Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations

Abstract

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We ideniified common variants associated with Parkinson′s disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

New developments in the biology of fibroblast growth factors

“…Parkinson's disease (PD) is a neurodegenerative disorder that predominately affects dopaminergic neurons in the substantia nigra of the brain (Y. Liu, Deng, et al, 2021). Genetic association analysis indicates that polymorphisms in FGF20 may be significantly associated with an increased risk of PD in Chinese and Indian populations (Jing et al, 2015; Rudakou et al, 2021; Sadhukhan et al, 2018; X. Y. Sun, Wang, et al, 2017; X. Wang, Sun, et al, 2017; X. Zhao, Wu, et al, 2016).…”

Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease

“…39 And finally, it is hoped that in the future, the availability of a larger dataset would enable us to integrate additional layers of genetic data, including rare and copy number variants. 40 Our findings clearly highlight the importance of combining GWAS from diverse populations, representative of worldwide populations, to refine the genetic architecture underlying a complex trait such as AAO. Our COURAGE-PD dataset suggests a role for additional pathways in addition to α-synuclein mechanisms of modulating PD pathogenesis and influencing AAO in worldwide PD populations.…”

“…uncertainty associated with random X Chr inactivation, we excluded the X Chr variants from the present analysis 39 . And lastly, it is hoped that in the future, the availability of a larger dataset would enable us to integrate additional layers of genetic data, including rare and copynumber variants 40 .…”

Long non‐coding RNA MALAT1 regulates cell proliferation and apoptosis via miR-135b-5p/GPNMB axis in Parkinson’s disease cell model

“…It was reported that GPNMB was abnormal expressed in various cells [ 24 , 44 ]. Besides, genome-wide association studies demonstrated that GPNMB should be considered as possible Parkinson’s disease-related genes for future studies [ 45 ]. Thus, we further investigate the effect of GPNMB in MALAT1/miR-135b-5p regulated the proliferation and apoptosis of neurons in PD.…”