CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Abstract

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01–0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10−10, 6.0 × 10−5, and 2.9 × 10−3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.

Phenome-wide Burden of Copy-Number Variation in the UK Biobank

“…Moreover, these effects are consistent, though slightly higher, than previous meta-analysis or targeted study of this locus in UK Biobank. 14,54 After controlling for multiple comparisons, burden testing for BMI identifies KLHL22 at chromosome 22q11.2, recapitulates the 16p11.2 deletions at the gene level (SH2B1, BOLA2 [MIM: 613182]), and associations at five additional loci each with strong evidence for causality ( Figure 3B). Mechanisms for these loci are related to risk of diabetes; mouse knockouts of USP2 (MIM: 604725) reduce insulin resistance, 55 NEUROD1 (MIM: 601724) variation is a known cause of diabetes, 56 and BHLHE40 (MIM: 604256) may modify diabetes in mice via disturbances in circadian rhythm.…”

Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk

“…Although our study has by far the largest sample size to explore disease-associated CNV (7), analyses of GWAS for CNV suffer from reduced statistical power due to the rarity of CNV compared with SNPs and the statistically challenging detection of CNV from SNP arrays (65). Low frequency CNVRs (<5%) represented the majority ($82%) of variation identified in this study and this distribution has also been observed in a study of over 190,000 European adults where 92.4% of the CNVs were present in <1 in 1,000 samples and 99.4% of them occurred with <1% frequency (65). While a metaanalysis of the two array sets may improve statistical power, we opted for a stratified analysis with comparative evaluations given the large discrepancy in probe coverage and CNV detection between arrays.…”

Functional and population genetic features of copy number variations in two dairy cattle populations

“…With the accumulation of data and analyses, the occurrence of CNVs in the genome was shown to be biased outside of functional elements [5]. Nevertheless, numerous studies have shown that CNVs play a role in determining a wide range of human health conditions, from obesity to neurodevelopmental diseases [8][9][10][11]. For instance, high copy numbers of the CCL3L1 and CYP2D6 genes confer reduced susceptibility to infection with HIV and the development of AIDS [12].…”