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The differential genetic architecture between posterior cortical atrophy and amnestic Alzheimer's disease
Author(s) -
Scelsi Marzia Antonella,
Napolioni Valerio,
Mead Simon,
Crutch Sebastian J.,
Schott Jonathan M.,
Greicius Michael D.,
Altmann Andre
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038851
Subject(s) - posterior cortical atrophy , genome wide association study , genetic association , genetic architecture , single nucleotide polymorphism , dementia , population , atrophy , biology , allele , snp , disease , genetics , medicine , genotype , pathology , quantitative trait locus , gene , environmental health
Background Posterior cortical atrophy (PCA) is a rare early‐onset form of dementia, typically due to Alzheimer’s disease (PCA‐AD) characterised by predominant deficits of higher‐order visual functions, with relatively preserved memory, verbal fluency and insight with respect to typical, amnestic AD (tAD). A prior genetic study by Schott et al. (2016) investigated genetic risk factors for PCA‐AD in comparison to healthy controls; it also compared the magnitude of effect of known tAD risk loci in PCA. However, little is known about whether the difference between PCA‐AD and tAD is modulated by genetic factors outside the established tAD risk loci. Here we present the first large‐scale genetic study directly comparing PCA‐AD and tAD, in order to identify novel genetic variants driving the difference between these two syndromic variants. Method We imputed autosomal Single Nucleotide Polymorphism (SNP) data for 287 PCA‐AD cases from Schott et al. (2016) and 1,687 tAD cases from Naj et al. (2011), all unrelated Caucasians. We compared PCA to tAD cases in a genome‐wide association study (GWAS). SNP associations with diagnosis were tested through logistic regression, including sex, age‐at‐onset, and ten principal components of population structure as covariates. A sensitivity analysis was conducted omitting age‐at‐onset from the covariates, after detecting a significant difference in the mean age‐at‐onset of PCA and tAD cases (Table 1). Result Eleven independent genome‐wide significant loci were identified (Figure 1). APOE ε4 almost reached genome‐wide significance (p = 5.11 × 10 −8 ). GWAS‐significant SNPs mapped to the following genes: MORN1 , CNTNAP5 , SPPL3 , MARK3 . The sensitivity analysis increased statistical power, with APOE ε4 and 6 additional loci reaching significance. Conclusion We present the first GWAS of PCA vs tAD and identify five genes. In keeping with previous findings we confirm that APOE ε4 has a weaker effect in PCA than tAD, also showing that CNTNAP5 increases risk not only vs controls (Schott et al. 2016) but also over tAD. Of the new genes identified, SPPL3 is a presenilin‐like protein, and MARK3 is involved in the phosphorylation of tau proteins MAP2 and MAP4 . These findings suggest that differential genetic factors may influence the development of AD, but also its phenotypic expression.