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. 2015 Mar;2(3):215-30.
doi: 10.1002/acn3.161. Epub 2015 Jan 26.

Variation in Longevity Gene KLOTHO Is Associated With Greater Cortical Volumes

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Free PMC article

Variation in Longevity Gene KLOTHO Is Associated With Greater Cortical Volumes

Jennifer S Yokoyama et al. Ann Clin Transl Neurol. .
Free PMC article

Abstract

Objective: Identifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype "KL-VS" in longevity gene KLOTHO (KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies.

Methods: We performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL-VS and gray matter volume using voxel-based morphometry.

Results: We found that KL-VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex (rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL-VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition.

Interpretation: These results suggest that variation in KL is associated with bigger brain volume and better function.

Figures

Figure 1
Figure 1
Multi-stage study design for discovery, validation, and replication of brain regions associated with KL-VS genotype in healthy cognitive aging. The first stage of analysis consisted of two unbiased whole-gray matter (GM) analyses of separate “discovery” and “validation” groups. Noncarriers were matched to KL-VS heterozygotes for age, sex, years of education, scan type, APOE ε4 genotype and handedness to reduce heterogeneity. In the full Cohort 1 analysis, additional noncarriers were added. Samples from Cohort 1 are from the UCSF Memory and Aging Center. Replication was performed using a region of interest-based analysis conducted in Cohort 2, an independent community-based sample from the Rush University Memory and Aging Project. Whole-GM meta-analysis was used to confirm findings from Cohorts 1 and 2.
Figure 2
Figure 2
KL-VS heterozygosity is associated with greater volumes of right dorsolateral prefrontal cortex (DLPFC) in two independent cohorts and meta-analysis of healthy older adults, independent of age. (A–C) Voxel-based morphometry (VBM) results are shown as statistical T-value maps (in color) overlaid on an axial slice of the template brain from DARTEL. Significant findings are highlighted by yellow circles. Maps are thresholded at the specified T-values to reflect stated P-value. Left side of image corresponds to left side of brain. (A) In blue, full Cohort 1 analysis demonstrated association between carrying one copy of the KL-VS haplotype and greater gray matter (GM) volume in right DLPFC (rDLPFC). Greater rDLPFC volume remained significant after permutation-based correction for multiple testing for two ROIs of interest, rDLPFC (PFWE-ROI = 0.04) and left supplemental motor area (data not shown). T-map is thresholded at T = 3.35–5.3 (Puncorr < 0.001). (B) In red, significant replication of greater rDLPFC volume in KL-VS heterozygotes was demonstrated in Cohort 2 VBM analysis (Puncorr < 0.05). T-map is thresholded at T = 1–2.2 for visualization purposes. (C) In purple, meta-analysis of Cohorts 1 and 2 showed greater volume in rDLPFC in KL-VS heterozygotes (Puncorr < 0.001). T-map is thresholded at T = 1.65–3.7 (Puncorr < 0.05). (D–F) Quantitation of rDLPFC volume Z-scores in KL-VS heterozygotes and noncarriers in (D) Cohort 1, (E) Cohort 2, and (F) meta-analysis. Data are means ± SEM. *P < 0.05, ***P < 0.001 versus noncarrier (two-tailed, linear statistical model). (G–I) Quantitation of rDLPFC volume Z-scores as a function of age in KL-VS heterozygotes and noncarriers. KL-VS heterozygosity was associated with greater rDLPFC volume across all ages in (G) Cohort 1, (two-tailed P = 4.07 × 10−5), (H) Cohort 2, (P = 0.02), and (I) meta-analysis (P = 2.64 × 10−5). There was a significant difference in intercepts (P < 0.0001) but not in slopes (P = 0.58) between the two linear predictions. Data in (D–I) are adjusted by age, sex, education, APOE ε4 carrier status, total intracranial volume (TIV), and (in F and I) test center.
Figure 3
Figure 3
