Assessing Genetic Overlap Between Platelet Parameters and Neurodegenerative Disorders

Abstract

Neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) suffer from the lack of risk-predictive circulating biomarkers, and clinical diagnosis occurs only when symptoms are evident. Among potential biomarkers, platelet parameters have been associated with both disorders. However, these associations have been scarcely investigated at the genetic level. Here, we tested genome-wide coheritability based on common genetic variants between platelet parameters and PD/AD risk, through Linkage Disequilibrium Score Regression. This revealed a significant genetic correlation between platelet distribution width (PDW), an index of platelet size variability, and PD risk (r g [SE] = 0.080 [0.034]; p = 0.019), which was confirmed by a summarysummary polygenic score analysis, where PDW explained a small but significant proportion PD risk (<1%). AD risk showed no significant correlations, although a negative trend was observed with PDW (rg [SE] =-0.088 [0.053]; p=0.096), in line with previous epidemiological reports. These findings suggest the existence of limited shared genetic bases between PDW and PD and warrant further investigations to clarify the genes involved in this relation. Additionally, they suggest that the association between platelet parameters and AD risk is more environmental in nature, prompting an investigation into which factors may influence these traits.

Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities

“…First of all, the shared genetic bases between platelet variability and MDD, despite some first attempts [ 149 , 294 ], still needs to be elucidated through larger genetic epidemiology studies. The latter should take into account important features such as gender differences that are known to be linked to both platelet variability [ 313 ] and to the occurrence of MDD risk [ 314 ].…”

“…However, we found no evidence of significant genetic correlations for any of the platelet parameters tested. This suggests that the significant associations observed in previous epidemiological studies may be mainly due to shared environmental influence between platelet parameters and AD risk, and that common genetic influences on these traits are likely very limited, at least those of common SNPs [ 294 ].…”

“…Nalls et al [ 297 ] tested genetic correlations between Plt/MPV and PD risk through linkage disequilibrium (LD) score regression [ 157 , 158 ], using summary statistics from the largest PD case–control GWAS meta-analysis carried out so far (involving ~56,300 PD cases and ~1.4 million controls), reporting no significant genetic correlations [ 297 ]. More recently, we extended this analysis to PDW and observed a significant positive genetic correlation with PD risk, suggesting the existence of a genomic overlap based on common genetic variants and indicating PDW as a new potential biomarker for PD [ 294 ]. In spite of the interesting finding, which is in line with the implication of PDW in neurodegenerative disorders [ 10 , 183 , 187 , 188 ] and in comorbid disorders like major depression [ 149 ], it should be noted that previous epidemiological studies reported negative associations between PDW and the risk of cognitive impairment [ 183 , 187 , 188 ], which is co-morbid and partly shares biological bases with PD [ 298 ].…”

“…In spite of the interesting finding, which is in line with the implication of PDW in neurodegenerative disorders [ 10 , 183 , 187 , 188 ] and in comorbid disorders like major depression [ 149 ], it should be noted that previous epidemiological studies reported negative associations between PDW and the risk of cognitive impairment [ 183 , 187 , 188 ], which is co-morbid and partly shares biological bases with PD [ 298 ]. At the genetic level, our group only identified a trend of (negative) correlation between PDW and AD risk [ 294 ]. Again, our limited knowledge of these disorders and of PDW itself does not currently allow us to further disentangle these aspects, although we are working towards identifying genes with pleiotropic influences on platelet variation and function and neurodegenerative risk.…”

Genomic Overlap between Platelet Parameters Variability and Age at Onset of Parkinson Disease

“…Neurodegenerative disorders like Parkinson Disease (PD) suffer from a lack of easy-tomeasure biomarkers which can predict their incident risk before the onset of symptoms [1]. With this regard, platelets have received increasing attention in the last few years [2].…”