A study conducted by CHOP reveals how genetic variations can influence the variety of common diseases

While subtle differences in the number of genes copied from one individual and passed on to the next can be found in many healthy people, their role in disease can be much greater than previously thought.

A large multi-center study conducted by researchers from the Philadelphia Children’s Hospital (CHOP) compared the genomic data of over 100,000 people of European origin and found that relatively rare, though recurrent, genetic variations can affect a variety of common diseases.

Furthermore, existing drugs could be re-proposed to target these conditions – ranging from autoimmune diseases to neuropsychological diseases and even cancer – now that the genetic basis of these conditions are known. The results were published online on January 14, 2019 in the journal Nature Communications.

A change in the number of copies (CNV) is a gain or loss of genomic information and occurs when the number of copies of a particular gene or genomic region varies from one individual to another. Rare CNVs are events that often predispose people to medical conditions, while the most common CNVs are generally well tolerated and common in healthy people. However, there are previously established examples where CNVs can have a negative impact on a person’s health. Indeed, previous studies suggest that they could have a widespread impact on human health, but most of these studies were based on samples of limited size, thus not providing researchers with a complete picture of their true meaning.

This analysis provides us with a dense map of the impact of the rare variations in the number of recurring copies, which represent an important source of genetic variation in our genome, often predisposing us to, and sometimes causing, complex diseases. Our study has shown that previous methods probably do not capture the accurate incidence or prevalence of the rare regions of variation in the number of copies that directly affect human health.

Senior author Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP

The study team identified 100,028 individuals of populations of European origin using genome-level SNP arrays or comparative genomic hybridization platforms of arrays. The vast majority (over 99%) of the CNV regions discovered, although singularly rare, were recurrent, which means that they occurred in at least two individuals.

Among these regions that are clinically more relevant are those with homozygous deletions, or the loss of both alleles or both copies of a gene from the same chromosomal pair. The study team identified 375 previously not reported regions like this. In addition to confirming CNV regions associated with diseases from previous studies, researchers have discovered several previously unreported regions that correspond to genes that are already of clinical interest, in some cases because drugs may already exist that affect relevant pathways.

Some specific regions of interest identified in this study include chr7p15.3 deletion associated with autoimmune diseases, as it overlaps the gene encoding ITGB8a, a consolidated pharmacological target for ovarian cancer; a homozygous deletion region associated with autoimmunity to chr2q34 which disrupts the coding region of the ERBB4 gene, a key oncogene that can be targeted by multiple FDA approved small molecule inhibitors; and the chr19p13.3 locus, which codes for the HCN2 gene and could be a potential target for therapies to treat both epilepsy and pain.

“The number of genetic candidates found in our study justifying further studies establishes the strong correlation between regions of copy number variations and what we already know about the genome,” said Hakonarson. “While important large-scale studies focusing on new discoverers are underway, we believe that further parallel analysis of these newly identified regions will continue to provide even more clinically relevant information and accelerate precision medicine.”


Philadelphia Children’s Hospital

Journal reference:

Li, Y. R. et al. (2020) Variants of rare copy numbers in over 100,000 individuals of European origin reveal multiple disease associations. Nature Communications. doi.org/10.1038/s41467-019-13624-1


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