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Cited by 96Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis

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Zhou, Xiaopu, Chen, Yu, Mok, Kin Y., Zhao, Qianhua, Chen, Keliang, Chen, Yuewen, Hardy, John, Li, Yun +363 more·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1715554115PMC PMC5828602
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Abstract

Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10 −14 ), two common variants, GCH1 (rs72713460, P = 4.36 × 10 −5 ) and KCNJ15 (rs928771, P = 3.60 × 10 −6 ), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE , GCH1 , and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

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  • Zhou et al. identified four SNPs located in GCH1, APOC1, KCNJ15, and LINC01413.

    “Zhou et al. obtained WGS data from 477 AD patients and 2187 healthy subjects [28], and association analysis, which excluded the APOE region, identified four SNPs located in GCH1, APOC1, KCNJ15, and LINC01413.”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [28]

    The Results section (page unavailable) lists four sentinel SNPs at GCH1, APOC1, KCNJ15, and LINC01413 and reports 477 AD cases and 2,187 controls in the combined analysis. But the claim that the association analysis excluded the APOE region is not supported: the paper says it analyzed APOE and identified the APOC1 sentinel variant near that locus. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A transethnic meta-analysis of three European cohorts identified rs72713460 located 11.7 kb downstream from GCH1 and rs928771 located in the intron of KCNJ15.

    “Additionally, a transethnic meta-analysis of three European cohorts (ADNI, ADC, and LOAD) also identified rs72713460, which was located 11.7 kb downstream from GCH1 and rs928771, located in the intron of KCNJ15.”

    From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [28]

    The Results sections on Chinese susceptibility loci and non-Asian replication identify rs72713460 (GCH1) and rs928771 (KCNJ15), and include ADNI, ADC, and LOAD in a meta-analysis. But the variants were identified in the Chinese cohort; the paper describes its transethnic meta-analysis as combining Chinese and non-Asian cohorts, not as an analysis of only the three named cohorts. It also says the non-Asian meta-analysis failed to replicate the risk effect of rs928771. The retrieved passages do not verify the stated 11.7-kb or intronic locations. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Authors
Zhou, X., Chen, Y., Mok, K. Y., Zhao, Q., Chen, K., Chen, Y., Hardy, J., Li, Y., Fu, A. K. Y., Guo, Q., Ip, N. Y., Initiative, F. T. A. D. N., Saykin, A. J., Toga, A. W., Borowski, B., Ward, C., DeCarli, C., Mathis, C., Jack, C. R., Harvey, D., Holtzman, D., Jones, D., Gessert, D., Lilly, E., Reiman, E. M., Franklin, E., Hefti, F., Sorensen, G., Jimenez, G., Fillit, H., Gunter, J., Salazar, J., Hsiao, J., Morris, J., Trojanowki, J. Q., Neu, K. C. S., Kantarci, K., Faber, K., Harless, K., Chen, K., Nho, K., Beckett, L., Thal, L., Thal, L., Shaw, L. M., Kuller, L., Shen, L., Hergesheimer, L., Taylor-Reinwald, L., Mesulam, M. M., Korecka, M., Raichle, M., Carrillo, M., Albert, M., Senjem, M., Bernstein, M., Donohue, M., Weiner, M., Figurski, M., Buckholtz, N., Fox, N., Cairns, N. J., Schuff, N., Foster, N., Aisen, P., Thompson, P., Davies, P., Snyder, P. J., Snyder, P., Vemuri, P., Frank, R., Koeppe, R. A., Green, R. C., Petersen, R., Walter, S., Paul, S., Potkin, S., Kim, S., Foroud, T. M., Montine, T., Lee, V., Jagust, W., Potter, W., Cabrera, Y., Khachaturian, Z., Fleisher, A., Pierce, A., Mintz, A., Lerner, A., Norbash, A., Levey, A. I., Rosen, A., Smith, A., Ulysse, A., Budson, A. E., Kertesz, A., Oliver, A., Hake, A. M., Burke, A., Sarrael, A., Porsteinsson, A. P., Lamb, A., Lee, A., Raj, B. A., Lane, B., Yanez, B., Ances, B., Mudge, B., Lind, B., Stefanovic, B., Goldstein, B. S., Bonakdarpour, B., Matthews, B. R., Ott, B. R., Reynolds, B., Miller, B. L., Spann, B. M., Sadowsky, C., Bernick, C., Smith, C. D., Onyike, C., Heyn, C. (., Hosein, C., Leach, C., Belden, C. M., van Dyck, C. H., Clark, C. M., Wu, C.-K., Albers, C. S., Brand, C., Bodge, C., Tatsuoka, C., Carlsson, C. M., Mathews, D., D’Agostino, D., Silverman, D. H. S., Marson, D., Wolk, D. A., Bachman, D., Clark, D., Geldmacher, D., Hart, D., Knopman, D., Perry, D., Winkfield, D., Miller, D. D., Kerwin, D., Drost, D., Simpson, D. M., Munic, D., Scharre, D. W., Bartha, R., Celmins, D., Zimmerman, E. A., Teng, E., Coleman, E., Zamrini, E., Mitsis, E., Finger, E., Oates, E., Sosa, E., Woo, E., Rogalski, E., Fletcher, E., Parfitt, F., Thai, G., Marshall, G. A., Conrad, G., Tremont, G., Bartzokis, G., Hsiung, G.-Y. R., Chiang, G., Pearlson, G. D., Jicha, G., Vanderswag, H., Grossman, H., Capote, H., Bergman, H., Chertkow, H., Feldman, H., Rosen, H. J., Koleva, H., Shim, H., Rachinsky, I., Mintzer, J., Ziolkowski, J., Brewer, J., Lah, J. J., Singleton-Garvin, J., Cellar, J. S., Brosch, J. R., Tinklenberg, J., Karlawish, J. H., Villanueva-Meyer, J., Kaye, J. A., Burns, J. M., Petrella, J. R., Yesavage, J., Allard, J., Lord, J. L., Hetelle, J., Brockington, J., Morris, J. C., Olichney, J., Rogers, J., Quinn, J., Kass, J. S., Taylor, J. L., Heidebrink, J. L., Anderson, K., Blank, K., Smith, K. E., Bell, K. L., Johnson, K., Tingus, K., DeMarco, K., Sink, K. M., Johnson, K. A., Makino, K. M., Spicer, K., Nam, K. W., Martin, K., Poki-Walker, K., Johnson, K., Fargher, K., Lipowski, K., Womack, K., Flashman, L. A., Honig, L. S., Apostolova, L., Teodoro, L., Silbert, L. C., Ravdin, L., Schneider, L. S., Daiello, L. A., Ismail, M. S., Seltzer, M., Mesulam, M.-M., Carroll, M., Kataki, M., Greig-Custo, M. T., Love, M. N., Mintun, M. A., Farlow, M. R., Sadowski, M., Creech, M. L., Hynes, M. L., Quiceno, M., Oakley, M., Becerra, M., Witbracht, M., Keltz, M., Lamar, M., Yang, M., Borrie, M., Lin, M., Assaly, M., Rainka, M., Dang, M., Sheikh, M. O., Gaikwad, M., Chowdhury, M., Trncic, N., Johnson, N., Kowalksi, N., Pacini, N., Kowall, N., Graff-Radford, N. R., Relkin, N., Oyonumo, N. E., Pomara, N., James, O., Ogunlana, O., Lopez, O. L., Carmichael, O., Doraiswamy, P. M., Fatica, P., Johnson, P. L., Samuels, P., Malloy, P., Ogrocki, P., Maillard, P., Hardy, P., Tariot, P., Lu, P. H., Varma, P., Doody, R. S., Carter, R., Shah, R. C., Griffith, R., Yeh, R., Duara, R., Tarawneh, R., Turner, R. S., Hernando, R., Sperling, R. A., Carson, R. E., El Khouli, R., Santulli, R. B., Killiany, R., Rodriguez, R., Swerdlow, R. H., Borges-Neto, S., Black, S., Weintraub, S., Asthana, S., Vaishnavi, S., Dolen, S., Mason, S. S., Kremen, S., Herring, S., Sirrel, S. A., Kittur, S., Pawluczyk, S., Schneider, S., Kielb, S., Reeder, S., Correia, S., Pasternack, S., Pasternak, S., Salloway, S., Johnson, S., Chao, S., Arnold, S. E., Schultz, S. K., Rountree, S., Lee, T.