Polygenic Determinants Of Parkinson’s Disease And The Establishment Of Autosomal Dominant Parkinson’s Disease Genetic Diagnosis Platform

Background:Parkinson’s disease (PD) is one of the most common neurodegenerative disorder with major clinical features of bradykinesia, rigidity, resting tremor and postural instability. The hallmark pathological features are loss of dopaminergic neurons from the substantia nigra and the formation of Lewy bodies. With the discovery of PD related susceptibility gene, more and more attention is taken to the genetic factors in the pathogenesis of PD. However, epidemiological investigation shows that only 5%-10% of patients have genetic factors. Majority of the PD patients is sporadic, monogenic forms of the disease are rare. There have been suggesting that some variants in SNCA、LRRK2、MAPT and GBA gene are susceptible factors to PD. Recently, researches on Cancer, type 2 Diabetes proposed that interaction of gene or variants promote the risk of diseases. Our study did an interaction polygenic analysis of PD.Objective:A systemic evaluation of the independent and combined effects of Rep1, rs11931074,rs356165in SNCA gene; G2385R,R1628P in LRRK2 gene; rs242562, rs2435207 in MAPT gene and L444P in GBA gene on the sporadic PD patients and normal controls in Chinese population was done to discuss that multiple genes may interact with one another. Methods:Gene mutation analysis of SNCA、LRRK2、MAPT and GBA gene were carried out by polymerase chain reaction (PCR) combined with DNA direct sequencing in 1011 sporadic PD patients and 1016 normal controls to discuss the interactions of multiple genes.Results:Rep1, rs356165 in SNCA gene, G2385R in LRRK2 gene, L444P in GBA gene were associated with PD with adjustment of sex and age (P<0.05) in the analysis of eight variants. PD risk was increased when Rep1 and rs11931074, rs356165, Repl and G2385R, rs356165 and G2385R were combined for association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (OR for carrying 5 variants:8.456).Conclusion:In this study, we first confirm that Rep1,rs356165 in SNCA gene and G2385R in LRRK2 gene have an independent and combined significant association with PD. L444P in GBA gene was speculated as an independent risk factor. SNPs in four genes have a cumulative effect with PD. Background:To date, LRRK2、SNCA、UCHL1、HTRA2 and GIGYF2 genes of autosomal dominant PD (ADPD) loci have been cloned, which laid a theoretical foundation to set up the genetic diagnosis platform of ADPD.Objective:To set up the genetic diagnosis platform of ADPD by investigating the mutation characteristics of LRRK2、SNCA、UCHL1、HTRA2 and GIGYF2 genes in Chinese patients with ADPD.Methods:Gene mutation analysis of LRRK2、SNCA、UCHL1、HTRA2 and GIGYF2 were carried out by polymerase chain reaction (PCR) combined with DNA direct sequencing in index patients with ADPD from 16 unrelated families based on the diagnosis platform.Results:One ADPD family proband had a causative mutation on LRRK2 gene (c.1847A>G/p.K616R) was identified. The variant was not found in 400 control chromosomes or in dbSNP. And the absence of the variant in his family numbers suggests it was probably pathogenic. None causative mutation of SWCA、UCHL1、HTRA2 and GIGYF2 genes was found. Four unreported LRRK2 polymorphisms (Ivs1+47C>A Ivs28+44G>A. Ivs33+33T>A and Ivs45+27G>A) and one unreported GIGYF2 polymorphisms (Ivs6+117T>A) were found. Conclusion:In this study, we first confirm that LRRK2 gene mutation is relative common in Chinese Han ADPD patients, and tentatively set up the diagnosis platform to regulate the genetic diagnosis process of ADPD.