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

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.Electronic supplementary materialThe online version of this article (10.1007/s00439-018-1906-z) contains supplementary material, which is available to authorized users.

Overexpression of Limb-Bud and Heart (LBH) promotes angiogenesis in human glioma via VEGFA-mediated ERK signalling under hypoxia

“…LBH can regulate neural crest cell development and migration [33], maintain the stemness of multipotent mammary stem cells and inhibit their differentiation [20,21]. LBH was also found to be downregulated in neurodegenerative diseases, such as stroke, Parkinson's disease and Alzheimer's disease [11,19,34,35]. These studies all indicated that LBH may participate in the survival and function of neurons and neural stem cells.…”

Identification of Electroencephalogram Signals in Alzheimer's Disease by Multifractal and Multiscale Entropy Analysis

“…In AD, there are three significant anatomical changes: progressive neuronal death, neurofibrillary tangles, and senile plaques in extensive brain areas (Sims et al, 2017 ; Yamaguchi-Kabata et al, 2018 ). Positron emission tomography (PET) and magnetic resonance imaging (MRI) are often used to diagnose AD and detect neurotransmitter activity disorders, amyloid beta plaque deposition, and brain atrophy (Ewers et al, 2011 ; McKhann et al, 2011 ; Sperling et al, 2011 ).…”

Classification Methods Based on Complexity and Synchronization of Electroencephalography Signals in Alzheimer’s Disease

“…With a growing aging population, we are awaiting an effective treatment strategy and an early diagnosis test for Alzheimer's disease (AD) (1)(2)(3)(4). In AD, three main anatomical changes are observed: progressive neuronal death, neurofibrillary tangles, and senile plaques in widespread brain regions; moreover, recent progress of genome wide association studies have revealed the genes associated with AD (5,6). For diagnosis, positron emission tomography (PET) imaging and magnetic resonance imaging (MRI) are widely used to detect neurotransmitter activity deficits and deposition of amy loid beta plaques, and brain atrophy, respectively (2)(3)(4).…”