Abstract
Genome-wide association studies (GWAS) in Parkinson’s disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11–1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.
Highlights
Parkinson’s disease (PD) was not historically considered a genetic disease until in depth studies of the segregation of genetic variants in families revealed several inherited mutations in genes such as SNCA, LRRK2, and PARK2[1, 2]
Causal genes have been nominated for a few of the loci but the majority of genome-wide association studies (GWAS) loci are defined by large regions of linkage disequilibrium (LD) containing several different genes
Our screening at the PD GWAS locus at 2q24.3 identified a risk haplotype defined by rs2102808 allele T as well as a six base pair deletion in exon 1 of the Serine Threonine Kinase 39 (STK39) gene
Summary
Parkinson’s disease (PD) was not historically considered a genetic disease until in depth studies of the segregation of genetic variants in families revealed several inherited mutations in genes such as SNCA, LRRK2, and PARK2[1, 2]. These first discoveries were followed by population based genome-wide association studies (GWAS) aimed at identifying risk factors for sporadic PD, which represents up to 90% of PD cases[3]. Causal genes have been nominated for a few of the loci (mostly because they overlap with familial PD genes) but the majority of GWAS loci are defined by large regions of linkage disequilibrium (LD) containing several different genes. In order to identify the potential causal variant(s) responsible for the GWAS signal, the region needs to be re-sequenced and fine-mapped
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