Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.
paper
Cited
Public
- Authors
- Walters, Robin G; Coin, Lachlan J M; Ruokonen, Aimo; de Smith, Adam J; El-Sayed Moustafa, Julia S; Jacquemont, Sebastien; Elliott, Paul; Esko, Tánu; Hartikainen, Anna-Liisa; Laitinen, Jaana; MÀnnik, Katrin; Martinet, Danielle; Meyre, David; Nauck, Matthias; Schurmann, Claudia; Sladek, Rob; Thorleifsson, Gudmar; Thorsteinsdóttir, Unnur; Valsesia, Armand; Waeber, Gerard; Zufferey, Flore; Balkau, Beverley; Pattou, François; Metspalu, Andres; Vâlzke, Henry; Vollenweider, Peter; Stefansson, KÑri; JÀrvelin, Marjo-Riitta; Beckmann, Jacques S; Froguel, Philippe; Blakemore, Alexandra I F
- Year
- 2013
- Journal
- PloS one
- PMID
- 23554873
- DOI
- 10.1371/journal.pone.0058048
- PMCID
- PMC3595275
The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (ORβ₯25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2Γ10(-4) (95% confidence interval [9.6Γ10(-5)-3.1Γ10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8Γ10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
Procedure for identification of GSVs.Following data export and QC, GSV calling was carried out using the cnvHap algorithm. Illustrative data for 3 GSV loci (shaded) show all positive GSV calls (black) together with examples of calls not meeting the necessary criteria (grey); probes at which copy number changes were identified are also indicated (circles).
Metabolic phenotype of carriers of a 220 kb deletion at chromosome 16p11.2. (a) Fasting plasma insulin levels relative to BMI, for 558 normoglycaemic severely obese children from northern France either carrying a deletion (black) or not (grey). (b) Fasting plasma insulin levels relative to BMI, for 5254 normoglycaemic 31 year-old Finns either carrying a deletion (black circles) or not (grey circles). Also shown are the parents of obese French child probands who carry a deletion (black triangles) or not (white triangles). (c) Plasma insulin levels in response to a 75 g oral glucose load in parents of obese child probands. Data shown are mean Β± SEM for carrier parents (n = 3, mean BMI = 28.6 kg.mβ2, black triangle) and unaffected parents (n = 4, mean BMI = 27.0 kg.mβ2, white triangles).
Reduced BMI in carriers of deletions in the FOXP2 region.Deletions within FOXP2 are shown relative to selected tracks from the UCSC browser (http://genome.ucsc.edu) for the corresponding region of chromosome 7: FOXP2 coding transcripts (UCSC Genes); histone modifications H3K4Me1, H3K4Me3, H3K27Ac (ENCODE Regulation); and binding by transcription factor NF-ΞΊB (ENCODE TFBS). Multiple additional transcription factors bind at the apparent NF-ΞΊB binding site. The minimum extent of each predicted deletion, the probes at which copy number changes were identified and the BMI for carriers of each deletion are as shown. Grey shading indicates the region previously associated with BMI [16].
| Name | Type |
|---|---|
| 11 loci local | gene |
| 16p11.2 220kb deletion local | variant |
| 16p11.2 593 kb deletion local | variant |
| 16p11.2 593kb deletion local | variant |
| 16p11.2 deletion | variant |
| 16p11.2 duplication | variant |
| 16p11.2 GSV locus 1 local | variant |
| 16p11.2 GSV locus 2 local | variant |
| 16p11.2 obesity locus local | variant |
| 220 kb deletion local | variant |
| 220β―kb deletion on 16p11.2 local | variant |
| 220 kb deletion on chromosome 16p11.2 local | variant |
| 593 kb deletion of chromosome 16p11.2 local | variant |
| 593β―kb locus on 16p11.2 local | variant |
| adipocyte differentiation | phenotype |
| adipocyte proliferation local | phenotype |
| adult case-control cohort local | cohort |
| adults | cohort |
| adult severe obesity cohorts local | cohort |
| attention deficit hyperactivity disorder | phenotype |
| BAF | drug |
| balanced translocation disrupting SIM1 local | variant |
| bariatric patients local | phenotype |
| BMI | phenotype |
| case-control sample | cohort |
| child case-control cohort local | cohort |
| child cohorts with common obesity local | cohort |
| childhood obesity | phenotype |
| child obesity local | phenotype |
| children | cohort |
| children with common obesity local | cohort |
| chromosome 17 GSV locus local | variant |
| chromosome 22 GSV locus local | variant |
