{"id":5087,"date":"2024-05-23T11:18:11","date_gmt":"2024-05-23T09:18:11","guid":{"rendered":"https:\/\/www.uni.lu\/lcsb-en\/?post_type=news&p=5087"},"modified":"2024-11-06T10:30:04","modified_gmt":"2024-11-06T09:30:04","slug":"genetic-risk-scores-for-parkinson-for-precision-medicine-approach","status":"publish","type":"news","link":"https:\/\/www.uni.lu\/lcsb-en\/news\/genetic-risk-scores-for-parkinson-for-precision-medicine-approach\/","title":{"rendered":"Genetic risk scores for Parkinson\u2019s for precision medicine approach"},"content":{"rendered":"\n
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An interdisciplinary team from the Luxembourg Centre for Systems Biomedicine<\/a> (LCSB) at the University of Luxembourg, together with international collaborators, established that a combination of small variations in genes regulating mitochondria, an important component of human cells, is associated with a higher risk for Parkinson\u2019s disease. For the first time in the field, the researchers demonstrated that these genetic predictions translate into mitochondrial dysfunction in cellular models derived from Parkinson\u2019s patients with a high polygenic risk score. Importantly, using data from a recent clinical trial for a drug targeting mitochondria, they also showed that Parkinson\u2019s patients with high risk scores responded better to the treatment. These results, recently published in Annals of Neurology<\/em><\/a>, pave the way for intelligent clinical trial designs and will have a considerable impact on precision medicine for Parkinson\u2019s disease.<\/p>\n\n\n\n

Parkinson\u2019s disease is the fastest growing neurodegenerative disorder, affecting around 2% of the population over the age of sixty. Unravelling the complex genetic architecture of this disease remains a major challenge. While familial forms due to a single mutation account for 5 to 10% of all cases, the contribution of genetics in the remaining patients is poorly understood. Studies now suggest that a combination of common variations, called variants, in multiple genes may act as a risk factor for the disease. To explore their joint impact, polygenic risk scores have been developed by the research community in recent years.<\/p>\n\n\n\n

\nPolygenic risk: Measuring the combined effect of multiple genetic variants<\/h3>\n\n\n\n

The idea is to estimate the risk associated with the sum of the different genetic variants carried by an individual. \u201cMost common variants have little to no effect, but when combined with several others, they can become relevant to the disease,\u201d explains Dr Patrick May<\/a>, researcher in the LCSB Bioinformatics Core<\/a>. He led the genetic analysis for this study together with Dr Zied Landoulsi<\/a> who continues: \u201cWe use statistics from large-scale genetic studies to understand if each variant is associated with the disease or a specific trait. By adding up the estimated effects of these small changes in several genes, we can calculate a risk score and hopefully identify people with a higher likelihood of developing Parkinson\u2019s disease.\u201d<\/p>\n\n\n\n

Additionally, for disorders that are very heterogeneous, with a wide array of genes and molecular mechanisms involved, this type of approach could be useful to stratify patients, meaning divide them into different groups, enabling precision medicine. Patients having a high polygenic risk score for genes that regulate a specific biological function could for example be more responsive to drugs targeting this specific pathway.<\/p>\n\n\n\n

\nIdentifying patients with impaired mitochondria<\/h3>\n\n\n\n

\u201cIt is well-known that mitochondria, the powerhouses of our cells, play a role in Parkinson\u2019s disease. There is evidence that points to mitochondrial dysfunction as an early and causative event in the pathogenesis,\u201d explains Prof. Anne Gr\u00fcnewald<\/a>, head of the Molecular & Functional Neurobiology<\/a> group. \u201cSo, we worked on the hypothesis that some patients may harbour a combination of variants in different nuclear-encoded mitochondrial genes that contributes to neurodegeneration.\u201d<\/p>\n\n\n\n

Working on datasets from two large and well-characterised cohorts, the Luxembourg Parkinson\u2019s Study<\/a> and COURAGE-PD<\/a>, the researchers calculated mitochondria-specific polygenic risk scores for over 14.000 patients and controls. They demonstrated that having multiple common mutations in genes regulating a specific mitochondrial pathway, namely oxidative phosphorylation (OXPHOS), is significantly associated with the disease. \u201cThese first results reinforce the idea that impaired mitochondrial respiration is a relevant aspect in Parkinson\u2019s disease and indicate that polygenic risk scores provide a tool to genetically stratify patients, allowing us to effectively identify a subgroup of people with relevant alterations of mitochondrial function,\u201d details Dr Giuseppe Arena<\/a>, researcher in the Translational Neuroscience<\/a> group and one of the first authors of this study.<\/p>\n\n\n\n

\nValidating genetic scores in patients\u2019 cells<\/strong><\/h3>\n\n\n\n

Next, the researchers wanted to determine whether these specific genetic risk scores could be linked to corresponding characteristics in patient cells. They performed functional experiments in skin cells donated by participants of the Luxembourg Parkinson\u2019s Study and in neuronal progenitors derived from these skin cells in the lab. In both cases, they observed significant differences in mitochondrial respiration between the cells of patients with high and low risk scores for the OXPHOS pathway. \u201cFor the first time in this field, our study validated the existence of profiles in the cellular models corresponding to the calculated risk scores,\u201d underlines Dr Arena.<\/p>\n\n\n\n

\nAnd testing their relevance for clinical trials<\/strong><\/h3>\n\n\n
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