Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes

Abstract

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

Figure 1.

Manhattan plots showing the association of (A) imputed SNPs and (B) DASH segments. Lower panels show association results conditioned on the LRRK2 and GBA mutation carrier status, for (C) imputed SNPs and (D) DASH segments. Markers color-coded red surpass the Bonferroni-corrected genome-wide significance thresholds.

Figure 2.

Association of imputed SNPs and DASH segments at the four genome-wide significant loci either also associated in other studies, or replicated as part of this study: (A) chr12q12 (with the associated LRRK2 gene), (B) chr17q21 (MAPT), (C) chr1q21 (GBA) and (D) chr2q14 (CNTNAP5).