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

Yumi Yamaguchi-Kabata, Takashi Morihara, Tomoyuki Ohara, Toshiharu Ninomiya, Atsushi Takahashi, Hiroyasu Akatsu, Yoshio Hashizume, Noriyuki Hayashi, Daichi Shigemizu, Keith A. Boroevich, Manabu Ikeda, Michiaki Kubo, Masatoshi Takeda, Tatsuhiko Tsunoda

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)521-533
Number of pages13
JournalHuman Genetics
Volume137
Issue number6-7
DOIs
Publication statusPublished - 01-07-2018

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Medical Genetics
Genetic Association Studies
Transcriptome
Amyloid
Alzheimer Disease
Genes
Gene Expression
Hippocampus
Genome-Wide Association Study
Disease Susceptibility
Brain
Gene Expression Profiling
Single Nucleotide Polymorphism
Dementia
Genome

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Yamaguchi-Kabata, Yumi ; Morihara, Takashi ; Ohara, Tomoyuki ; Ninomiya, Toshiharu ; Takahashi, Atsushi ; Akatsu, Hiroyasu ; Hashizume, Yoshio ; Hayashi, Noriyuki ; Shigemizu, Daichi ; Boroevich, Keith A. ; Ikeda, Manabu ; Kubo, Michiaki ; Takeda, Masatoshi ; Tsunoda, Tatsuhiko. / 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. In: Human Genetics. 2018 ; Vol. 137, No. 6-7. pp. 521-533.
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abstract = "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.",
author = "Yumi Yamaguchi-Kabata and Takashi Morihara and Tomoyuki Ohara and Toshiharu Ninomiya and Atsushi Takahashi and Hiroyasu Akatsu and Yoshio Hashizume and Noriyuki Hayashi and Daichi Shigemizu and Boroevich, {Keith A.} and Manabu Ikeda and Michiaki Kubo and Masatoshi Takeda and Tatsuhiko Tsunoda",
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Yamaguchi-Kabata, Y, Morihara, T, Ohara, T, Ninomiya, T, Takahashi, A, Akatsu, H, Hashizume, Y, Hayashi, N, Shigemizu, D, Boroevich, KA, Ikeda, M, Kubo, M, Takeda, M & Tsunoda, T 2018, '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', Human Genetics, vol. 137, no. 6-7, pp. 521-533. https://doi.org/10.1007/s00439-018-1906-z

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. / Yamaguchi-Kabata, Yumi; Morihara, Takashi; Ohara, Tomoyuki; Ninomiya, Toshiharu; Takahashi, Atsushi; Akatsu, Hiroyasu; Hashizume, Yoshio; Hayashi, Noriyuki; Shigemizu, Daichi; Boroevich, Keith A.; Ikeda, Manabu; Kubo, Michiaki; Takeda, Masatoshi; Tsunoda, Tatsuhiko.

In: Human Genetics, Vol. 137, No. 6-7, 01.07.2018, p. 521-533.

Research output: Contribution to journalArticle

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

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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