Study Finds Copy Number Variant Ties to Complex Human Traits

"The role of CNVs in severe genomic syndromes is well-established. … However, the full spectrum of traits affected by CNVs was never fully appreciated," first author Chiara Auwerx, a Ph.D. student affiliated with the University of Lausanne's Center for Integrative Genomics and its computational biology department, the Swiss Institute of Bioinformatics, and the University Center for Primary Care and Public Health, explained in an email. "We show that some CNVs have extremely broad downstream consequences, impacting multiple physiological systems."

Starting with array-based CNV data for more than 331,500 participants in the UK Biobank project, the researchers did a genome-wide association analysis focused on CNVs in relation to 57 continuous traits. In the process, they narrowed in on more than 130 associations involving 47 of the traits of interest, including polygenic associations, CNV signals that overlapped with SNP sites identified in prior GWAS, and associations falling in parts of the genome previously linked to Mendelian conditions.

Along with validation analyses done using data from the Estonian Biobank effort, the team demonstrated that large CNVs turned up in a significant subset of the study's participants, hinting that at least some CNVs implicated in clinical conditions in the past may be more widespread — and have a broader range of potential effects — than previously appreciated.

"[A]t least four out of 10 seemingly healthy individuals from the general UK population carry a sizable CNV and these have a more heterogenous effect than previously known," Auwerx said. "For instance, individuals carrying CNVs that were believed to be highly pathogenic might present with mild phenotypic alterations aligning with the clinical description of the corresponding disorder, without necessarily being sick enough to receive a clinical diagnosis."

Even so, the researchers noted, there are hints that enhanced CNV burdens tend to coincide with shorter-than-usual lifespans, poorer health outcomes, and reduced socioeconomic status, the researchers noted, consistent with a possible continuum between Mendelian disease and complex conditions.

"Our study revealed the nuanced role of CNVs along the rare-versus-common disease spectrum, their shared mechanisms with SNPs, as well as a widespread polygenic CNV architecture, consolidating the growing body of evidence implicating CNVs in the shaping of complex human traits," the authors wrote.

Although they cautioned that "collective efforts will be required to validate and interpret these discoveries," those involved in the study "hope that this resource will be useful for researchers and clinicians aiming at improving the characterization of recurrent CNVs."

"[T]his information is useful for researchers aiming at understanding the molecular mechanisms and biological pathways that connect CNVs to phenotypes, as well as shed light on the genes associated with a trait in a GWAS-identified locus," Auwerx said. "Insights gained from improved understanding of these mechanisms could in turn help develop treatment modalities."