NEW YORK – Investigators at Brigham and Women's Hospital, Harvard Medical School, the Broad Institute, and elsewhere have linked complex human traits to rare copy number changes with the help of a computational method that bolsters CNV detection in biobank collections.
As they reported in Cell on Thursday, the researchers analyzed haplotype sharing patterns in some 452,500 UK Biobank participants with available SNP genotyping data using their "haplotype-informed copy number variation" (HI-CNV) approach. In the process, they picked up a slew of CNVs that have been missed in the past, unearthing almost 13 duplications and more than 18 deletions per person, on average — results that were subsequently validated with copy number profiles for more than 500 genome-sequenced individuals in the UK Biobank.
From there, the team searched for ties between these CNVs and some 56 heritable quantitative complex traits — ranging from blood cell or blood serum biomarkers to blood pressure or bone mineral density profiles — with CNV-level, probe-level, and gene-level analyses.
The investigators narrowed in on 269 complex trait-CNV associations spanning more than 250 CNVs at 97 genomic loci. All but 10 of the associations stemmed from rare CNVs, they noted, and the trait-related variant set included ultra-rare CNVs in the UHRF2 and JAK2 genes that appeared to have large impacts on height or blood platelet counts, respectively.
"The human genome contains hundreds of thousands of regions exhibiting copy number variation (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs have been ascertainable from SNP array data generated by large biobanks," co-senior and co-corresponding authors Po-Ru Loh from the Broad, Chikashi Terao with the RIKEN Center for Integrative Medical Sciences and the University of Shizuoka, and their colleagues wrote.
They noted that the latest findings "demonstrate the ability of haplotype-informed analysis to provide insights into the genetic basis of human complex traits."
The team validated a subset of the complex trait associations by applying the HI-CNV method to 179,538 BioBank Japan participants, who carried an average of 28 detectable CNVs apiece. The Biobank Japan analysis and an analysis that included a subset of the UK Biobank participants also pointed to the potential for finding new CNVs in smaller biobank cohorts.
Bringing in additional data, the investigators flagged almost three dozen potential target genes at the 72 newly detected loci. When it came to CNVs linked to complex human traits in the past, meanwhile, they noted that 13 of the 25 loci were home to CNVs implicated in syndromic genetic conditions.
"Putative target genes were identifiable for nearly half of the loci, enabling insights into dosage sensitivity of these genes and uncovering several gene-trait relationships," they added.
Even so, the authors cautioned that "the CNVs we detected from SNP array data still represent only a small fraction of the thousands of CNVs typically present in each human genome," noting that additional copy number changes will likely be unearthed as computational strategies such as HI-CNV are used to assess larger cohorts and whole-genome sequence or exome sequencing datasets.
"We anticipate that future studies analyzing short- and long-read sequencing data will provide many more insights into the phenotypic consequences of copy-number variation," they concluded.