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P3‐015: Novel PSEN1 mutation (E280K) in a malaysian family
Author(s) -
Bagyinszky Eva,
Ch'ng Gaik-Siew,
Bae SeunOh,
Youn Young Chul,
An Seong Soo,
Kim SangYun
Publication year - 2015
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.2015.06.881
Subject(s) - psen1 , genetics , mutation , dementia , gene , biology , proband , in silico , presenilin , prnp , medicine , disease , alzheimer's disease , genotype , pathology
rare variants (MAF < 0.05) in RELN with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of RELN with quantitative biomarkers of LOAD using whole genome sequencing (WGS). Methods: 757 non-Hispanic Caucasian participants from a WGS data set (Illumina HiSeq2000; N1⁄4815) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort were used in this analysis. Short-read sequences were processed using next generation sequencing analysis pipeline with BWA and GATK. We assessed imaging ([F] Florbetapir PET, processed using standard techniques and intensity-normalized to the whole cerebellum) and cerebrospinal fluid (CSF) Ab1-42 level as LOAD-related quantitative endophenotypes. Common variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results:A total of 5,551 rare or low frequency variants (417 short indels) were found within a region of 650Kb from RELN. Among them, 75 exonic (48 non-synonymous) single nucleotide variants were observed. RELN was significantly associated with CSFAb1-42 and global cortical amyloid burden measured by [F] Florbetapir PET (p< 1 X 10) (Table 1). After adjusting for APOE ε4 allele status, gene-based analysis of rare variants resulted in slightly diminished but still significant associations. By contrast, gene-based analysis of common RELN variants showed a nominal association with only CSF Ab1-42 after adjusting for APOEε4 allele status (Table 2).Conclusions: RELN rare variants collectively show a significant association with amyloid biomarkers, providing further support for a role of RELN in LOAD. Reduced RELN expression was shown to accelerate amyloid-b plaque formation in transgenic AD mice (Kocherhans et al. 2010). Combining rare variants from sequencing with imaging and other intermediate phenotypes could help explain the missing heritability in LOAD.

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