| chromosome 3 GSV locus local | variant |
| Clinical obesity local | phenotype |
| cnvHap local | drug |
| cohort allelic sums test local | cohort |
| cohort of <300 patients with severe early-onset obesity local | cohort |
| CoLaus prospective population cohort local | cohort |
| common obesity GSVs local | variant |
| complex diseases | phenotype |
| complex traits | phenotype |
| control cohorts of normal weight local | cohort |
| control individuals from general population local | cohort |
| DD | phenotype |
| deCODE population cohort local | cohort |
| deletion | variant |
| deletion 7q31.1 local | variant |
| deletion (GSV) local | variant |
| deletion within FOXP2 local | variant |
| developmental delay | phenotype |
| developmental delay cohort local | cohort |
| discovery sample | cohort |
| DNA | drug |
| duplication 17q22 local | variant |
| duplication between KIF2B and TOM1L1 local | variant |
| early-onset obesity | phenotype |
| EGCUT BioBank local | cohort |
| European ancestry | cohort |
| extreme hyperinsulinaemia local | phenotype |
| extreme obesity | phenotype |
| extreme obesity discovery cohort local | cohort |
| extreme obesity GSV loci local | variant |
| extreme obesity GSVs local | variant |
| Extreme obesity phenotype local | phenotype |
| Foxp2 | gene |
| FOXP2 deletion local | variant |
| French child cohort local | cohort |
| French cohort local | cohort |
| French non-overweight control cohort local | cohort |
| French obesity case-control cohort local | cohort |
| French severely obese cohort local | cohort |
| general population | cohort |
| general population cohort local | cohort |
| genomic structural variant local | variant |
| Genomic Structural Variant local | variant |
| Genomic structural variants local | variant |
| genuine associations local | phenotype |
| geographically-matched controls local | cohort |
| glucose | drug |
| GSV local | variant |
| GSV-associated obesity local | phenotype |
| GSV region local | variant |
| GSV regions local | variant |
| GSVs local | variant |
| heavily-selected cohort local | cohort |
| highly-penetrant causative variant local | variant |
| highly-selected cohort local | cohort |
| hyperinsulinaemia local | phenotype |
| Illumina Human CNV370-duo arrays local | drug |
| independent cohorts local | cohort |
| insulin | drug |
| insulin resistance | phenotype |
| insulin response to oral glucose local | phenotype |
| KIF2B local | gene |
| KIF2B duplication local | variant |
| large GSVs local | variant |
| LRR | drug |
| MC4R | gene |
| NFBC1966 local | cohort |
| NFBC1966 cohort local | cohort |
| NF-ΞΊB | gene |
| Nordic adult cohort local | cohort |
| normal weight | phenotype |
| Normal weight/underweight local | phenotype |
| Northern Finland Birth Cohort 1966 local | cohort |
| Northern Finland general population cohort local | cohort |
| obesity | phenotype |
| obesity case-control cohort local | cohort |
| obesity plus cohorts local | cohort |
| oral glucose local | drug |
| original report local | cohort |
| other population cohorts local | cohort |
| overweight | phenotype |
| Patients with extreme obesity local | cohort |
| phenotype | phenotype |
| population | cohort |
| previously published data local | cohort |
| rare GSVs local | variant |
| Rare GSVs local | variant |
| rare point mutation local | variant |
| rare variant | cohort |
| reciprocal GSVs local | variant |
| severely obese children cohort local | cohort |
| SH2B1 | gene |
| SH2B1 deletion local | variant |
| SHIP cross-sectional survey cohort local | cohort |
| SIM1 local | gene |
| SIM1 common variants local | variant |
| SIM1 rare variants local | variant |
| single nucleotide polymorphism | variant |
| smaller deletions local | variant |
| small GSVs local | variant |
| SNP | cohort |
| study cohort | cohort |
| syndromic obesity local | phenotype |
| thgenetics local | drug |
| TOM1L1 local | gene |
| UK child cohort local | cohort |
| underweight | phenotype |
| unselected population cohorts local | cohort |
| waist-hip ratio (adjusted for BMI) local | phenotype |
| worldwide local | cohort |
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis. | 2014 | 24884913 |
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