Ethnicity- and sex-specific genome wide association study on Parkinson's disease

Abstract

Most previous genome-wide association studies (GWASs) on Parkinson's disease (PD) focus on the European population. There are several sex-specific clinical differences in PD, but little is known about its genetic background. We aimed to perform an ethnicity-specific and sex-specific GWAS on PD in the Korean population. A total of 1050 PD patients and 5000 controls were included. For primary analysis, we performed a GWAS using a logistic additive model adjusted for age and sex. The same statistical models were applied to sex-specific analyses. Genotyping was performed using a customized microarray chip optimized for the Korean population. Nine single nucleotide polymorphisms (SNPs) including four in the SNCA locus and three from the PARK16 locus were associated with PD in Koreans. The rs34778348 in the LRRK2 locus showed a strong association, though failed to pass cluster quality control. There were no notable genome-wide significant markers near the MAPT or GBA1 loci. In the female-only analysis, rs34778348 in LRRK2 and the four other SNPs in the SNCA showed a strong association with PD. In the male-only analysis, no SNP surpassed the genome-wide significance threshold under Bonferroni correction; however, the most significant signal was rs708726 in the PARK16 locus. This ethnicity- and sex-specific GWAS on PD implicate the pan-ethnic effect of SNCA, the universal but East-Asian inclined effect of PARK16, the East Asian-specific role of LRRK2 G2385R variants, and the possible disproportionate effect of SNCA and PARK16 between sexes for PD susceptibility. These findings suggest the different genetic contributions to sporadic PD in terms of ethnicity and sex.

Fig. 1. Manhattan plots of the study.

Primary analysis (a), female-only analysis (b), and male-only analysis (c). The red lines denote the Bonferroni threshold.

Fig. 2. Regional association plots of the primary genome-wide association study.

Plots around (a) rs3796661 and (b) rs708726.

Fig. 3. An example of cluster quality control.

In general, the three genotypes denoted as blue, purple, and red dots, are clearly clustered (a). The markers were excluded if the three genotypes were not clearly separated as in (b).