Linking rare and common diseases

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(© Image: Depositphotos)
(© Image: Depositphotos)

A study conducted at the University of Lausanne and the SIB has demonstrated that a little-studied category of genetic variants, generally associated with serious rare diseases, also influences the risk of more common diseases in the general population. Their results, published in the January 8, 2024 issue of the journal "Genome Medicine", are promising for the development of personalized medicine.

Copy-Number Variants (CNVs) are a poorly understood type of genetic mutation, in which an individual possesses more (duplication) or fewer (deletion) than two copies of some element of their DNA. Historically, CNVs have been studied in clinical cohorts of individuals suffering from ’genomic disorders’. These are generally characterized by severe clinical symptoms appearing in childhood, such as neurodevelopmental delays, physical malformations or disorders such as autism.

In previous work, the Lausanne-based teams studied the presence of CNVs in 500,000 people from the UK Biobank, a large cohort of volunteers from the general British population for whom genetic data is available. This study has shown that CNVs are present in the general population at a higher frequency than previously thought, and that they affect certain traits, such as cholesterol levels, an indicator for certain pathologies", says Alexandre Reymond , full professor at the Centre intégratif de génomique in the Faculty of Biology and Medicine at the University of Lausanne. This led us to ask: what if these mutations had a role in susceptibility to more common diseases?

New statistical approach reveals links between CNVs and common diseases

In order to answer this difficult question, we had to develop an analytical framework to assess the reliability of the associations discovered between CNVs and diseases", explains Zoltán Kutalik , head of the statistical genetics group at Unisanté and the Department of Computational Biology at the University of Lausanne, as well as a member of the Swiss Institute of Bioinformatics (SIB). Indeed, the binary nature of diseases (you’re either sick or you’re not) in relation to continuous characteristics such as height or weight, as well as the relative rarity of CNVs in the population listed in the UK Biobank, meant that scientists had to adapt existing statistical approaches to support their findings.

The researchers found 73 links between CNVs and disease, involving 45 unique genomic regions and 40 common pathologies such as asthma, epilepsy, kidney failure or heart disorders. In addition to increasing the risk of disease, these mutations also lead to earlier onset. For example, deletions of the BRCA1 gene have been found to lead to an increased risk of ovarian cancer, confirming the observation that genetic alterations in this gene represent one of the most important genetic risk factors for breast and ovarian cancer.

A single CNV can increase the risk of several pathologies

The scientists also studied a phenomenon known as ’pleiotropy’. This term refers to the fact that a single genetic variant can have an impact on the risk of several diseases. This phenomenon has been observed for many CNVs, particularly those linked to genomic disorders. In particular, a CNV known as 16p11.2 BP4-5 has been shown to affect the risk of 15 different diseases", notes Chiara Auwerx, a PhD student in the groups of Zoltán Kutalik and Alexandre Reymond, and first author of the article published in Genome Medicine.

A potential avenue for personalized medicine

As the CNVs analyzed are quite rare, the proportion of diseases that can be attributed to them remains small. The researchers estimate that around 0.02% of all disease cases are caused by CNVs, with a slightly higher percentage for diseases such as schizophrenia, for which CNVs are an important risk factor. However, for a given individual, the presence of a CNV can have non-negligible effects, as it increases the risk of disease by several orders of magnitude and thus has much more serious consequences than other, more common types of genetic variants. These results are promising for the development of personalized medicine. Identifying individuals who carry these mutations could enable the development of prevention strategies and tailor-made treatments", concludes Zoltán Kutalik.