Genomewide association study for susceptibility genes contributing to familial Parkinson disease

Abstract

Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 x 10(-6); OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 x 10(-5); OR = 1.35) and MAPT (recessive model: p = 2.0 x 10(-5); OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 x 10(-7)) and the MAPT region (recessive model: p = 9.8 x 10(-6); additive model: p = 4.8 x 10(-5)). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.

Fig. 1

Sample processing. Diagram of sample processing from initial receipt of samples from CIDR to the final analyzed dataset. ¹Samples from whole genome amplified (WGA) DNA had lower call rates, particularly near the telomeres, and for a subset of the SNPs the minor allele frequency estimates from WGA DNA differed significantly from that obtained from other sources of DNA (p < 1 × 10⁻⁷ for 65 markers)

Fig. 2

Additive and recessive models. Results from genomewide association analysis modeling two modes of inheritance (additive and recessive). The X-axis indicates the chromosomal position of each SNP while the Y-axis denotes the evidence of association [shown as −log(p value)]. The line indicates the inclusion threshold for the results presented in the Tables (p < 10⁻⁴)

Fig. 3

Evidence of association in particular chromosomal regions. Along the X-axis is the physical position in the region (in kB) with known genes shown in their orientation The left Y-axis denotes the association test result as −log(p value) corresponding to diamonds in the figure. The blue diamond identifies the primary SNP result labeled with an rs# and p value. The color of additional diamonds depicts the pairwise linkage disequilibrium with the primary SNP: red indicates r² > 0.8, orange 0.5 < r² < 0.8, yellow 0.2 < r² < 0.5, white r² < 0.2. r² values were obtained from the control sample genotyped as part of this study using Haploview (Barrett et al. 2005). The right Y-axis indicates the recombination rate, obtained from the available HapMap data in the CEPH Caucasians, and shown within the figure by the solid blue line. a Additive results around GAK/DGKQ; b additive results around GPRIN3/SNCA/MMRN1; c Recessive results around C17orf69/MAPT/IMP5/STH