Genetic findings from the Tracking Parkinson’s Study
Original article: Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study, Brain: July 19, 2019.
The results of the largest UK population based study of Parkinson’s has found that up to 10% of affected individuals carry a pathogenic mutation.
Why is it important?
Understanding the genetics of Parkinson’s, and the mutation that may be central to someone’s condition, makes it increasingly likely that it can be precisely targeted using drugs. Intervening earlier is key.
The prevalence of Parkinson’s in the UK has been estimated at 14 people in 10,000. Genes play an important role, and several have been identified, including LRRK2, PINK1, PARKIN, SNCA, which have been found in up to 10% of patients. These different genes in combination with environmental triggers and aggravators have an effect on age of onset, symptoms and progression.
Since many studies have focused on smaller cohorts of people often drawn from clinics, the current study aimed to get around these potential biases. The ‘Tracking Parkinson’s study’ is a large-scale population-based effort recruiting recently diagnosed and young-onset people with Parkinson’s in the UK. It is the largest single cohort study including focus on genetic mutations, in 424 young onset (defined as being diagnosed when they were younger than 50) and 1799 late onset people with Parkinson’s. Each participant underwent an extensive set of neurological and cognitive assessments, and submitted their biological samples for genetic analysis.
The authors aimed to get a more accurate estimate of genetic risk, and discover potential links between genes and aspects of Parkinson’s. A total of 1.4% (29/2005) individuals whose genes were sequenced had pathogenic mutations, across both young onset and late onset patients. When all the different mutations were taken into account, including GBA mutations, the authors estimate that up to 10% of people with Parkinson’s carry a gene that could form the basis of a targeted drug therapy.
The analysis also showed that LRRK2 mutations are present in 2.2% of people with early onset Parkinson’s, but almost half of these reported no family history of the condition. The effects of this mutation are strongly dependent on increasing age, so the authors predict that the number of people with Parkinson’s who carry it are likely to increase in the UK as the population ages. However, the results also indicate that LRRK2 mutations are present in young onset people with Parkinson’s as well, which has direct implications for genetic testing in this population as well as people with late onset.
SNCA mutations were present in 1.5% of people with a strong family history of the condition.
Looking at associations between different mutations and the features of Parkinson’s, the authors found no differences as a function of LRRK2, but among young onset people with Parkinson’s there were differences as a result of PRKN and PINK1: these carriers had more postural problems at diagnosis but did better on tests of cognition than other young-onset patients.
These results have direct implications for genetic testing in both young and late onset people with Parkinson’s, as well as for clinical trials of therapeutics targeting the effects of specific mutations.
Original article: Tan MMX, Malek N, Lawton MA, Williams NM, Morris HR. July 19, 2019. Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study.