Large, rare chromosomal deletions associated with severe early-onset obesity

Abstract

Obesity is a highly heritable and genetically heterogeneous disorder1. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P < 5 × 10−5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism2-4 and mental retardation5; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling6. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…2,4,6,7,9,15,17 As shown by 4C-seq, FISH, and Hi-C, the two 16p11.2 CNV-prone regions are reciprocally engaged in evolutionary-conserved complex chromatin looping, as well as coordinated expression of encompassed genes. 17,45 Here we assessed whether these findings were paralleled by genetic interactions between the 28 and 9 single-copy genes within the 16p11.2 600 kb BP4-BP5 and 220 kb BP2-BP3 intervals, respectively.…”

“…[9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia. 3,[13][14][15][16] Moreover, the BP2-BP3 deletion and reciprocal duplication have mirror effects on BMI and HC, whereas the duplication of this interval, like the deletion, is associated with ASD. 17 Thus, genomic rearrangements at both the 16p11.2 600 kb BP4-BP5 and the 220 kb BP2-BP3, two loci 650 kb apart, present similar clinical patterns: large effect sizes on BMI and HC, as well as association with ASD and other neuropsychiatric traits.…”

Implications of gene copy-number variation in health and diseases

“…The region in question has PPYR1 gene, regulating energy balance. 57,58 Amylase gene CNVs is found not only contributing to the disease in general but also is found to be involved with diet, such as salivary amylase gene (AMY1 gene), which is associated with the starchy food consumption in a population. It has been reported that higher copy number of AMY1 gene is correlated positively with salivary amylase protein levels and a population with high-starch food consumption has higher copy number of AMY1 gene and improves the digestion of starchy foods and may reduce the burden of intestinal diseases.…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…[19][20][21] Similarly, the importance of rare variants in complex diseases is also being recognized. 56,90,115,116 This implies that future disease association studies need to interrogate non-SNP and rare genetic variations as well, and for this to be feasible, a detailed catalog of human genetic variations is a prerequisite. Common SNPs are well documented in the dbSNP, but rarer SNPs (or lower frequency SNPs) are still under-represented in the database and the information of indels and structural variations is far from complete.…”