KL-VS heterozygosity is associated with enhanced executive function in two independent cohorts and meta-analysis of healthy older adults, independent of age. KL-VS heterozygotes showed higher composite executive Z-scores than noncarriers in (A) Cohort 1, (B) Cohort 2, and (C) meta-analysis. Data are means ± SEM and were analyzed by a linear model adjusting for age, education, sex, APOE ε4 carrier status and (in C) center. *P < 0.05, **P < 0.01, ***P < 0.001 versus noncarrier (two-tailed). (D–F) KL-VS heterozygosity-associated enhancements in executive function were observed across all ages in (D) Cohort 1 (two-tailed P = 2.06 × 10−3), (E) Cohort 2 (P = 0.04), and (F) meta-analysis (P = 4.71 × 10−4). (G) In meta-analysis, right dorsolateral prefrontal cortex (rDLPFC) volume was positively correlated with composite executive Z-scores in both KL-VS heterozygotes and noncarriers (P = 0.003). (H) Mediation analysis of KL-VS heterozygosity and rDLPFC volume as predictors of executive function in Cohorts 1 and 2. Bivariate (black shaded arrows, middle and bottom) and multivariate (purple outlined arrows, top) analyses of direct and indirect effects of KL-VS heterozygosity and rDLPFC volume demonstrated that each were significant predictors of executive function, indicating that KL-VS-associated enhancement in executive function was partially mediated by rDLPFC volume. Estimated effects (beta, in bold) of genotype and/or volume as predictors of cognition, along with the standard error (in parentheses), are provided for each analysis. **P < 0.01 (two-tailed).
Figure 4
Figure 4
KL-VS heterozygosity and homozygosity are associated with right dorsolateral prefrontal cortex (DLPFC) volume, independent of age. (A) KL-VS heterozygotes showed greater rDLPFC volume and KL-VS homozygotes showed smaller rDLPFC volume than noncarriers via meta-analysis (P = 0.01). Data are means ± SEM and were analyzed by a linear model adjusting for age, education, sex, APOE ε4 carrier status and center. Post hoc pairwise tests demonstrated there was a significant difference between KL-VS heterozygotes versus noncarriers. *P < 0.05 (two-tailed Tukey's multiple comparisons test). rDLPFC volume in homozygotes showed significantly lower volume only when compared to noncarriers in a separate VBM analysis (P < 0.05). (B) rDLPFC volume Z-scores as a function of age across KL-VS genotype. Across all ages, KL-VS heterozygosity was associated with greater rDLPFC volume while KL-VS homozygotes showed lower rDLPFC volume via meta-analysis (P = 0.01). Overall genotype effects on baseline (P < 0.0001), but not their slopes over time (P = 0.41), were significantly different across groups. Data are adjusted by age, sex, education, APOE ε4 carrier status, total intracranial volume (TIV), and test center.
Figure 5
Figure 5
KL-VS heterozygosity and homozygosity are associated with executive function and this is partially mediated by right dorsolateral prefrontal cortex (DLPFC) volume. (A) KL-VS heterozygotes showed higher composite executive Z-scores than noncarriers and KL-VS homozygotes in meta-analysis (P = 0.03). Data are means ± SEM and were analyzed by a linear model adjusting for age, education, sex, APOE ε4 carrier status, and center. Post hoc pairwise comparisons using this model showed that executive function in KL-VS heterozygotes was significantly better (P < 0.005, one-tailed) and in KL-VS homozygotes tended to be worse (P = 0.16, one-tailed), compared to noncarriers. (B) Composite executive Z-scores as a function of age across KL-VS genotype. Across all ages, KL-VS heterozygotes had enhanced executive function whereas KL-VS homozygotes showed lower executive function via meta-analysis (P = 0.03). Overall genotype effects on baseline (P < 0.0001), but not their slopes over time (P = 0.49), were significantly different across groups. (C) rDLPFC volume positively correlated with executive function across KL-VS genotypes (P = 0.002). (D) Mediation analysis of direct and indirect effects of KL-VS genotype and rDLPFC volume as predictors of executive function in both Cohorts. Bivariate (black shaded arrows, middle, and bottom) and multivariate (teal outlined arrows, top) analyses show that each were significant predictors of executive function, indicating that KL-VS genotype effects on executive function were partially mediated by rDLPFC volume. Estimated effects (beta, in bold) of genotype and/or volume as predictors of cognition, along with the standard error (in parentheses), are provided for each analysis. *P < 0.05, **P < 0.01.

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