Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Figure 1

Regional association plots from the three-stage meta-analysis with LOAD. P_M values for association are shown for: (A) MS4A gene cluster, (B) CD2AP, (C) EPHA1, and (D) CD33. For each locus, the genomic position (NCBI Build 37.1) is plotted on the X-axis against –log₁₀(P-value) on the Y-axis. For the SNP with the lowest P-value at each locus in Stage 1 analyses, three P-values for association are shown: P₁ meta-analysis of the ADGC Discovery (Stage 1) dataset (highlighted with a black diamond), P₁₊₂ meta-analysis of the Combined ADGC Discovery and Replication (Stages 1 + 2) datasets (highlighted with a blue diamond), and P₁₊₂₊₃ meta-analysis of the combined ADGC dataset and the external replication (Stages 1 + 2 + 3) datasets (highlighted with a red diamond). Computed estimates of linkage disequilibrium (r²) with the most significant SNP at each locus are shown as an orange diamond for r² ≥ 0.8, a yellow diamond for 0.5 ≤ r² < 0.8, a grey diamond for 0.2 ≤ r² < 0.5, and a white diamond for r² < 0.2. Genes in each region are indicated at the bottom of each panel. The length and the direction of the arrowhead represent the scaled size and the direction of the gene, respectively.