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Rare CNVs Associated With Major Disease Categories in Large Study of European Subjects

NEW YORK – In a new study of copy number variants (CNVs) in more than 100,000 individuals of European ancestry, researchers have found that rare, recurrent CNVs are associated with several common, complex human diseases, presenting previously unreported opportunities for new therapies.

"We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities," the authors wrote in their paper, published this week in Nature Communications. "Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease."

Hakon Hakonarson of the Children’s Hospital of Philadelphia and his collaborators at the University of Pennsylvania Perelman School of Medicine and elsewhere examined the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. They observed an average CNV burden of about 650 kb, and identified a total of 11,314 deletion, 5,625 duplication, and 2,746 homozygous deletion CNV regions (CNVRs). In all, 13.7 percent of these were unreported, 58.6 percent overlapped with at least one gene, and 32.8 percent interrupted coding exons.

A vast majority of CNVRs — 11,287 deletions (99.75 percent) and 5,614 duplications (99.96 percent) — were recurrent, the researchers found. And although individual CNVRs were rare, the presence of CNVs in the human genome was collectively common. Although CNVRs were heterogeneously distributed across the genome, they didn't find any large stretches of the genome that were exempt from harboring CNVs, and more than 99 percent of CNVRs harbored both deletions and duplications.

Importantly, the researchers found that CNVRs were 2.94-fold more likely to overlap OMIM genes, 1.52-fold more likely to overlap GWAS loci, and 1.44-fold more likely to overlap non-coding RNAs compared with random distribution. These findings underscored the important impact of natural selection in driving human genetic diversity and CNV distribution, as well as the importance of CNVs in phenotypic variation and human disease, they noted.

When they evaluated the most clinically important CNVRs, the researchers found that homozygous deletions were most likely to be pathologic, and that a lower percentage of them was recurrent. To identify potential associations between recurrent CNVs and human disease, they clustered individuals into groups of healthy controls and four major disease categories: 11,489 autoimmune/inflammatory disease sufferers, 9,105 people with cancers, 2,581 individuals with cardiovascular or metabolic diseases, and 43,841 people with various psychiatric, neurodevelopmental, and neurological diseases.

They identified candidate genes in disease-associated CNVRs (DA-CNVRs) in a number of well-established disease-associated loci, including chr2p24.3 (MYCN amplification in cancer), chr22q11.21 (COMT and TBX1 deletion in neuropsychiatric disease and congenital heart conditions), and chr17q21.1 (NR1D1, deletion and duplication associated with response to lithium in bipolar disease and major depressive disorder). In addition, the researchers uncovered multiple, putatively unreported DA-CNVRs that map to relevant candidate genes, including several well-established drug targets.

When they performed enrichment analyses across each set of the domain-specific DA-CNVRs, they observed that many of the functional and genomic elements were enriched in multiple disease domains.

"Our analysis presents a dense map of CNVs across the human genome and refines the frequencies of rare recurrent CNVs across the genome," the authors concluded. "Collectively, our findings support a biological model in which recurrent CNVRs play a role across multiple common human diseases due to pleiotropic functions and/or broad expression of the affected gene(s)."