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P2‐088: Hereditary Spastic Paraplegia and Alzheimer's Disease: Hypothesis of a Founder Effect of a SPG4/ Spast Mutation
Author(s) -
Pedace Lucia,
Mearini Marzia,
Casella Antonella,
Montecchiani Celeste,
Miele Marialuisa,
Caltagirone Carlo,
Kawarai Toshitaka,
Orlacchio Antonio
Publication year - 2016
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 - 10.1016/j.jalz.2016.06.1293
Subject(s) - hereditary spastic paraplegia , proband , medicine , disease , dementia , genetic heterogeneity , founder effect , pediatrics , pathology , genetics , mutation , genotype , phenotype , haplotype , biology , gene
tion with dose of the e2 in total sample including e2+ and e33 subjects. The most significant SNP was examined for gene expression of all the genes within +/500kb from the SNP. Results:Genomewide significant association (P<5x10) was identified among e2+ subjects with rs192939675, resides near the 5’ end of PPP2CB and has a minor allele frequency of 7% in this subgroup (P1⁄49.8 x10, OR1⁄42.86, 95% CI1⁄42.01-4.07) but not associated with AD among e33 subjects (P1⁄40.44). Interaction between rs192939675 and dose of the e2 was significant in the total sample (P1⁄41.4x10). Rs192939675 significantly modulates expression of PPP2CB in blood (P1⁄45.9 x10), but not of other transcripts in the region. The most significant SNP from the MAPT/KANSL1 region (rs187270294) is located in KANSL1 and is more strongly associated in e2+ (P1⁄44.5 x10) than in e33 (P1⁄40.02) subjects. We also observed significant interaction between rs187270294 and dose of the e2 in the total sample (P1⁄42.6 x10). Conclusions: We identified a novel AD gene, PPP2CB, for which the effect on AD risk is modulated by the APOE e2 allele. PPP2CB encodes the catalytic subunit (beta isozyme) of protein phosphatase 2A, which is known to dephosphorylate tau protein. Future studies are needed to confirm the novel gene association and determine its precise roles in AD pathogenesis.