Decoding health and disease
The purpose of this blog is to present, discuss and share knowledge on topics related to population health and medical research. Blog posts are written mainly by researchers from the Faculty of Medicine.
A genome-wide association study provides new information about the hereditary background of lumbar disc herniation
Lumbar disc herniation is one of the most common structural changes in the lower back. It causes radicular pain, also known as sciatica, which affects up to 300,000 Finns annually. Despite the known influence of genetic factors on the risk of herniations, few large genetic studies have been conducted. In a recent study by the University of Oulu, researchers identified up to 41 new genome regions associated with disc herniations, in addition to the previously known 23 regions. This blog post discusses the most important research methods and the most important findings of the study.
Figure: Copilot
Who and what was studied?
The study analysed genetic and health data from nearly 830,000 participants across the FinnGen project, the Estonian Biobank, and the UK Biobank, highlighting the critical role of biobanks in advancing modern genetic research (see our blog post about biobanks). Patients suffering from lumbar disc herniations were identified based on International Classification of Diseases (ICD) diagnosis codes, yielding over 80,000 cases across the biobank data from the three countries. The study also included 748,975 controls who did not have the diagnosis codes. In addition, 7,347 Finns who required surgical treatment for their symptoms were identified in the FinnGen, and these more severe cases were analysed separately.
How was it investigated?
The central analysis method of the study was a genome-wide association study (GWAS), which determines links between millions of genetic variants to the trait of interest, i.e., in this case, the lumbar disc herniations. GWAS studies primarily focus on single nucleotide substitutions, where one “letter” in the DNA sequence replaces another. The sequence variations can be determined using genotyping chips, or they can be imputed, i.e. computationally predicted variations. The connection of each sequence variant to the trait of interest is tested separately, which requires considerable computing power. Due to the large number of tests, a p-value <5x10-8 is considered as the limit for a significant finding in GWAS studies.
The findings of GWAS studies are large genome regions, often harbouring numerous genes. Therefore, after the GWAS analysis, several downstream analyses are carried out to increase the understanding of the biological processes related to the disease under investigation. In this study, gene sets related to lumbar disc herniations were analysed, genetic correlations between herniations and other traits were evaluated, and cause-and-effect relationships were investigated using genetic epidemiology methodology.
What was found?
The study found a total of 64 genome regions modifying the risk of lumbar disc herniations, 41 of which had not been linked to herniations in previous studies. The functions of the genes in these regions were often related to the structure of the intervertebral discs or inflammatory processes. In addition, previously unknown associations with genes related to the nervous system and nerve function were observed. The study also identified five new genetic regions associated with more severe disc herniations requiring surgery.
Downstream analyses strongly supported the notion that gene sets related to the function and structure of cartilage and connective tissue are central to the risk of disc herniations, as are gene sets related to the nervous system regulating the structure and function of presynapses. Genetic correlation analyses showed that the gene regions related to disc herniations are also linked with other pain conditions. Causal analyses, on the other hand, confirmed the view that disc herniations cause back pain.
What are the conclusions of the study?
The study's findings can help to understand why sciatica can be prolonged, why patients experience different levels of pain, or why some people develop symptoms of disc herniations at a young age and others later. When the genetic factors and biological pathways underlying disc herniations and sciatica are better understood, new opportunities will open up for the development of treatment for patients suffering from sciatica, thereby improving their quality of life.
The study was published on 7.11.2024 in the Nature Communications publication series.
The authors: