Abstract
Alzheimer’s disease (AD) and Parkinson’s disease (PD) have overlapping pathological mechanisms and genetic background, suggesting it would be meaningful to replicate PD-related genetic variants in AD population to identify new loci of AD. Here, in order to discover potential AD-related loci, we investigated the association between late-onset AD (LOAD) susceptibility and nine single-nucleotide polymorphisms (SNPs) (rs11724635 of BST1, rs12637471 of MCCC1, rs15553999 of TMEM229, rs17649553 of MAPT, rs34311866 of TMEM175-GAK-DGKQ, rs356182 of SNCA, rs6430538 of ACMSD-TMEM163, rs76904798 of LRRK2 and rs823118 of RAB7L1-NUCKS1) which were reported to have genome-wide significant associations with PD risk in a recent Genome Wide Association Study performed among white population. We included 2350 samples comprising with 992 sporadic LOAD patients and 1358 gender- and age-matched control subjects who were unrelated northern Han Chinese residents. Finally, among these included genetic variants, only rs76904798 of LRRK2 was proved to significantly reduce LOAD risk in a multivariate analysis in a dominant model after adjusting for age, sex, and apolipoprotein E (APOE) ε4 status (OR = 0.616; 95 % CI 0.446–0.849; Bonferroni corrected P = 0.027). In addition, when these data were stratified by APOE ε4 status, rs76904798 was still evident among subjects without APOE ε4 allele. Our results first time indicated rs76904798 of LRRK2 is also a common risk genetic variant for LOAD susceptibility in a northern Han Chinese people.
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Yu JT, Tan L, Hardy J (2014) Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci 37:79–100. doi:10.1146/annurev-neuro-071013-014300
Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 10(8):852–867
Jiang T, Yu JT, Zhu XC, Zhang QQ, Tan MS, Cao L, Wang HF, Lu J, Gao Q, Zhang YD, Tan L (2014) Angiotensin-(1–7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a Mas/eNOS-dependent pathway. Br J Pharmacol 171(18):4222–4232. doi:10.1111/bph.12770
Hauser PS, Ryan RO (2013) Impact of apolipoprotein E on Alzheimer’s disease. Curr Alzheimer Res 10(8):809–817
Wang HF, Yu JT, Tang SW, Jiang T, Tan CC, Meng XF, Wang C, Tan MS, Tan L (2015) Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry 86(2):135–143. doi:10.1136/jnnp-2014-307659
Kempster PA, O'Sullivan SS, Holton JL, Revesz T, Lees AJ (2010) Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain 133(Pt 6):1755–1762. doi:10.1093/brain/awq059
Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Striatal beta-amyloid deposition in Parkinson disease with dementia. J Neuropathol Exp Neurol 67(2):155–161. doi:10.1097/NEN.0b013e31816362aa
Kalaitzakis ME, Pearce RK, Gentleman SM (2009) Clinical correlates of pathology in the claustrum in Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 461(1):12–15. doi:10.1016/j.neulet.2009.05.083
Compta Y, Parkkinen L, O'Sullivan SS, Vandrovcova J, Holton JL, Collins C, Lashley T, Kallis C, Williams DR, de Silva R, Lees AJ, Revesz T (2011) Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important? Brain 134(Pt 5):1493–1505. doi:10.1093/brain/awr031
Lippa CF, Pulaski-Salo D, Dickson DW, Smith TW (1997) Alzheimer’s disease, Lewy body disease and aging: a comparative study of the perforant pathway. J Neurol Sci 147(2):161–166
Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto L, Halonen P, Kontula K (1995) Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med 333(19):1242–1247. doi:10.1056/NEJM199511093331902
