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P3‐018: INFLUENCE OF RARE PSEN1 VARIANTS ON QUANTITATIVE STRUCTURAL IMAGING AND CSF PHENOTYPES IN LATE ONSET ALZHEIMER'S DISEASE
Author(s) -
Nho Kwangsik T.,
Kim Sungeun,
Risacher Shan Leigh,
Shen Li,
Foroud Tatiana,
Aisen Paul,
Petersen Ronald,
Jack Clifford,
Shaw Leslie,
Trojanowski John Q.,
Weiner Michael Walter,
Green Robert,
Toga Arthur,
Saykin Andrew J.
Publication year - 2014
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.2014.05.1105
Subject(s) - psen1 , endophenotype , alzheimer's disease neuroimaging initiative , minor allele frequency , neuroimaging , allele , genetic association , medicine , alzheimer's disease , oncology , disease , allele frequency , genetics , gene , pathology , presenilin , biology , genotype , single nucleotide polymorphism , neuroscience , cognition
surrounding APOE on chromosome 19 has shown consistent association signals with LOAD. However, common variants in the region remain significant after adjusting for APOE ε4 (Jun et al, 2012). We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) biomarkers of LOAD. Methods: Awhole genome sequencing (WGS) data set (N1⁄4815) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 576 non-Hispanic Caucasian participants underwent WGS from a blood sample and had CSF biomarkers at baseline. We extracted all rare variants (MAF < 0.05) within a 300 Kb region in APOE’ s vicinity including 9 Genes (Table 1). We assessed CSF biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Age, sex, and number of APOE ε4 alleles were used as covariates. Results: A total of 2,608 rare or low frequency variants (MAF < 0.05) were found within a region of 610Kb from 9 genes near APOE. Among them, 76 rare non-synonymous variants were observed. All 8 genes except APOC4 spanning the entire region were significantly associated with CSF Ab 1-42 with TOMM40 showing near genome-wide level significance (p < 5 X 10 -7) (Table 1). However, gene-based analysis resulted in greatly diminished associations after adjusting for APOE ε4 allele count. Only 3 genes (CBLC, BCAM, APOE) remained significant after correcting for the number of tests (p < 0.05/9 1⁄4 0.0056). Particularly noteworthy were rare variants in APOE that showed significant association independent of ε4 allele count. Conclusions: Rare variants within genes near the APOE region are significantly associated with CSF Ab 1-42 after adjusting for APOE ε4 allele count. BCAM may meditate intracellular signaling and CBLC plays important roles in cell signaling. These findings warrant further investigation and illustrate the role of next generation sequencing in assessing rare variants which may in turn help explain missing heritability in AD and other complex diseases.