Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement MINECO (Ministerio de Economia y Competitividad) grants SAF2016-76340-R to E.S. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Samples were acquired after death with informed consent from Parkinson patients at Hospital Clinic Barcelona, Spain. Ethical approval for the study was gained from the hospital's Clinical Research Ethics Committee (Reference HCB/2016/0259) in accordance with LIB 14/2007 and RD 1716/2011. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Sequencing data are available on request and will be deposited in a public repository. Methods including COSMOS are available in GitHub