In addition to these common CNVs, three recent reports (20–22) underlined the importance of rare, large CNVs for body weight regulation. Two of these studies (20,21) depicted a genomic region on chromosome 16p11.2 which harbours highly penetrant microdeletions (∼500 kb) associated with (extreme) obesity. This region was previously reported to be associated with autism and mental retardation (20,21,23); in fact, some of the obese patients analysed by Bochukova et al. (20) additionally had developmental disorders. However, the association of these microdeletions and obesity was also found in individuals ascertained for obesity only (21), suggesting a possible direct association of the deletions at 16p11.2 with obesity apart from the cognitive phenotype. Wang et al. (22) performed a genome-wide CNV survey focusing on large (>1 Mb) CNVs, which were found to be over-represented in case versus control subjects. However, to explain a substantial part of the ‘missing heritability’, thousands of such rare CNVs have to be assumed. Recent considerations (24,25) showed that even meta-analyses of large-scale consortia will be underpowered to detect most of these multiple, rare variants.
