# Genomic Overlap between Platelet Parameters Variability and Age at Onset of Parkinson Disease
## 4 Discussion  
In this work, we carried out a detailed analysis of the genomic overlap between platelet parameters' variability and age at onset of Parkinson Disease, first by investigating the presence and entity of the overlap and then by attempting to identify single variants, genes and pathways at the basis of this co-heritability. We observed a significant negative genetic correlation between PD-AAO and MPV, suggesting that there may be a link between platelet parameters and an important endophenotype of PD. However, this relation is in contrast with a study reporting higher MPV in PD cases compared to controls [3] and with previous reports associating lower MPV with increased PD severity [3,4]. Indeed, lower AAO is usually associated with an increased H&Y score as the disease progresses, since neurodegeneration is expected to have more time to exert disruptive effects in younger rather than older PD patients. Of note, lower MPV is also associated with an increased platelet activity, a characteristic which was found in PD cases compared to controls [18], and it is indicative of increased circulating inflammation levels [19]. These apparently contrasting findings may be explained by the existence of a PD (sporadic and late onset) subtype which might be more influenced by systemic inflammation, be it of environmental or of genetic origins, in line with previous evidence [18,20]. While research on PD etiology has not yet reached such a fine-grained resolution, evidence that serum levels of inflammatory cytokines correlate with H&Y staging [21] may support this hypothesis, which warrants further epidemiological and functional studies in order to be verified. The multitrait analysis of PD-AAO and MPV revealed diverse novel variants associated with both traits, which were not detected in the original GWAS studies [8,16]. Among these variants, significant associations were detected in genes previously implicated in PD pathology or coagulation pathways, like _KALRN_, _DNM3_, _ARHGEF3_ and _IQGAP2_. A gene-based enrichment test of multitrait associations revealed different overlaps between PD-AAO and MPV. Indeed, the most significantly enriched genes for associations with PD-AAO--_ARHGEF3_, _KALRN_ and _IQGAP2_--were also among those most enriched for associations with MPV. Interestingly, some of these genes have been implicated in known neurodegenerative related processes and diseases, like depression (_ARHGEF3_) [22], Alzheimer's Disease and schizophrenia (_KALRN_) [23], or even Parkinson Disease (_KALRN_, _IQGAP2_) [23,24]. Of particular interest, _KALRN_ encodes the kalirin protein, a key regulator of structural and functional plasticity at dendritic spines [25], which interacts with synphilin-1 (leading to the recruitment of aggresomes) and, indirectly, with alfa-synuclein, a key protein in PD etiology [26]. A pathway-based enrichment analysis further supported the idea of a common genetic and biological basis for PD-AAO and MPV, since both traits showed an enrichment of coagulation-related pathways. While this may result as being obvious for MPV, it may not appear that obvious for PD-AAO, especially considering that PD is, among all common neurodegenerative disorders, the least investigated for associations with platelet parameters (see the review by [PERSON] et al., 2020 [27]). In particular, pathways like _coagulation_, _megakaryocyte development and platelet production_ may be directly involved in this common link. It is known that PD is accompanied by dysregulation in blood clotting, as previously suggested by proteome analyses within two mouse models of PD [28]. Our results support the hypothesis that the abovementioned pathways may be simultaneously related to both platelet parameters' variability and to neuropathological mechanisms in sporadic, late-onset forms of PD. Further functional studies are warranted to investigate this fascinating hypothesis, as has been successfully done for Alzheimer's disease [29].