Genome-wide association study reveals genetic risk underlying Parkinson's disease

Abstract

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Figure 1

Graphical representation of p values in stage I and stage II. A) In stage I, p values are log transformed (y-axis) and plotted against chromosomes (x-axis). The red line indicates the Bonferroni threshold. Signals indicated in red are on chromosome 4 and chromosome 17 and surpass Bonferroni threshold for genome wide significance. B) log transformed p-values of Stage II SNPs (y-axis) are plotted against chromosomes (x-axis). Signals indicated in red are on chromosome 4 and chromosome 17 and surpass Bonferroni threshold for multiple testing

Figure 2

Association and recombination rates across SNCA, MAPT, PARK16 and LRRK2. −log₁₀ p values are shown for stage I and II analyses, annotated transcripts are shown across the top of each plot. Red dotted line indicates threshold for genome wide significance in stage I and orange line indicates threshold for significance of stage II.

Figure 3

Expression quantitative trait loci across the MAPT locus measured in 133 human frontal cortex samples; panel A shows association between genotypes and transcript levels across the MAPT locus. In this analysis the allelic load at genotyped polymorphisms across the locus is tested for association with transcript levels of each gene across the locus. The results of the analysis are shown as log transformed p values color-coded to match the transcript of interest. Notably genotypes across this locus are associated with MAPT (pink) and LRRC37A (blue) levels. Boxplots in panels B and C illustrate a dose relationship between allele load at the most significantly associated PD SNP (rs393152) and expression of MAPT (B) and LRRC37A (C), p values 4.1×10⁻⁶ and 1.7×10⁻¹³ respectively. Notably, the allele associated with higher risk for PD, A, is associated with high levels of MAPT expression and low levels of LRRC37A expression.