A loss of function variant in CASP7 protects against Alzheimer’s disease in homozygous APOE ε4 allele carriers

BMC Genomics

Research Article

Ke Hao¹  Rong Chen¹  Kristin L. Ayers¹  Benjamin S. Glicksberg¹  Shuyu Li¹  David J. Carey²  Uyenlinh L. Mirshahi²  Amr H. Wardeh²  Michael F. Murray² 

[1] Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA;Geisinger Clinic, 17822, Danville, PA, USA;

关键词: Alzheimer’s disease;    Genetic variants;    Protective alleles;    CASP7;    Resilience;    Loss of function;   

DOI  :  10.1186/s12864-016-2725-z

来源: Springer

【 摘 要 】

BackgroundAlzheimer’s disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer’s disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease.MethodsHere we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases.ResultsWe discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ε4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ε4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio = 0.45 (p = 0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined.ConclusionsTaken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ε4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations.

【 授权许可】

CC BY   
© Ayers et al. 2016