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 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 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.

Figure 1. Effect of the 16p11.2 duplication on BMI and head circumference

Z-score values of BMI (top row) and head circumference (bottom row) of 16p11.2 duplication carriers stratified by gender and age group. The most severe effect is observed in children 0–5 years of age. Abscise: age groups in years. Boxplots represent the 5th, 25th, median, 75th and 95th percentile for each age group. Light grey and dark grey background represent −2 and −3 SD respectively, which correspond to the WHO definition of moderate and severe underweight. BMI is decreased in adolescent and adult females.

Figure 2. Transcript levels for genes within and near to the 16p11.2 rearrangements

(A) Relative expression levels in boxplot format of 27 genes mapping to 16p11.2 in deletion and duplication carriers (red and green, respectively) and control cell lines (blue). Grey lines denote the extent of the 16p11.2 CNV (29.5–30.1 Mb). Complete lists of genes mapping within the rearranged interval and of the quantitative PCR assays can be consulted in Supplementary Table S1 and S11, respectively. Possible relevance of each of these genes to obesity/leanness and/or developmental delay/cognitive deficits can be consulted in . (B) Rank comparison (Kruskal-Wallis test) between expression of 27 genes mapping to 16p11.2 in deletion and duplication carriers (red and green, respectively) and control cell lines (blue). Distinction is made between genes mapping telomeric (or centromeric) to the rearranged interval and those within the rearranged interval. Dots correspond to the mean group rank and bars indicate the comparison interval, groups with non-overlapping intervals are significantly different (at α=5%).