ANALYSIS OF GWAS-IDENTIFIED VARIANTS ASSOCIATED WITH ALZHEIMER’S DISEASE RISK IN CASS4, TREM2, CD2AP, AND MS4A4E GENES
Abstract
Understanding genetic and biochemical aspects of complex diseases like Alzheimer’s disease (AD) is crucial for developing new treatments. Genome-wide association studies (GWAS) identify genetic risk factors, but validating these variants is necessary to confirm their role in disease susceptibility. This observational analytical case-control genetic association study included 221 unrelated participants, comprising 82 patients with late-onset Alzheimer’s disease (LOAD) and 139 older adults without dementia. Four GWAS-identified variants associated with LOAD were analyzed: rs911159 in CASS4, rs75932628 in TREM2, rs9349407 in CD2AP, and rs670139 in MS4A4E, using real-time PCR and PCR-RFLP. Logistic regression showed an association between rs911159 in CASS4 and LOAD (OR = 0.187; 95% CI 0.059–0.59; p = 0.005), suggesting a protective effect in our sample. However, no association was found for rs9349407 in CD2AP and rs670139 in MS4A4E. The rs75932628-T variant was not detected in our sample. These findings contribute to the understanding of the genetic basis of LOAD in an admixed Brazilian population. However, these results should be interpreted with caution due to the limited sample size, and further studies with larger cohorts are needed to confirm these associations.
Author Biographies
Human and Molecular Genetics Center, Department of Biological Sciences, Center for Human and Natural Sciences, Federal University of Espírito Santo, Vitória, ES, Brazil.
Human and Molecular Genetics Center, Department of Biological Sciences, Center for Human and Natural Sciences, Federal University of Espírito Santo, Vitória, ES, Brazil; Graduate Program in Biotechnology, Federal University of Espírito Santo, Vitória, ES, Brazil.
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY, 10461, USA.
Graduate Program in Biotechnology, Federal University of Espírito Santo, Vitória, ES, Brazil.
Higher School of Sciences of the Santa Casa de Misericórdia de Vitória, Vitória, ES, Brazil.
Human and Molecular Genetics Center, Department of Biological Sciences, Center for Human and Natural Sciences, Federal University of Espírito Santo, Vitória-ES, Brazil.
Human and Molecular Genetics Center, Department of Biological Sciences, Center for Human and Natural Sciences, Federal University of Espírito Santo, Vitória-ES, Brazil.
Higher School of Sciences of the Santa Casa de Misericórdia de Vitória, Vitória, ES, Brazil; Santa Casa de Misericórdia de Vitória Hospital, Higher School of Sciences of the Santa Casa de Misericórdia de Vitória, Vitória, ES, Brazil.
Higher School of Sciences of the Santa Casa de Misericórdia de Vitória, Vitória, ES, Brazil.
