H1 haplotype of the MAPT gene is associated with lower regional gray matter volume in healthy carriers

Abstract

The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n ¼ 141) in contrast to H2H2 homozygous (n ¼ 9), and H1H1 homozygous (n ¼ 85) in contrast to H2 carriers (n ¼ 65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.

Population genetic and Alzheimer’s disease related gene-interaction studies on 17q21.31 genomic inversion

“…clade is involved in pathophysiologic processes probably as a consequence of more various alternative splicing and expression with clear genetic association to Parkinson's disease (Zabetian et al, 2007), progressive supranuclear palsy , argyrophilic grain disease (Fujino et al, 2005), corticobasal degeneration , frontotemporal dementia (Verpillat et al, 2002) and lower regional cerebral gray matter volume in healthy individuals (Canu et al, 2009). Its association to Alzheimer's disease is also supported by many findings (Myers et al, 2007) but there are controversial results too (Caffrey and Wade-Martins, 2012).…”

GSK3B and MAPT Polymorphisms Are Associated with Grey Matter and Intracranial Volume in Healthy Individuals

“…We note, however, that one of the two regions in our study with a nominally significant effect of MAPT was the left insula. This region showed the largest cluster difference in H1H1 versus H2 carriers and the second largest cluster size difference in H2H2 versus H1 carriers in the Canu et al [24] study.…”

“…Lastly, we were not able to replicate the previously observed regional grey matter volume differences between MAPT diplotype groups after correction for multiple comparisons. This may reflect the fact that our analysis was based on comparison of previously parcellated regional grey matter volumes, rather than the voxel-based morphometry analysis in the original study [24]. We note, however, that one of the two regions in our study with a nominally significant effect of MAPT was the left insula.…”

“…We examined whether MAPT diplotype was associated with grey matter volume differences in candidate brain regions (right orbital frontal cortex, left insula, right caudate, right inferior temporal gyrus, right inferior lobe of cerebellum (Crus II)) previously identified by Canu et al [24] (Table 3). Linear regression analysis using age, sex and intracranial volume as a priori predictors revealed that MAPT diplotype was a predictor of left insula and right cerebellar Crus II lobar volumes at a nominally significant level ( p  = 0.039 and p  = 0.033, respectively), with the H1 haplotype predicting lower grey matter volumes.…”

“…A voxel-based morphometry (VBM) study found reduced grey matter (GM) volumes in several brain regions in H1 carriers [24]. Subsequently, a genome-wide association study found significant association between intracranial volume (ICV), a measurement reflecting lifetime maximal brain size, and H1/H2 diplotype [25].…”