-Y., Wong, T. Z., Villena, T., Obisesan, T. O., Pavlik, V., Bates, V., Sossi, V., Shibley, V., Brooks, W. M., Pavlosky, W., Stern, Y., Simon, A., Dongre, A., Dean, B., Navia, B., Spellman, D., Lee, D., Shera, D., Siemers, E., Pickering, E., Swenson, F., Immerman, F., Nomikos, G., Soares, H., Wan, H., Seeburger, J., Waring, J., Trojanowski, J., Siuciak, J., Duffin, K., Shaw, L., Wang, L.-S., Thambisetty, M., Walton, M., Savage, M., Ferm, M., Kuhn, M., Buckholtz, N., Zagouras, P., Cole, P., Hendrickson, R., Xie, S., Allauzen, S., Koroshetz, W., & Potter, W.
Affiliations
  • Hong Kong University of Science and Technology (HK)
  • Chinese Academy of Sciences (CN)
  • Fudan University (CN)
  • UCL Queen Square Institute of Neurology (GB)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
  • Guo, Qihao
  • Ip, Nancy Y.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-02-05
Volume
115
Issue
8
Pages
1697-1706
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1715554115
PMC
PMC5828602
OpenAlex
W2792688330
Cited by
96
References
8
Citations by year
2026: 4 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 15 · 2021: 14 · 2020: 15 · 2019: 7 · 2018: 4
FWCI
7.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • U.S. Department of Defense (AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, U24 AG021886, AG024904, U01 AG016976, N01-AG-12100)
  • Alzheimer's Association (U01 AG016976, U01 AG032984, ADGC-10–196728, U24AG021886, AG033193, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012)
  • Biogen (W81XWH-12-2-0012, AG024904)
  • University of Southern California (W81XWH-12-2-0012)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904)
  • Meso Scale Diagnostics (AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01 AG032984, U01AG024904, AG024904, W81XWH-12-2-)
  • BioClinica (W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, AG024904)
  • Northern California Institute for Research and Education (W81XWH-12-2-0012)
  • Wellcome Trust (082604/2/07/Z, 082604)
  • Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
  • Université de Lille
  • Institut National de la Santé et de la Recherche Médicale
  • National Natural Science Foundation of China (2013CB530900, 31671047, W81XWH-12-2-0012)
  • University Grants Committee (T13-607/12R, AoE/M-604/16)
  • Bundesministerium für Bildung und Forschung (01GI0102, 01GI0711, 01GI0420)
  • Chinese Academy of Sciences (172644KYSB20160026)
  • Erasmus Medisch Centrum
  • Eisai (W81XWH-12-2-0012, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012)
  • Hjartavernd (N01-AG-1-2100)
  • H. Lundbeck A/S (AG024904, W81XWH-12-2-0012)
  • Centre hospitalier régional universitaire de Lille (503480, 503176, 082604/2/07/Z)
  • IXICO (AG024904, W81XWH-12-2-0012)
  • Shenzhen Knowledge Innovation Program (JCYJ20151030154629774, JCYJ20170413173717055, JCYJ20151030140325152, JCYJ20160428145818099)
  • National Institutes of Health (AG081220, n01ag12100-57-0-2, N01-AG-1-2100, 5u01ag024904-10, W81XWH-12-2-0012, NIA AG081220, AG016976, U01-AG024904, AG024904)
  • Genentech (W81XWH-12-2-0012, AG024904)
  • Canadian Institutes of Health Research
  • Medical Research Council (503480)
  • National Key Research and Development Program of China (2013CB530900, W81XWH-12-2-0012)
  • Shenzhen Peacock Plan
  • National Institute on Aging (U01-AG-024904, AG 016976, W81XWH-12-2–0012, N01-AG12100, N01-AG012100, AG 024904, AG081220, U01AG016976, NIA AG081220, U01AG032984, AG033193, AG032984, R01AG033193, AG021886, U24AG021886)
  • National Heart, Lung, and Blood Institute (HL-105756, R01HL105756, AG033193)
  • National Institute of Mental Health (W81XWH-12-2-0012, 01GI0711, 082604/2/07/Z, NIA AG081220, 01GI0102, 503176, 01GI0420)
  • NIH Office of the Director (U01 AG016976)
  • National Cancer Institute
  • National Institute of Biomedical Imaging and Bioengineering (P41EB015922)
  • Common Fund
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, genetic risk factors, apolipoprotein E, GTP cyclohydrolase I, KCNJ15, immune system, Chinese population, age of onset, transcriptome, plasma biomarkers, hippocampus, blood transcriptome, regulatory variants, immune pathways
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, China, Female, Genotype, Humans, Immune System, Male, Middle Aged, Risk Factors, Cohort Studies, Age of Onset, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, Asian People, Genome-Wide Association Study

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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