Large copy-number variations are enriched in cases with moderate to extreme obesity.
paper
Cited
Public
- Authors
- Wang, Kai; Li, Wei-Dong; Glessner, Joseph T; Grant, Struan F A; Hakonarson, Hakon; Price, R Arlen
- Year
- 2010
- Journal
- Diabetes
- PMID
- 20622171
- DOI
- 10.2337/db10-0192
- PMCID
- PMC3279563
OBJECTIVE: Obesity is an increasingly common disorder that predisposes to several medical conditions, including type 2 diabetes. We investigated whether large and rare copy-number variations (CNVs) differentiate moderate to extreme obesity from never-overweight control subjects. RESEARCH DESIGN AND METHODS: Using single nucleotide polymorphism (SNP) arrays, we performed a genome-wide CNV survey on 430 obese case subjects (BMI >35 kg/m(2)) and 379 never-overweight control subjects (BMI <25 kg/m(2)). All subjects were of European ancestry and were genotyped on the Illumina HumanHap550 arrays with ∼550,000 SNP markers. The CNV calls were generated by PennCNV software. RESULTS: CNVs >1 Mb were found to be overrepresented in case versus control subjects (odds ratio [OR] = 1.5 [95% CI 0.5-5]), and CNVs >2 Mb were present in 1.3% of the case subjects but were absent in control subjects (OR = infinity [95% CI 1.2-infinity]). When focusing on rare deletions that disrupt genes, even more pronounced effect sizes are observed (OR = 2.7 [95% CI 0.5-27.1] for CNVs >1 Mb). Interestingly, obese case subjects who carry these large CNVs have moderately high BMI and do not appear to be extreme cases. Several CNVs disrupt known candidate genes for obesity, such as a 3.3-Mb deletion disrupting NAP1L5 and a 2.1-Mb deletion disrupting UCP1 and IL15. CONCLUSIONS: Our results suggest that large CNVs, especially rare deletions, confer risk of obesity in patients with moderate obesity and that genes impacted by large CNVs represent intriguing candidates for obesity that warrant further study.
Candidate genes impacted by large CNVs unique to obese case subjects. A: CNV on chromosome 4 is a 3.3-Mb deletion that disrupts the imprinted gene NAP1L5, which has been shown to affect birth and adult body weight. B: CNV on chromosome 4 is a 2.1-Mb deletion of a region containing two candidate genes, UCP1 and IL15. For each CNV, the corresponding log R ratio and B allele frequency for all markers (as blue dots) were shown. Deletions are verified by decreased log R ratio and the lack of heterozygous SNPs in B allele frequency values.
1–15 of 15
| Name | Type |
|---|---|
| 10q11 CNV local | variant |
| 16p11.2 deletion | variant |
| 16p11.2 duplication | variant |
| 4q22.1 deletion local | variant |
| 4q31 deletion (2.1-Mb) local | variant |
| BMI | phenotype |
| BMI ≥70 kg/m2 local | phenotype |
| body mass index | phenotype |
| body weight | phenotype |
| candidate genes | cohort |
| case subjects | cohort |
| cCNVR local | variant |
| childhood obesity | phenotype |
| Chinese | cohort |
| CNV | variant |
| CNV >1 Mb local | variant |
| CNV >2 Mb local | variant |
| CNVs | variant |
| common CNV local | variant |
| common susceptibility variants local | variant |
| common variants | cohort |
| complex diseases | phenotype |
| control subjects | cohort |
| CTSC local | gene |
| Dlg2 | gene |
| European ancestry | cohort |
| exonic CNV local | variant |
| Extremely obese case subjects local | cohort |
| FTO | gene |
| gene-disrupting CNV local | variant |
| GPRIN2 local | gene |
| GWAS | cohort |
| high-fat diet | drug |
| IL15 local | gene |
| Illumina SNP arrays local | drug |
| Kirov et al. study local | cohort |
| large and rare gene-disrupting deletion CNVs local | variant |
| large CNV | variant |
| large CNVs | variant |
| MC4R | gene |
| ME3 local | gene |
| MIPEP local | gene |
| Moderate obesity case subjects local | cohort |
| monogenic forms of complex disorders local | phenotype |
| NAP1L5 | gene |
| Need et al. study local | cohort |
| NOX4 local | gene |
| obesity | phenotype |
| obesity genes local | gene |
| our study | cohort |
| Parkinson's disease | phenotype |
| PPYR1 local | gene |
| rare CNV | variant |
| rare CNVs | variant |
| rare variant | cohort |
| schizophrenia | phenotype |
| SNCA | gene |
| UCP1 | gene |
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