A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Figure 1. Identification and validation of deletions at 16p11.2

(a) aCGH data showing the location of the 16p11.2 deletion. The data show the log₂ intensity ratio for a deletion carrier compared to an undeleted control sample. Grey bars connected by a broken line denote the segmental duplication flanking the deletion region. Vertical bars indicate the positions of the probe pairs used for MLPA validation. Note that CGH and genotyping array probes targeted against segmental duplications may not accurately report copy number due to the increased number of homologous sequences in the diploid state. Genome coordinates are according to the hg18 build of the reference genome. (b) MLPA validation of 16p11.2 deletions. Representative MLPA results are shown, illustrating one instance of maternal transmission and two instances of de novo deletions. Genotyping data excluded the possibility of non-paternity. Full results for MLPA validation and inheritance analysis are shown in Supplementary Figure S1. Each panel shows the relative magnitude of the normalised, integrated signal at each probe location, in order of chromosomal position of the MLPA probe pairs as indicated in (a). Each panel corresponds to its respective position on the associated pedigree, as shown.

Figure 2. Dependence of BMI on age in subjects having a deletion at 16p11.2

Data are for all individuals carrying a deletion for whom phenotypic data are available. Similar data from this study only are shown in Supplementary Figures S2 and S3. Lines denote the age- and gender-corrected thresholds (solid/broken – male/female) for obesity and morbid obesity. Symbols are: Square/circle – male/female; black/grey – ascertained/not ascertained for developmental delay; filled/open – ascertained/not ascertained for obesity; diamond – first-degree relative of proband; cross – previously published data-. The 31 year old male with BMI ~20 kg.m⁻² was diabetic based on fasting blood glucose >7 mmol/L.