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Effect of CLU Genetic Variants on Cerebrospinal Fluid and Neuroimaging Markers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts

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Effect of CLU Genetic Variants on Cerebrospinal Fluid and Neuroimaging Markers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts

Lin Tan et al. Sci Rep.

Abstract

The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer's disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in β-amyloid (Aβ) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Aβ deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Aβ deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Aβ deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Aβ deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Aβ loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD.

Figures

Figure 1
Figure 1. The correlation between CLU genetic variants and Aβ accumulation on AV45.
(A) Heatmap of correlation between CLU genetic variants and Aβ accumulation on AV45. The statistical relations (FDR-corrected P values) between Aβ accumulation on AV45 (rows) and CLU loci (columns) (B) rs11136000 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (C) rs1532278 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (D) rs2279590 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (E) rs7982 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (F) rs9331888 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (G) rs2279590 was associated with the level of cingulate SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the cingulate AV45 retention at baseline. (H) rs2279590 was associated with the level of frontal cortex SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the frontal AV45 retention at baseline. (I) rs7982 was associated with the level of frontal cortex SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the frontal AV45 retention at baseline. Note: SUVR, standard uptake value ratios; AV45, amyloid tracer.
Figure 2
Figure 2. The correlation between significant loci and AV45 SUVR at baseline in NC group.
(A) rs11136000 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (B) rs7982 was associated with the level of summary SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention at baseline. (C) rs7982 was associated with the level of frontal cortex SUVR at baseline. The X-axis represents three genotypes while the Y-axis represents the frontal AV45 retention at baseline. Note: SUVR, standard uptake value ratios; AV45, amyloid tracer.
Figure 3
Figure 3. The correlation between rs9331888 and AV45 SUVR in two-year follow-up study in MCI group.
(A) rs9331888 was associated with the level of frontal cortex SUVR at two-year follow study. The X-axis represents three genotypes while the Y-axis represents the frontal AV45 retention. (B) rs9331888 was associated with the level of temporal cortex SUVR at two-year follow study. The X-axis represents three genotypes while the Y-axis represents the temporal AV45 retention. (C) rs9331888 was associated with the level of parietal cortex SUVR at two-year follow study. The X-axis represents three genotypes while the Y-axis represents the parietal AV45 retention. (D) rs9331888 was associated with the level of cingulate SUVR at two-year follow study. The X-axis represents three genotypes while the Y-axis represents the cingulate AV45 retention. (E) rs9331888 was associated with the level of summary SUVR at two-year follow study. The X-axis represents three genotypes while the Y-axis represents the summary AV45 retention. Note: SUVR, standard uptake value ratios; AV45, amyloid tracer.

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