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.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

Fig. 1

Genome-wide Manhattan plots for four anthropometric traits. Genome-wide association study for CNVs associated with BMI, height, weight, and waist-to-hip ratio in 191,161 Europeans

Fig. 2

Regional association plot for the 16p11.2 220 kb rearrangement. The blue dots represent −log10 BMI-association P values, the red dots show the corresponding effect sizes. At the bottom the black and gray lines are the deletion and duplication frequencies. Finally, the dots at the bottom indicate the probe positions for the GIANT cohorts (above) and the UK Biobank (below). Positions of the protein-coding genes are shown at the top of the plot. The probes positions correspond to the human genome build 36

Fig. 3

Regional association plot for the rearrangement near MC4R. The blue dots represent –log10 BMI-association P values, the red dots show the corresponding effect sizes. At the bottom the black and gray lines are the deletions and duplications frequencies. Finally, the dots at the bottom are the probes positions for the GIANT cohorts above and the UK BioBank below. Positions of the protein-coding genes are shown at the top of the plot along with the position of the BMI-associated GWAS SNP. The probes positions correspond to the human genome build 36