry of Health for their support in the development of several array-CGH platforms, and the Centres Labellisés Anomalies du Development in France. The Helmholtz Zentrum Munich and the State of Bavaria financed the KORA study, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). S.W.S. holds the GlaxoSmithKline-Canadian Institutes of Health Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children, and is supported by Genome Canada and the McLaughlin Centre. Funding for deCODE came in part from NIH grant MH071425 (K.S.), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds. NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE). The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. We thank M. Hass, Z. Jaros, M. Jussila, M. Koiranen, P. Rantakallio, M. C. Rudolf, V. Soo, O. Tornwall, S. Vaara, T. Ylitalo and the French DHOS national CGH network for their help, as well as all participating patients and clinicians. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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S.J., A.Reymond, P.F. and J.S.B. wrote the manuscript with contributions from F.Z., L.H., R.G.W., N.D.B., Z.K., A.I.F.B. and A.V. L.H., A.V. and A.Reymond produced and analyzed the expression data. Z.K., A.V., R.G.W. and N.D.B. conducted the statistical analyses, guided by S.J., A.Reymond, P.F. and J.S.B. S.J., A.Reymond, F.Z., L.H., D.M., Y.S., G.T., M.B., S.B., D.C., N.d.L., B.B.A.d.V., B.A.F., F.F.A., M.G., A.G., J.H., A.K., C.L.C., K.M., O.S.P. D.S., M.M.V.H., S.V.G., A.T.V.-v.S., F.W., B.-L.W., Y.Y., J.A., X.E., J.F.G., A.M., S.W.S., K.S., U.T., A.I.F.B., J.S.B., P.F. and all other authors phenotyped and/or genotyped patients and/or individuals of the general population. S.J., A.Reymond and J.S.B. designed the study. All authors commented on and approved the manuscript.

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Correspondence to Jacques S. Beckmann.

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Jacquemont, S., Reymond, A., Zufferey, F. et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478, 97–102 (2011). https://doi.org/10.1038/nature10406

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