Polymorphisms in the WWOX gene are associated with brain glucose metabolism and influence cerebrospinal fluid p‐tau181 levels

Abstract

AbstractBackgroundGenome‐wide association studies (GWAS) studies can be a powerful tool for identifying new single nucleotide polymorphisms (SNPs) associated with multifactorial diseases. Previous GWAS have identified more than 20 genes as potential factors of genetic susceptibility in Alzheimer’s disease (AD). One of them is the protein coding gene WW Domain Containing Oxidoreductase (WWOX), which is highly expressed in mature astrocytes and neurons. Here, we investigated the association between WWOX SNPs, 18F‐FDG PET neuroimaging and cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p‐tau181) in elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).MethodsData was acquired from 537 participants (CU= 195; MCI= 314; AD= 28) of the ADNI database. The brain glucose metabolism was estimated using the standard uptake value ratio (SUVr, cerebellum as reference) of FDG‐PET. The presence of the SNPs were integrated to FDG PET images using voxel‐wise generalized linear regression models adjusted for age, gender, diagnostic status, and years of education (RMINC package). Through the Wilcoxon test we determined if the SNPs presence influenced p‐tau181 levels in CSF. All statistical analyzes were performed in the R statistical computing software (version 4.1.2) (significance level of p < 0.05).ResultsSixty‐seven WWOX SNPs were statistically associated with 18F‐FDG PET signal. Voxel‐wise analyses demonstrated that the top ten WWOX SNPs with the highest number of voxels altered in the FDG‐PET images were associated with cortical hypermetabolism (Figure 1, top three). Thirteen WWOX SNPs were significantly associated with lower p‐tau181 concentration in the CSF, including rs7193539 (p = 0.0004), rs7206890 (p = 0.0061), and rs11859281 (p = 0.0009), compared to the reference genotype.ConclusionSeveral SNPs of the WWOX gene were significantly correlated to brain metabolism. The presence of the SNPs can influence p‐tau181 levels, suggesting a role of WWOX in AD, as reported in other previous studies. Our findings suggest a protective effect of these WWOX gene variants. Additional studies are needed to better understand the biological implications of our findings.