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.

Background: Over the last 50 years, several studies have provided estimates of the prevalence of transsexualism. The variation in reported prevalence is considerable and may be explained by factors such as the methodology and diagnostic classification used and the year and country in which the studies took place. Taking these into consideration, this study aimed to critically and systematically review the available literature measuring the prevalence of transsexualism as well as performing a meta-analysis using the available data.Methods: Databases were systematically searched and 1473 possible studies were identified. After initial scrutiny of the article titles and removal of those not relevant, 250 studies were selected for further appraisal. Of these, 211 were excluded after reading the abstracts and a further 18 after reading the full article. This resulted in 21 studies on which to perform a systematic review, with only 12 having sufficient data for meta-analysis. The primary data of the epidemiological studies were extracted as raw numbers. An aggregate effect size, weighted by sample size, was computed to provide an overall effect size across the studies. Risk ratios and 95% confidence intervals (CIs) were calculated. The relative weighted contribution of each study was also assessed.Results: The overall meta-analytical prevalence for transsexualism was 4.6 in 100,000 individuals; 6.8 for trans women and 2.6 for trans men. Time analysis found an increase in reported prevalence over the last 50 years.Conclusions: The overall prevalence of transsexualism reported in the literature is increasing. However, it is still very low and is mainly based on individuals attending clinical services and so does not provide an overall picture of prevalence in the general population. However, this study should be considered as a starting point and the field would benefit from more rigorous epidemiological studies acknowledging current changes in the classification system and including different locations worldwide.