References
ARBOLEDA-BUSTOS, C. E. et al. The p.R47H variant of TREM2 gene is associated with late-onset Alzheimer disease in Colombian population. Alzheimer Disease and Associated Disorders, v. 32, p. 305-308, 2018. DOI: https://doi.org/10.1097/WAD.0000000000000275
ALZHEIMER'S ASSOCIATION. 2016 Alzheimer’s disease facts and figures. Alzheimer's & Dementia, v. 12, p. 459-509, 2016. DOI: https://doi.org/10.1016/j.jalz.2016.03.001
BECK, T. N.; NICOLAS, E.; KOPP, M. C.; GOLEMIS, E. A. Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer’s disease. Oncoscience, v. 1, p. 486-503, 2014. DOI: https://doi.org/10.18632/oncoscience.64
BEECHAM, G. W. et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genetics, v. 10, e1004606, 2014. DOI: https://doi.org/10.1371/journal.pgen.1004867
BENITEZ, B. A. et al. TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiology of Aging, v. 34, p. 1711.e15-1711.e17, 2013. DOI: https://doi.org/10.1016/j.neurobiolaging.2012.12.018
CAMPOREZ, D. et al. Positive association of a SIRT1 variant and parameters of oxidative stress on Alzheimer’s disease. Neurological Sciences, v. 42, p. 1843-1851, 2021. DOI: https://doi.org/10.1007/s10072-020-04704-y
CARRASQUILLO, M. M. et al. Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multicentre case-control study. Molecular Neurodegeneration, v. 6, art. 54, 2011. DOI: https://doi.org/10.1186/1750-1326-6-54
CHEN, H. et al. Analyzing 54,936 samples supports the association between CD2AP rs9349407 polymorphism and Alzheimer’s disease susceptibility. Molecular Neurobiology, v. 52, p. 1-7, 2015. DOI: https://doi.org/10.1007/s12035-014-8834-2
DELIZANNIS, A. T. et al. Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice. Acta Neuropathologica Communications, v. 9, art. 150, 2021. DOI: https://doi.org/10.1186/s40478-021-01251-1
DENEKA, A.; KOROBEYNIKOV, V.; GOLEMIS, E. A. Embryonal Fyn-associated substrate (EFS) and CASS4: the lesser-known CAS protein family members. Gene, v. 570, p. 25-35, 2015. DOI: https://doi.org/10.1016/j.gene.2015.06.062
DOURLEN, P. et al. Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of tau pathology. Molecular Psychiatry, v. 22, p. 874-883, 2017. DOI: https://doi.org/10.1038/mp.2016.59
GIN, A. et al. Towards early diagnosis and screening of Alzheimer’s disease using frequency locked whispering gallery mode microtoroid biosensors. Research Square, 2024. Preprint. DOI: https://doi.org/10.21203/rs.3.rs-4355995/v1
GUAN, P. P.; CAO, L. L.; WANG, P. Elevating the levels of calcium ions exacerbate Alzheimer’s disease via inducing the production and aggregation of β-amyloid protein and phosphorylated tau. International Journal of Molecular Sciences, v. 22, art. 5900, 2021. DOI: https://doi.org/10.3390/ijms22115900
GUNTER, N. B. et al. Machine learning models of polygenic risk for enhanced prediction of Alzheimer disease endophenotypes. Neurology: Genetics, v. 10, e200120, 2024. DOI: https://doi.org/10.1212/NXG.0000000000200120
HOLLINGWORTH, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nature Genetics, v. 43, p. 429-435, 2011.
HOU, M.; XU, G.; RAN, M.; LUO, W.; WANG, H. APOE-ε4 carrier status and gut microbiota dysbiosis in patients with Alzheimer disease. Frontiers in Neuroscience, v. 15, art. 619051, 2021. DOI: https://doi.org/10.3389/fnins.2021.619051
HU, N. et al. Increased expression of TREM2 in peripheral blood of Alzheimer’s disease patients. Journal of Alzheimer’s Disease, v. 38, p. 497-501, 2013. DOI: https://doi.org/10.3233/JAD-130854
ISMAIL, A. B. et al. Alzheimer disease associated loci: APOE single nucleotide polymorphisms in Marmara region. Biomedicines, v. 12, art. 968, 2024. DOI: https://doi.org/10.3390/biomedicines12050968
JIAO, B. et al. Polygenic analysis of late-onset Alzheimer’s disease from mainland China. PLoS One, v. 10, p. 1-10, 2015. DOI: https://doi.org/10.1371/journal.pone.0144898
JONSSON, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. The New England Journal of Medicine, v. 368, p. 107-116, 2013.
