Associations of Bcl-2 rs956572 genotype groups in the structural covariance network in early-stage Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disease, and genetic differences may mediate neuronal degeneration. In humans, a single-nucleotide polymorphism in the B-cell chronic lymphocytic leukemia/lymphoma-2 (Bcl-2) gene, rs956572, has been found to significantly modulate Bcl-2 protein expression in the brain. The Bcl-2 AA genotype has been associated with reduced Bcl-2 levels and lower gray matter volume in healthy populations. We hypothesized that different Bcl-2 genotype groups may modulate large-scale brain networks that determine neurobehavioral test scores.MethodsGray matter structural covariance networks (SCNs) were constructed in 104 patients with AD using T1-weighted magnetic resonance imaging with seed-based correlation analysis. The patients were stratified into two genotype groups on the basis of Bcl-2 expression (G carriers, n = 76; A homozygotes, n = 28). Four SCNs characteristic of AD were constructed from seeds in the default mode network, salience network, and executive control network, and cognitive test scores served as the major outcome factor.ResultsFor the G carriers, influences of the SCNs were observed mostly in the default mode network, of which the peak clusters anchored by the posterior cingulate cortex seed determined the cognitive test scores. In contrast, genetic influences in the A homozygotes were found mainly in the executive control network, and both the dorsolateral prefrontal cortex seed and the interconnected peak clusters were correlated with the clinical scores. Despite a small number of cases, the A homozygotes showed greater covariance strength than the G carriers among all four SCNs.ConclusionsOur results suggest that the Bcl-2 rs956572 polymorphism is associated with different strengths of structural covariance in AD that determine clinical outcomes. The greater covariance strength in the four SCNs shown in the A homozygotes suggests that different Bcl-2 polymorphisms play different modulatory roles.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0344-4) contains supplementary material, which is available to authorized users.

Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation

“…It is also worth mentioning that the SNP rs956572 (BCL2) that interacted with SNPs in IGF1R gene in our analysis ( Table 2 ), on itself has been intensively studied for more than a decade, and appears to be broadly involved in aging and AD-related traits (e.g., Salvadore et al, 2009 ; Uemura et al, 2011 ; Liu et al, 2013 ; Chang et al, 2018 ), which might contribute to its propensity to genetic interactions that influence human lifespan. One should note that individual associations of this SNP with survival did not reach statistical significance in our analysis ( P -v2 in Table 2 ).…”

Gray matter structural covariance networks changes along the Alzheimer's disease continuum

“…To achieve SCN t-maps, we performed the general linear analysis on modulated GM images. Specifically, we extracted the GM volume from a 4-mm radius sphere (Montembeault et al, 2016; Chang et al, 2018; Chang et al, 2017) around those coordinates on modulated images. Then, we performed four separate correlation analysis by entering the GM volumes of each ROI as a regressor and the total intracranial volume, gender, age, and education as covariates.…”

“…We set the threshold at P ≤ 0.01 corrected for false discovery rate (FDR). Considering the physiological meanings of the SCN clusters, we reported clusters showing cluster size >100 voxels (Chang et al, 2018; Chang et al, 2017). To achieve qualitative group-wise comparisons, we displayed the results on a standard brain template (ICBM152).…”

“…To explore the clinical significance of the identified peak voxel volume, we performed the correlation analysis (Chang et al, 2018; Chang et al, 2017). To be specific, for the peak clusters showing significant between-group differences, we extracted the GM volume using a 4-mm radius sphere placing on the peak voxel.…”

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“…It is also worth mentioning that the SNP rs956572 (BCL2) that interacted with SNPs in IGF1R gene in our analysis (Table 2), on itself has been intensively studied for more than a decade, and appears to be broadly involved in aging and AD-related traits (e.g., Salvadore et al, 2009;Uemura et al, 2011;Liu et al, 2013;Chang et al, 2018), which might contribute to its propensity to genetic interactions that influence human lifespan. One should note that individual associations of this SNP with survival did not reach statistical significance in our analysis (P-v2 in Table 2).…”