TY - JOUR
T1 - Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer’s disease
AU - Yamaguchi-Kabata, Yumi
AU - Morihara, Takashi
AU - Ohara, Tomoyuki
AU - Ninomiya, Toshiharu
AU - Takahashi, Atsushi
AU - Akatsu, Hiroyasu
AU - Hashizume, Yoshio
AU - Hayashi, Noriyuki
AU - Shigemizu, Daichi
AU - Boroevich, Keith A.
AU - Ikeda, Manabu
AU - Kubo, Michiaki
AU - Takeda, Masatoshi
AU - Tsunoda, Tatsuhiko
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Alzheimer’s disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aβ accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.
AB - Alzheimer’s disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aβ accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.
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U2 - 10.1007/s00439-018-1906-z
DO - 10.1007/s00439-018-1906-z
M3 - Article
C2 - 30006735
AN - SCOPUS:85049853309
SN - 0340-6717
VL - 137
SP - 521
EP - 533
JO - Human Genetics
JF - Human Genetics
IS - 6-7
ER -