Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Abstract

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.

Advances in genetic diagnosis of neurological disorders

“…We recently confirmed a number of disease associations in a large Scandinavian study of Parkinson's disease (12). However, the results from risk-profile analysis showed that the group of individuals with the largest number of risk alleles only had an about three times higher disease risk than individuals with few risk alleles.…”

<b><i>CCDC62</i></b> Variant rs12817488 Is Associated with the Risk of Parkinson's Disease in a Han Chinese Population

“…rs10847864 in the HIP1R gene with linkage disequilibrium to rs12817488 (r 2 = 0.85), was used to compensate for probe design to reflect the signal of the initial locus [8]. The association of rs10847864/ HIP1R with PD was later confirmed by other groups [6,9,10]. In this study, we present the first direct evidence validating that rs12817488/ CCDC62 is associated with PD, wherein the A allele represents a risk factor for PD predisposition.…”

“…Recently, 5 new variants were identified as PD-susceptible genes ( ACMSD, STK39, MCCC1/LAMP3, SYT11 , and CCDC62/HIP1R ) in a GWAS meta-analysis by the International Parkinson's Disease Genomics Consortium (IPDGC) [8]. These newly identified loci were thereafter investigated in different populations, except for the variant rs12817488 of CCDC62 which was substituted by a proxy SNP rs10847864/ HIP1R in these studies [6,9,10]. CCDC62 (coiled-coil domain-containing protein 62), also named ERAP75, is involved in estrogen receptor activation and has been shown to play a role in cancer immunogenicity [11,12].…”

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].…”