Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease

Abstract

BackgroundThe dysfunction of immune system and inflammation contribute to the Parkinson’s disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk.MethodsStandard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them.ResultsWe included 36 variants in 18 genes for final pooled analysis. As a result, IL-6 rs1800795, TNF-α rs1799964, PON1 rs854560, CYP2D6 rs3892097, HLA-DRB rs660895, BST1 rs11931532, CCDC62 rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in IL-1α, IL-1β, IL-10, MnSOD, NFE2L2, CYP2E1, NOS1, NAT2, ABCB1, HFE and MTHFR were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by BST1) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by PON1) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]).ConclusionSeveral polymorphisms from inflammatory genes of IL-6, TNF-α, PON1, CYP2D6, HLA-DRB, BST1, CCDC62 were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis.

Joint-tissue integrative analysis identifies high-risk genes for Parkinson’s disease

“…For instance, HLA-DRB1 ( Le Guen et al, 2023 ) has been identified as an immune-related PD gene. Additionally, polymorphisms in STX1B ( Wang et al, 2015 ) and CCDC62 ( Lauterbach, 2012 ; Yi et al, 2023 ) are connected to PD. Numerous other DNA methylations, such as CRHR1 ( Cheng et al, 2020 ; Rasmi et al, 2023 ) and ABCB9 ( Chuang et al, 2017 ) have implications on PD development.…”

Genetic polymorphisms of bone marrow stromal cell antigen-1 (BST-1/CD157): implications for immune/inflammatory dysfunction in neuropsychiatric disorders

“…Parkinson’s disease (PD) is a common and complex neurological disorder that exhibits classical motor dysfunctions, including bradykinesia, resting tremor and gait disturbance, and non-motor features, such as psychiatric symptoms, sleep disorder and cognitive impairment ( 36 ). Epidemiological studies have revealed that both genetic and environmental factors are attributable to PD ( 36 – 41 ).…”

“…Hence any of them alone could not be an appropriate diagnostic or prognostic biomarker for PD. It is worth examining, however, whether these SNPs could be integrated effectively into polygenic risk score analysis ( 73 ) in combination with SNPs of IL-6, TNF-α and many other PD-related genes ( 41 ).…”

Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit

“…Many genes contribute to the pathogenesis of PD, including α-synuclein ( SNCN ), leucine-rich repeat kinase 2 ( LRRK2 ), glucocerebrosidase ( GBA ), vacuolar protein sorting associated protein 35 ( VPS35 ), phosphatase homolog-induced kinase ( PINK1 ) and Parkinson protein 7 ( PAPK7 ) [ 3 , 4 ]. The interaction between the susceptible genes and environmental elements influences the onset of PD [ 5 ].…”