Genome-wide assessment of Parkinson's disease in a Southern Spanish population

Abstract

Here, we set out to study the genetic architecture of Parkinson’s disease (PD) through a Genome-Wide Association Study (GWAS) in a Southern Spanish population. 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score (GRS). Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697 and SREBF/RAI1. Subjects in the highest GRS quintile showed significantly increased risk of PD versus the lowest quintile (OR=3.6, p-value < 4e−7), but no significant difference in AAO. We found evidence of runs of homozygosity in two PD-associated regions: one intersecting the HLA-DQB1 gene in six patients and one control; and another intersecting the GBA-SYT11 gene in one PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases respectively, replicating previous work. A structural variant was found in one case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics.

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

“…The SNP with the strongest association in Stage 1 (rs17763050, p = 2.74 x10 -9 ) is in high LD with the known H1/H2 haplotype tag SNP rs8070723 (SI Fig 7E). Both SNPs are associated with ORs ~0.75 (95% CI ± 0.1) for the H2 haplotype, and OR 1.22 (95% CI ± 0.1) for the H1 haplotype (SI Table 6), consistent with previously reported effect sizes 3,5 . Due to a smaller cohort size and consequent lack of power, the association with 17q21.31 is less prominent in Stage 2 data.…”

The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

“…In brief, PRS profiling is calculated traditionally based on weighted allele dose manner as per previous work. [25][26][27][28][29][30][31][32] We used the R package PRSice2. 33 Permutation testing and P-value aware LD pruning was used to identify best P thresholds in external GWAS data to construct the PRS, allowing us to utilize variants below the common GWAS significance threshold of 5E-08.…”

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

“…Although common genetic polymorphisms in the vicinity of the ACMSD gene were previously shown to be associated with increased risk for PD by several GWAS studies [1][2][3][4], we know of no reports on specific mutation in this gene in patients with sporadic PD. Recently, a stop codon ACMSD mutation (p.Trp26Stop) has been reported in a family with cortical myoclonus, epilepsy, and parkinsonism [5].…”

“…The first large-scale meta-analysis of GWAS in PD nominated single nucleotide polymorphisms (SNP) in five new susceptibility loci including ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R [1]. The association of ACMSD, aminocarboxymuconate semialdehyde decarboxylase, variants and PD has been later replicated by different groups [2][3][4]. A recent study has reported a rare ACMSD stop codon mutation (p.Trp26Stop) in a family with autosomal-dominant cortical myoclonus, epilepsy, and parkinsonism [5].…”