Genome-wide association study of language performance in Alzheimer's disease

Abstract

Language impairment is common in prodromal stages of Alzheimer's disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome-wide association study (GWAS) using a composite measure of language performance from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p<5×10-8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD.

Keywords: Alzheimer’s disease; GLI3; GWAS; Language performance; Neuroimaging.

Conflict of interest statement

Conflicts of interest: The authors declare no conflict of interest.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1

Global regions associated with the language composite score pre-adjusted for episodic memory performance in ADNI participants. Grey matter density was positively correlated with the language composite score in the temporal lobe and language areas for both ADNI-1 (a) and ADNI-GO/2 (b). Covariates included age, sex, intracranial volume, APOE ε4 status, and handedness. Results are displayed at p<0.001 (uncorrected) and at a threshold (k) of 100 voxels.

Figure 2

Manhattan, regional association, and quantile-quantile plots for GWAS of language performance. (a) Observed –log10 p-values (y-axis) are displayed for all tested SNPs on each chromosome (x-axis). A SNP was considered genome-wide significant if p < 5 × 10−8 (above red line). Suggestive SNP associations were identified as those reaching genome-wide significance of p < 1 × 10−5 (above blue line). (b) Regional association plot showing the region around the most significant SNP in the GWAS. The SNPs within 500 kb of rs3801203 are plotted as their GWAS −log10P-values against their NCBI 37 genomic position. The blue line indicates recombination rates estimated from the 1000 Genomes Project reference data. The color scale of r2 values is used to label SNPs based on their correlation with rs3801203. (c) The genomic inflation factor (λ) was 1.026 suggesting no population stratification effect.

Figure 3

GLI3 SNPs are associated with lower language performance. (a) Linkage disequilibrium map of the four GLI3 SNPs significantly associated with language performance. The minor allele of rs3801203 (b-c, p = 3.21 × 10−9) was associated with lower language composite score in older adults at risk for or with AD, with the exception of the SMC group. Means adjusted for age, sex, years of education, genotyping platform, handedness, and APOE ε4 status. Standard errors are displayed. CN = cognitively normal; SMC = significant memory concern; EMCI = early mild cognitive impairment; LMCI = late mild cognitive impairment; AD = Alzheimer’s disease

Figure 4

The minor allele of GLI3 SNP rs3801203 is associated with lower grey matter density in the temporal cortex of ADNI-1 participants (a) and the orbitofrontal cortex for ADNI-GO/2 participants (b). Covariates included age, sex, intracranial volume, APOE ε4 status, and handedness. Results are displayed at p<0.001 (uncorrected) and at a threshold (k) of 100 voxels.