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      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

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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.

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

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          Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

          The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.
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            Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

            Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
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              Emerging roles of Wnts in the adult nervous system.

              The roles of the Wnt signalling pathway in several developmental processes, including synaptic differentiation, are well characterized. The expression of Wnt ligands and Wnt signalling components in the mature mammalian CNS suggests that this pathway might also play a part in synaptic maintenance and function. In fact, Wnts have a crucial role in synaptic physiology, as they modulate the synaptic vesicle cycle, the trafficking of neurotransmitter receptors and the interaction of these receptors with scaffold proteins in postsynaptic regions. In addition, Wnts participate in adult neurogenesis and protect excitatory synaptic terminals from amyloid-beta oligomer toxicity. Here, the latest insights into the function of Wnt signalling in the adult nervous system and therapeutic opportunities for neurodegenerative diseases such as Alzheimer's and Parkinson's disease are discussed.
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                Author and article information

                Contributors
                tatsuhiko.tsunoda@riken.jp
                Journal
                Hum Genet
                Hum. Genet
                Human Genetics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-6717
                1432-1203
                13 July 2018
                13 July 2018
                2018
                : 137
                : 6
                : 521-533
                Affiliations
                [1 ]Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
                [2 ]ISNI 0000 0001 2248 6943, GRID grid.69566.3a, Tohoku Medical Megabank Organization, , Tohoku University, ; 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8573 Japan
                [3 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Psychiatry, Graduate School of Medicine, , Osaka University, ; Osaka, 565-0871 Japan
                [4 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Neuropsychiatry, Graduate School of Medical Sciences, , Kyushu University, ; 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
                [5 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Department of Epidemiology and Public Health, Graduate School of Medical Sciences, , Kyushu University, ; 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
                [6 ]Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
                [7 ]ISNI 0000 0004 0378 8307, GRID grid.410796.d, Department of Genomic Medicine, Research Institute, , National Cerebral and Cardiovascular Center, ; Osaka, 565-8565 Japan
                [8 ]ISNI 0000 0001 0728 1069, GRID grid.260433.0, Graduate School of Medical Sciences and Medical School, , Nagoya City University, ; Nagoya, 467-8601 Japan
                [9 ]GRID grid.440408.c, Institute of Neuropathology, , Fukushimura Hospital, ; Toyohashi-shi, Aichi, 441-8124 Japan
                [10 ]RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
                [11 ]ISNI 0000 0001 1014 9130, GRID grid.265073.5, Department of Medical Science Mathematics, Medical Research Institute, , Tokyo Medical and Dental University, ; 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan
                [12 ]Present Address: Division of Genomic Medicine, Medical Genome Center, National Center for Geriastrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511 Japan
                Author information
                http://orcid.org/0000-0002-5439-7918
                Article
                1906
                10.1007/s00439-018-1906-z
                6061045
                30006735
                549a3283-443e-4de5-8eca-8437e174078f
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 6 March 2018
                : 6 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science and Technology;
                Categories
                Original Investigation
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Genetics
                Genetics

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