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

摘要

Both underweight and obesity have been associated with increased mortality^,. Underweight, defined as body mass index (BMI) ≤ 18,5 kg/m² in adults and ≤ −2 standard deviations (SD) in children^,, is the main sign of a series of heterogeneous clinical conditions such as failure to thrive (FTT) ^–, feeding and eating disorder and/or anorexia nervosa^,. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported ^, . We previously demonstrated that hemizygosity of a ~600 kb region on the short arm of chromosome 16 (chr16:29.5–30.1Mb), causes a highly-penetrant form of obesity often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with underweight. We identified 138 (132 novel cases) duplication carriers (108 unrelated carriers) from over 95,000 individuals clinically-referred for developmental or intellectual disabilities (DD/ID), psychiatric disorders or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight (mean Z-score −0.6; p=4.4×10⁻⁴) and BMI (mean Z-score −0.5; p=2.0×10⁻³). In particular, half of the boys younger than 5 years are underweight with a probable diagnosis of FTT, while adult duplication carriers have an 8.7-fold (p=5.9×10⁻¹¹; CI_95=[4.5–16.6]) increased risk of being clinically underweight. We observe a significant 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 feeding behaviours and a significant reduction in head circumference (mean Z-score −0.9; p=7.8×10⁻⁶). Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus, correlating with changes in transcript levels for genes mapping within the duplication but not within flanking regions. The reciprocal impact of these 16p11.2 copy number variants suggests that severe obesity and being underweight can have mirror etiologies, possibly through contrasting effects on eating behaviour.