KARCH, C. M.; GOATE, A. M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biological Psychiatry, v. 77, p. 43-51, 2015. DOI: https://doi.org/10.1016/j.biopsych.2014.05.006
KARCH, C. M. et al. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PLoS One, v. 7, e50976, 2012. DOI: https://doi.org/10.1371/journal.pone.0050976
KONG, F. et al. Knowledge domains and emerging trends of genome-wide association studies in Alzheimer’s disease: a bibliometric analysis and visualization study from 2002 to 2022. PLoS One, v. 19, e0295008, 2024. DOI: https://doi.org/10.1371/journal.pone.0295008
LAFERLA, F. M. Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nature Reviews Neuroscience, v. 3, p. 862-872, 2002. DOI: https://doi.org/10.1038/nrn960
LAMBERT, J. C.; AMOUYEL, P. Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Current Opinion in Genetics & Development, v. 21, p. 295-301, 2011. DOI: https://doi.org/10.1016/j.gde.2011.02.002
LAMBERT, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nature Genetics, v. 45, p. 1452-1458, 2013.
LIANG, Y. et al. Structural organization of the human MS4A gene cluster on chromosome 11q12. Immunogenetics, v. 53, p. 357-368, 2001. DOI: https://doi.org/10.1007/s002510100339
LIN, E. et al. Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population. Oncotarget, v. 8, p. 24088-24098, 2017. DOI: https://doi.org/10.18632/oncotarget.15493
LINS, T. C. et al. Genetic composition of Brazilian population samples based on a set of twenty-eight ancestry informative SNPs. American Journal of Human Biology, v. 22, p. 187-192, 2010. DOI: https://doi.org/10.1002/ajhb.20976
LIU, W. S. et al. Inflammation and brain structure in Alzheimer’s disease and other neurodegenerative disorders: a Mendelian randomization study. Molecular Neurobiology, v. 61, p. 1593-1604, 2024. DOI: https://doi.org/10.1007/s12035-023-03648-6
MA, J. et al. Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer’s disease in Chinese Han population. Neurological Research, v. 36, p. 894-896, 2014. DOI: https://doi.org/10.1179/1743132814Y.0000000376
MANINGER, J. K. et al. Cell type-specific functions of Alzheimer’s disease endocytic risk genes. Philosophical Transactions of the Royal Society B: Biological Sciences, v. 379, art. 20220378, 2024. DOI: https://doi.org/10.1098/rstb.2022.0378
MAO, Y. F. et al. Association of CD33 and MS4A cluster variants with Alzheimer’s disease in East Asian populations. Neuroscience Letters, v. 609, p. 235-239, 2015. DOI: https://doi.org/10.1016/j.neulet.2015.10.007
MEHDIZADEH, E. et al. Association of MS4A6A, CD33, and TREM2 gene polymorphisms with late-onset Alzheimer’s disease. BioImpacts, v. 9, p. 219-225, 2019. DOI: https://doi.org/10.15171/bi.2019.27
MEHRJOO, Z. et al. Association study of the TREM2 gene and identification of a novel variant in exon 2 in Iranian patients with late-onset Alzheimer’s disease. Medical Principles and Practice, v. 24, p. 351-354, 2015. DOI: https://doi.org/10.1159/000430842
MELCHIOR, B. et al. Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro, v. 2, AN20100010, 2010. DOI: https://doi.org/10.1042/AN20100010
MILLER, S. A.; DYKES, D. D.; POLESKY, H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, v. 16, p. 1215, 1988. DOI: https://doi.org/10.1093/nar/16.3.1215
MIYASHITA, A. et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One, v. 8, e58618, 2013.
