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

Abstract

Underweight and obese phenotypes can both pose health risks. But whereas obesity has been associated with a number of genetic variants, little is known about the genetic basis of underweight. A large-scale screen of data from 28 cytogenetic centres in Europe and North America now shows that being underweight is frequently associated with duplication of a short region on chromosome 16. Deletion of this same chromosomal region has previously been associated with obesity. The observed associated phenotypes are opposites, or mirrors, of those reported in carriers of deletions at this locus, and correlate with changes in transcript levels for genes within the duplication but not within the adjacent regions. The suggestion is that severe obesity and being underweight could have mirror etiologies, possibly through contrasting effects on energy balance. 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.