Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is affected by several genetic variants. It has been demonstrated that genetic variants affect brain organization and function. In this study, using whole genome-wide association studies (GWAS), we analyzed the functional magnetic resonance imaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative dataset (ADNI) dataset and identified genetic variants associated with the topology of the functional brain network http://www.adni-info.org. We found three novel loci (rs2409627, rs9647533, and rs11955845) in an intron of the phosphodiesterase 4D (PDE4D) gene that contribute to abnormalities in the topological organization of the functional network. In particular, compared to the wild-type genotype, the subjects carrying the PDE4D variants had altered network properties, including a significantly reduced clustering coefficient, small-worldness, global and local efficiency, a significantly enhanced path length and a normalized path length. In addition, we found that all global brain network attributes were affected by PDE4D variants to different extents as the disease progressed. Additionally, brain regions with alterations in nodal efficiency due to the variations in PDE4D were predominant in the limbic lobe, temporal lobe and frontal lobes. PDE4D has a great effect on memory consolidation and cognition through long-term potentiation (LTP) effects and/or the promotion of inflammatory effects. PDE4D variants might be a main reasons underlyling for the abnormal topological properties and cognitive impairment. Furthermore, we speculated that PDE4D is a risk factor for neural degenerative diseases and provided important clues for the earlier detection and therapeutic intervention for AD.
Highlights
Alzheimer’s disease (AD) is a common, progressive, lethal neurodegenerative disorder
By using genome-wide association studies (GWAS) (p < 10−7 significance level), three single nucleotide polymorphism (SNP) that belonged to the phosphodiesterase 4D (PDE4D) (Table 2) had associations with the functional network properties, including Eg, Eloc, Lp, Cp, λ, γ, σ (Figure 1A)
Employing functional brain networks and whole-genome SNPs, we provided a methodological framework for systematically identifying the influences of genetic variants on the functional brain network
Summary
Alzheimer’s disease (AD) is a common, progressive, lethal neurodegenerative disorder. The study was performed with resting-state functional magnetic resonance imaging (fMRI) and genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The fMRI time series was computed in each of the 90 regions by averaging all voxels within each region at each time point in the time series, resulting in 130 time points for each of the 90 anatomical regions These time series were used to construct a 90node whole-brain functional connectivity network by calculating the Pearson correlation coefficient in the residual time courses between each pair of regions of interest (ROIs), and 90 × 90 correlation matrices were obtained for each subject. GWAS analysis on selected brain network properties of 137 subjects was completed using the quality-controlled SNP data, as follows. We used partial correlations controlled for age, gender, and education year to examine the relationship between properties and clinical performance
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