November 11, 2025

@michaelokun

Parkinson's genetics are critical to the PLAN. Though Ray and I frequently talk about the ~13% number for single faulty genes, there is much more to the story (genetic risk, aging, environment and lifestyle). We had a great recent conversation w/ Nacho Mata at the Cleveland Clinic about how important genetics will be to the future of Parkinson's. Polygenic means involving many genes and that each may add small pieces of risk, which together can influence whether a disease develops. Ashley Hall and colleagues in the International Journal of Molecular Sciences drew a really outstanding figure about the complexity of this topic. Their paper emphasized why focusing on a single gene mutation may miss the larger Parkinson's picture. Key points: - The authors share the reasons why polygenic risk scores and pathway thinking can help us understand causes and prevention. - The authors show Parkinson’s is shaped by a broad constellation of genetic factors and the interaction w/ the environment. - Polygenic risk scores reveal how many small genetic contributors combine to shape Parkinson’s susceptibility. - Variants differ by both ancestry and context. - Structural variants, rare variants and 'uncaptured genomic regions' likely contribute to missing heritability. My take: The book that Ray and I wrote www.pdplan.org talks about the ~13% of 'single gene' mutations, however you should not be blinded that genetics in Parkinson's are much more complex than this number. Genetics currently play, and will play, a much bigger role in the future. Great interviews with Andy Singleton, Ellen Sidransky and Tom Gasser. Here are 5 points that resonated w/ me about this paper and our conversation w/ Nacho about keeping genetics top of mind: 1-Understanding Parkinson’s requires looking at many genes, not just one gene that goes wrong. 2-Genes interact w/ age, environment and lifestyle, however none alone determine destiny. 3- Mitochondria inflammation and protein handling systems are key to brain cell vulnerability. 4- Better genetic tools may help predict who is at risk and may personalize strategies. 5- We need big data sets. #michaelokun #fixelinstitute #parkinson