Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort

Neurobiol Aging. 2017 Sep:57:247.e1-247.e8. doi: 10.1016/j.neurobiolaging.2017.05.007. Epub 2017 May 15.

Abstract

The pathogenic relevance in Alzheimer's disease (AD) presents a decrease of cerebrospinal fluid amyloid-ß42 (Aß42) burden and an increase in cerebrospinal fluid total tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study of T-tau/Aß42 ratio as an AD imaging quantitative trait on 843 subjects and 563,980 single-nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain "missing heritability". Linear regression method was used to detect SNP-SNP interactions among SNPs with uncorrected p-value ≤0.01 from the GWAS. Age, gender, and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1, and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. Genome-wide interaction study revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value ≤0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Aß42, demonstrating their potential association with AD pathology.

Keywords: ADNI; Amyloid-ß(42) (Aß(42)); Cerebrospinal fluid (CSF); GWIS; T-tau/Aß(42) ratio; Total tau (T-tau).

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Apolipoprotein C-I / genetics
  • Apolipoproteins E / genetics
  • Cohort Studies
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Peptide Fragments / cerebrospinal fluid*
  • Polymorphism, Single Nucleotide / genetics*
  • tau Proteins / cerebrospinal fluid*

Substances

  • APOC1 protein, human
  • Amyloid beta-Peptides
  • Apolipoprotein C-I
  • Apolipoproteins E
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Peptide Fragments
  • TOMM40 protein, human
  • amyloid beta-protein (1-42)
  • tau Proteins