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

Daniel J. Panyard*, Lianne M. Reus, Muhammad Ali, Jihua Liu, Yuetiva K. Deming, Qiongshi Lu, Gwendlyn Kollmorgen, Margherita Carboni, Norbert Wild, Pieter J. Visser, Lars Bertram, Henrik Zetterberg, Kaj Blennow, Johan Gobom, Dan Western, Yun Ju Sung, Cynthia M. Carlsson, Sterling C. Johnson, Sanjay Asthana, Carlos CruchagaBetty M. Tijms, Corinne D. Engelman, Michael P. Snyder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)5044-5053
Number of pages10
JournalAlzheimer's & Dementia
Volume20
Issue number7
Early online date1 May 2024
DOIs
Publication statusPublished - Jul 2024

Keywords

  • Alzheimer's disease
  • genomics
  • genome-wide association studies
  • glutathione peroxidase 3
  • proteomics
  • OXIDATIVE STRESS BIOMARKERS
  • MILD COGNITIVE IMPAIRMENT
  • RISK LOCI
  • METAANALYSIS

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