Linkage disequilibrium and association of MAPT H1 in Parkinson disease

Abstract

The MAPT H1 haplotype has been associated with four-repeat (4R) tauopathies, including progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. More controversial is that the same haplotype has been associated with Parkinson disease (PD). Using H1-specific single-nucleotide polymorphisms, we demonstrate that MAPT H1 is a misnomer and consists of a family of recombining H1 alleles. Population genetics, linkage disequilibrium, and association analyses have shown that specific MAPT H1 subhaplotypes are preferentially associated with Parkinson disease. Using a sliding scale of MAPT H1-specific haplotypes--in age/sex-matched PD cases and controls from central Norway--we have refined the disease association to within an approximately 90-kb interval of the 5' end of the MAPT locus.

Figure 1

Graphical overview of LD within the MAPT locus. PD cases and controls each consist of matched groups of 81 individuals homozygous for H1/H1 genotypes (as defined by the intron 9 in/del [Baker et al. 1999]). The relative positions of H1-SNPs are numbered on both axes, and all pairwise measures of D′ are considered. The relative positions of H1-SNPs are the same on both axes, of both plots, and as numbered for each abscissa; all pairwise measures of D′ are considered.

Figure 2

Ideogram of the CRHR1-MAPT region. Physical distances are given in Mb; gene assignments are oriented 5′→3′ with respect to their promoters (top). H1-SNPs are indicated by circles within genes and by numbers beneath, and their relative positions within MAPT are indicated (center). The relative positions of MAPT exons are also shown but are not to scale (bottom). Note, 4 denotes exon 4 and exon 4A.

Figure 3

LD units are shown with respect to the physical position of H1-SNPs across the CRHR1-MAPT loci (Maniatis et al. 2002). H1-SNPs 1–14 are indicated on each curve. Probable PD cases (red dashed line) and controls (black solid line) each consist of matched groups of 81 individuals homozygous for H1/H1 (as defined by the intron 9 in/del [Baker et al. 1999]). The H1 subhaplotype overrepresented in patients with PD, as defined by H1-SNPs 1 and 2, is indicated (bar with arrows).

Figure 4

−log₁₀ simulated P values are shown for counts of each haplotype trio compared between PD cases and controls. Empirical and simulated (10,000 Monte Carlo–Markov Chain iterations) P values were equivalent.