OMOUMI, A. et al. Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population. Neurobiology of Aging, v. 35, p. 936.e5-936.e12, 2014. DOI: https://doi.org/10.1016/j.neurobiolaging.2013.09.025
PENA, S. D. J. et al. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One, v. 6, e17063, 2011. DOI: https://doi.org/10.1371/journal.pone.0017063
RAMOS DE MATOS, M. et al. Quantitative genetics validates previous genetic variants and identifies novel genetic players influencing Alzheimer’s disease cerebrospinal fluid biomarkers. Journal of Alzheimer’s Disease, v. 66, p. 639-652, 2018. DOI: https://doi.org/10.3233/JAD-180512
ROSTAGNO, A. A. Pathogenesis of Alzheimer’s disease. International Journal of Molecular Sciences, v. 24, art. 107, 2023. DOI: https://doi.org/10.3390/ijms24010107
SHULMAN, J. M. et al. Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurology, v. 70, p. 1150-1157, 2013. DOI: https://doi.org/10.1001/jamaneurol.2013.2815
TAN, L. et al. Association of GWAS-linked loci with late-onset Alzheimer’s disease in a northern Han Chinese population. Alzheimer's & Dementia, v. 9, p. 546-553, 2013. DOI: https://doi.org/10.1016/j.jalz.2012.08.007
TAO, Q. Q. et al. Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer’s disease. Neurobiology of Aging, v. 56, p. 212.e5-212.e10, 2017. DOI: https://doi.org/10.1016/j.neurobiolaging.2017.03.013
TAO, Q. Q.; CHEN, Y. C.; WU, Z. Y. The role of CD2AP in the pathogenesis of Alzheimer's disease. Aging and Disease, v. 10, p. 901-907, 2019. DOI: https://doi.org/10.14336/AD.2018.1025
TEIXEIRA, L. C. R. et al. Role of long non-coding RNAs in the pathophysiology of Alzheimer’s disease and other dementias. Molecular Biology Reports, v. 51, art. 270, 2024. DOI: https://doi.org/10.1007/s11033-023-09178-7
UBELMANN, F. et al. BIN1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Reports, v. 18, p. 102-122, 2017. DOI: https://doi.org/10.15252/embr.201642738
UDDIN, M. S. et al. Revisiting the amyloid cascade hypothesis: from anti-Aβ therapeutics to auspicious new ways for Alzheimer's disease. International Journal of Molecular Sciences, v. 21, art. 5858, 2020. DOI: https://doi.org/10.3390/ijms21165858
VALDEZ-GAXIOLA, C. A. et al. Early- and late-onset Alzheimer’s disease: two sides of the same coin? Diseases, v. 12, art. 110, 2024. DOI: https://doi.org/10.3390/diseases12060110
VILLEGAS-LLERENA, C. et al. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Current Opinion in Neurobiology, v. 36, p. 74-81, 2016. DOI: https://doi.org/10.1016/j.conb.2015.10.004
WANG, H. Z. et al. Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations. Molecular Neurobiology, v. 53, p. 379-390, 2016. DOI: https://doi.org/10.1007/s12035-014-9015-z
WANG, P. et al. Lack of association between triggering receptor expressed on myeloid cells 2 polymorphism rs75932628 and late-onset Alzheimer’s disease in a Chinese Han population. Psychiatric Genetics, v. 28, p. 16-18, 2018. DOI: https://doi.org/10.1097/YPG.0000000000000188
WANG, L. et al. Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease. Molecular Neurodegeneration, v. 19, art. 1, 2024. DOI: https://doi.org/10.1002/alz.077275
WONG, W. et al. An adhesion signaling axis involving dystroglycan, β1-integrin, and CAS adaptor proteins regulates the establishment of the cortical glial scaffold. PLoS Biology, v. 21, e3002212, 2023. DOI: https://doi.org/10.1371/journal.pbio.3002212
XIAO, Q. et al. Risk prediction for sporadic Alzheimer's disease using genetic risk score in the Han Chinese population. Oncotarget, v. 6, p. 36955-36964, 2015. DOI: https://doi.org/10.18632/oncotarget.6271
YU, J. T.; TAN, L.; HARDY, J. Apolipoprotein E in Alzheimer’s disease: an update. Annual Review of Neuroscience, v. 37, p. 79-100, 2014. DOI: https://doi.org/10.1146/annurev-neuro-071013-014300
ZHENG, J. et al. TREM2 mediates MHCII-associated CD4+ T cell response against gliomas. Neuro-Oncology, v. 26, p. 811-825, 2024. DOI: https://doi.org/10.1093/neuonc/noad214
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