Genetic architecture of resilience of executive functioning

Abstract

The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H² = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10⁻⁷). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10⁻⁷). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.

Fig. 5

Regional association plot of the locus (rs3748348) nominally associated with resilience

Fig. 1

Kernel density plots* of a executive functioning, b residual for executive functioning when adjusting for demographics, Hachinski score and brain imaging parameters and c residual for executive functioning when adjusting for memory, demographics, Hachinski score and brain imaging parameters * Blue curves represent scores for people with normal cognition, red represents people with MCI, and green represents people with AD

Fig. 2

Quantile-quantile (Q-Q) plots for a residual for executive functioning when adjusting for demographics, Hachinski score and brain imaging parameters, and b residual for executive functioning when adjusting for memory, demographics, Hachinski score and brain imaging parameters

Fig. 3

Manhattan plots for a residual for executive functioning when adjusting for demographics, Hachinski score and brain imaging parameters and b residual for executive functioning when adjusting for memory, demographics, Hachinski score and brain imaging parameters. The X-axis refers to points along the genome (separated by chromosome) at which each of the several hundred thousand single nucleotide polymorphisms (SNPs; represented by a dot) evaluated are located. The y axis refers to the negative logarithm of the p-value for a test of association between each SNP and the quantitative trait

Fig. 4

The block of interest in the Linkage disequilibrium (LD) plot. Blocks of high LD are outlined as triangles and numbered as indicated in the figure. Shading reflects differences in pairwise LD (whiter r² = low LD; redder r² = near-perfect LD). Numbers in diamonds are estimates of pairwise coefficients (D′), expressed in percentages