NEW YORK – With the help of a phenome-wide association analysis of UK Biobank data, a team from Switzerland, Brazil, and the UK has started untangling the population-wide consequences of copy number variants (CNVs) in a chromosome 22 region known as 22q11.2.
The region was previously implicated in chromosome 22q11.2 deletion syndrome and a wide range of other cognitive, developmental, cardiac, immune, gastrointestinal, and psychiatric conditions, as well as facial and palate alterations.
"The 22q11.2 region is a structurally complex region of the genome because of the presence of segmental duplications or low-copy repeats … which predispose the region to genomic rearrangements, resulting in deletions or duplications of different segments," senior and corresponding author Zoltán Kutalik, a computational biology and statistical genetics researcher affiliated with the University of Lausanne and the Swiss Institute of Bioinformatics, and his colleagues wrote.
Even so, they cautioned that many prior studies of 22q11.2 variation have centered on clinical cohorts comprised of individuals with particularly pronounced symptoms or phenotypes, "leading to an incomplete and biased understanding of these variants' role in the human population."
Using array-based CNV profiles for more than 405,300 extensively phenotyped UK Biobank participants, the researchers studied traits or conditions associated with genes or regulatory sequences in the 22q11.2 region.
The team's findings, published in the American Journal of Human Genetics on Thursday, highlighted significant ties between chromosome 22q11.2 regions and eight continuous traits as well as nine binary traits, including measurements related to body size or composition, calcium levels, cardiomegaly, dental cavities, hypotension, hearing loss, and other traits.
"Our results have provided new insights to help further the understanding of the complex 22q11.2 region," the authors wrote, noting that "within the general population, 22q11.2 CNVs are associated with traits."
From there, the researchers turned to transcriptome-wide and to multivariable Mendelian randomization approaches to delve further into the consequences of altered 22q11.2 gene expression and causal ties to the traits identified, respectively.
In the process, they uncovered a relationship between body mass index and higher-than-usual expression of the gene ARVCF, which encodes a protein from the catenin family that is known for its role in adherent junction protein-protein interactions. Meanwhile, enhanced expression of another gene in the region — the potential regulatory gene DGCR6 — appeared to cause a dip in mean platelet volume.
Broadly speaking, the trait associations found for individuals with 22q11.2 CNVs tended to track with clinical features found in individuals with more pronounced alterations in the region, the authors noted, adding that the current analysis "provides a framework that can be adapted to study the phenotypic consequences of other clinically relevant genomic regions."