Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

Abstract

Introduction: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.

Methods: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.

Results: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]).

Discussion: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Keywords: APOE; Alzheimer's disease; GWAS; Genetics; Posterior cortical atrophy; Selective vulnerability.

Fig. 1

Manhattan plot of autosomes with the threshold for genome-wide significance (P < 5 × 10⁻⁸) indicated by the red line. Four loci achieved statistical significance at APOE (chromosome 19), SEMA3C (chromosome 7), FAM46A (chromosome 6), and CNTNAP5 (chromosome 2).

Fig. 2

SNP annotation and proxy (SNAP) plots for five regions of interest showing significance in either known genetic loci for AD (A, B) or in the exploratory GWAS (A,C,D,E). These plots illustrate the statistical evidence of association at a locus together with information about nearby genes and linkage disequilibrium between the most strongly associated SNP and its neighbors on the chromosome.