Abstract
SummaryThe impact of copy-number variations (CNVs) on complex human traits remains understudied. We called CNVs in 331,522 UK Biobank participants and performed genome-wide association studies (GWASs) between the copy number of CNV-proxy probes and 57 continuous traits, revealing 131 signals spanning 47 phenotypes. Our analysis recapitulated well-known associations (e.g., 1q21 and height), revealed the pleiotropy of recurrent CNVs (e.g., 26 and 16 traits for 16p11.2-BP4-BP5 and 22q11.21, respectively), and suggested gene functionalities (e.g., MARF1 in female reproduction). Forty-eight CNV signals (38%) overlapped with single-nucleotide polymorphism (SNP)-GWASs signals for the same trait. For instance, deletion of PDZK1, which encodes a urate transporter scaffold protein, decreased serum urate levels, while deletion of RHD, which encodes the Rhesus blood group D antigen, associated with hematological traits. Other signals overlapped Mendelian disorder regions, suggesting variable expressivity and broad impact of these loci, as illustrated by signals mapping to Rotor syndrome (SLCO1B1/3), renal cysts and diabetes syndrome (HNF1B), or Charcot-Marie-Tooth (PMP22) loci. Total CNV burden negatively impacted 35 traits, leading to increased adiposity, liver/kidney damage, and decreased intelligence and physical capacity. Thirty traits remained burden associated after correcting for CNV-GWAS signals, pointing to a polygenic CNV architecture. The burden negatively correlated with socio-economic indicators, parental lifespan, and age (survivorship proxy), suggesting a contribution to decreased longevity. Together, our results showcase how studying CNVs can expand biological insights, emphasizing the critical role of this mutational class in shaping human traits and arguing in favor of a continuum between Mendelian and complex diseases.
Highlights
With the advent of genome-wide associations studies (GWASs), the polygenic architecture of complex human traits has become apparent.[1–3] Still, single-nucleotide polymorphisms (SNPs) do not explain the totality of observed phenotypic variability—a phenomenon referred to as ‘‘missing heritability’’—and one proposed explanation is the contribution of additional types of genetic variants, such as copy-number variants (CNVs).[4]Characterized by the deletion or duplication of DNA fragments R 50 bases,[5] CNVs represent a highly diverse mutational class that, due to their possibly large size, constitute potent phenotypic modifiers that act through e.g., gene dosage sensitivity, truncation or fusion of genes, unmasking of recessive alleles, or disruption of cis-regulatory elements.[6]
No differences in CNV burden, measured as the number of Mb or genes affected by CNVs, was detected across sexes
We further provide evidence for a broad and nuanced role of CNVs in shaping complex traits, as both common and rare CNVs mapping to regions involved by SNP-GWAS contribute to phenotypic variability in the general population, and rare CNVs have larger effects sizes than common ones
Summary
With the advent of genome-wide associations studies (GWASs), the polygenic architecture of complex human traits has become apparent.[1–3] Still, single-nucleotide polymorphisms (SNPs) do not explain the totality of observed phenotypic variability—a phenomenon referred to as ‘‘missing heritability’’—and one proposed explanation is the contribution of additional types of genetic variants, such as copy-number variants (CNVs).[4]Characterized by the deletion or duplication of DNA fragments R 50 bases,[5] CNVs represent a highly diverse mutational class that, due to their possibly large size, constitute potent phenotypic modifiers that act through e.g., gene dosage sensitivity, truncation or fusion of genes, unmasking of recessive alleles, or disruption of cis-regulatory elements.[6]. With the advent of genome-wide associations studies (GWASs), the polygenic architecture of complex human traits has become apparent.[1–3]. Early GWASs failed to establish clear links between CNVs and complex traits and diseases.[8,9]. Specific to genome-wide copy-number association studies (CNV-GWASs), contributed to these negative results, such as the low frequency and variable breakpoints of CNVs in the population, as well as uncertainty and low resolution of CNV calls originating from genotyping microarrays.[10]. Focusing on a curated set of CNVs, a series of studies characterized the impact of well-established pathogenic CNVs on cognitive performance,[11] physical measurements,[12,13] common medical conditions,[14,15] and blood biomarkers.[16]. A recent study made use of the UK Biobank (UKBB)[22] to assess the impact of CNVs on over 3,000 traits, providing the research community with a large populationbased CNV-to-phenotype resource.[18]. Using an independent CNV calling and association pipeline and focusing on a set of 57 medically relevant continuous traits, we here confirm previously established associations, uncover biological insight through in-depth analysis of particular CNV-trait pairs, and expose a nuanced role of CNVs along
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
