Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

Abstract

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ₄₂), tau, and phosphorylated tau (ptau₁₈₁) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau₁₈₁, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ₄₂ near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10^-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10^-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10^-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10^-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10^-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ₄₂ (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau₁₈₁ levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Keywords: Alzheimer’s disease; Cerebrospinal fluid biomarkers; Endophenotype; Genome-wide association study.

Fig. 1

Association plots from single variant analyses of CSF ptau₁₈₁ levels. a Manhattan plot shows negative log₁₀-transformed P values from the joint analysis of ptau₁₈₁. The horizontal lines represent the genome-wide significance threshold, P = 5 × 10⁻⁸(red) and suggestive threshold, P = 1 × 10⁻⁵(blue). Red arrows point to novel loci. The y-axis is truncated, the lowest P value on chromosome 19 was 5.30 × 10⁻³³.b, c Regional association plots of novel loci are shown for SNPs associated with ptau₁₈₁ near PCDH8 (a) and between NFATC1 and CTDP1 (b). The SNPs labeled on each regional plot had the lowest P value at each locus and are represented by a purple diamond. Each dot represents a SNP and dot colors indicate LD with the labeled SNP. Blue vertical lines show recombination rate marked on the right-hand y-axis of each regional plot. Plots for previously reported loci are in Supplementary Fig. 7

Fig. 2

Association plots from single variant analyses of CSF Aβ₄₂. a Manhattan plot shows negative log₁₀-transformed P values from the joint analysis of Aβ₄₂. The horizontal lines represent the genome-wide significance threshold, P = 5 × 10⁻⁸(red) and suggestive threshold, P = 1 × 10⁻⁵(blue). Red arrows point to novel loci. The y-axis is truncated, the lowest P value on chromosome 19 was 4.78 × 10⁻⁹⁴. b, c Regional association plots of novel loci are shown for SNPs associated with Aβ₄₂ near GLIS1 (b) and within SERPINB1 (c). The SNPs labeled on each regional plot had the lowest P value at each locus and are represented by a purple diamond. Each dot represents a SNP and dot colors indicate LD with the labeled SNP. Blue vertical lines show recombination rate marked on the right-hand y-axis of each regional plot. Plots for previously reported loci are in Supplementary Fig. 7