Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3

Abstract

Introduction: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear.

Methods: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269).

Results: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10^-5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10^-7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10^-6) and CSF p-tau levels (P = 4.38 × 10^-9).

Discussion: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels.

Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

Keywords: Alzheimer's disease; genome‐wide association studies; genomics; glutathione peroxidase 3; proteomics.

FIGURE 1

Study overview. An overview is provided of the motivating GWAS results, the novel CSF proteomics discovery and replication analyses, and the supporting transcriptomic and functional genomic data sets and resources that were used in this study. AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; DIAN, Dominantly Inherited Alzheimer Network; EMIF‐AD MBD, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery; GWAS, genome‐wide association studies; WRAP/WI ADRC, Wisconsin Registry for Alzheimer's Prevention/Wisconsin Alzheimer's Disease Research Center.

FIGURE 2

Associations of CSF GPX3 with AD‐related measures in the WI ADRC and WRAP cohorts. A, CSF GPX3 levels (after regressing out the effects of age and sex) significantly decreased across amyloid and tau (AT) positivity categories (n = 137). B, CSF GPX3 levels were significantly associated with all CSF biomarkers of neurodegeneration and neuroinflammation except for IL‐6 (n = 137). In each case, GPX3 levels decreased as biomarker values indicated a worse clinical profile. C, Across the whole sample (n = 137), no difference in GPX3 levels were observed by genotype of either AD‐related variant alone. D, CSF GPX3 levels by both AT and genotype are shown for both relevant SNPs at the TNIP1/GPX3 locus. Among participants who were A+T+ (n = 42), CSF GPX3 levels were significantly decreased for homozygous recessive carriers of the rs34294852 allele (10 total participants were homozygous recessive for rs34294852; n = 5 were A–T–; n = 3 were A+T–; n = 2 were A+T+). AD, Alzheimer's disease; CSF, cerebrospinal fluid; GPX3, glutathione peroxidase 3; GWAS, genome‐wide association studies; IL‐6, interleukin 6; SNP, single nucleotide polymorphism; WI ADRC, Wisconsin Alzheimer's Disease Research Center; WRAP, Wisconsin Registry for Alzheimer's Prevention.

FIGURE 3

Proposed functional mechanism of the TNIP1/GPX3 locus in AD. Our hypothesis for a functional mechanism connecting the variant rs34294852 to AD outcomes is overlaid onto a map of the major types of omics data analyzed here. Major lines of post‐GWAS functional evidence supporting this hypothesis are summarized in the right‐hand list. AD, Alzheimer's disease; CSF, cerebrospinal fluid; EMIF‐AD MBD, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery; eQTL, expression quantitative trait loci; GWAS, genome‐wide association studies; ROSMAP, Religious Orders Study and Rush Memory and Aging Project; UW ADRC, University of Wisconsin Alzheimer's Disease Research Center; WRAP, Wisconsin Registry for Alzheimer's Prevention.