Laws SM, Friedrich P, Diehl-Schmid J, Muller J, Eisele T, Bauml J, Forstl H, Kurz A, Riemenschneider M (2007) Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer’s disease. Mol Psychiatry 12(5):510–517. doi:10.1038/sj.mp.4001935
Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, Chinnery PF, Barker RA, Sawcer SJ (2007) Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson’s disease. Ann Neurol 62(2):145–153. doi:10.1002/ana.21192
Williams-Gray CH, Goris A, Saiki M, Foltynie T, Compston DA, Sawcer SJ, Barker RA (2009) Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson’s disease. J Neurol 256(3):493–498. doi:10.1007/s00415-009-0119-8
Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46(9):989–993. doi:10.1038/ng.3043
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34(7):939–944
Tan L, Yu JT, Zhang W, Wu ZC, Zhang Q, Liu QY, Wang W, Wang HF, Ma XY, Cui WZ (2013) Association of GWAS-linked loci with late-onset Alzheimer’s disease in a northern Han Chinese population. Alzheimers Dement 9(5):546–553. doi:10.1016/j.jalz.2012.08.007
Jiang T, Yu JT, Wang YL, Wang HF, Zhang W, Hu N, Tan L, Sun L, Tan MS, Zhu XC (2014) The genetic variation of ARRB2 is associated with late-onset Alzheimer’s disease in Han Chinese. Curr Alzheimer Res 11(4):408–412
Zhu XC, Tan L, Jiang T, Tan MS, Zhang W, Yu JT (2014) Association of IL-12A and IL-12B polymorphisms with Alzheimer’s disease susceptibility in a Han Chinese population. J Neuroimmunol 274(1–2):180–184. doi:10.1016/j.jneuroim.2014.06.026
Yu JT, Song JH, Ma T, Zhang W, Yu NN, Xuan SY, Tan L (2011) Genetic association of PICALM polymorphisms with Alzheimer’s disease in Han Chinese. J Neurol Sci 300(1–2):78–80. doi:10.1016/j.jns.2010.09.027
Xia M, Yu JT, Miao D, Lu RC, Zheng XP, Tan L (2014) SIRT2 polymorphism rs10410544 is associated with Alzheimer’s disease in a Han Chinese population. J Neurol Sci 336(1–2):48–51. doi:10.1016/j.jns.2013.10.001
Chen X, Li S, Yang Y, Yang X, Liu Y, Hu W, Jin L, Wang X (2012) Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. J Thromb Haemost 10(8):1508–1514. doi:10.1111/j.1538-7836.2012.04815.x
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9(5):356–369. doi:10.1038/nrg2344
Wang J, Yu JT, Tan MS, Jiang T, Tan L (2013) Epigenetic mechanisms in Alzheimer’s disease: implications for pathogenesis and therapy. Ageing Res Rev 12(4):1024–1041. doi:10.1016/j.arr.2013.05.003
Xu W, Tan L, Yu JT (2015) The link between the SNCA gene and parkinsonism. Neurobiol Aging 36(3):1505–1518. doi:10.1016/j.neurobiolaging.2014.10.042
Li JQ, Tan L, Yu JT (2014) The role of the LRRK2 gene in Parkinsonism. Mol Neurodegener 9:47. doi:10.1186/1750-1326-9-47
Xie A, Gao J, Xu L, Meng D (2014) Shared mechanisms of neurodegeneration in Alzheimer’s disease and Parkinson’s disease. BioMed research international 2014:648740. doi:10.1155/2014/648740
Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JP, Bertram L (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8(3):e1002548. doi:10.1371/journal.pgen.1002548
Lopatina O, Yoshihara T, Nishimura T, Zhong J, Akther S, Fakhrul AA, Liang M, Higashida C, Sumi K, Furuhara K, Inahata Y, Huang JJ, Koizumi K, Yokoyama S, Tsuji T, Petugina Y, Sumarokov A, Salmina AB, Hashida K, Kitao Y, Hori O, Asano M, Kitamura Y, Kozaka T, Shiba K, Zhong F, Xie MJ, Sato M, Ishihara K, Higashida H (2014) Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson’s disease. Front Behav Neurosci 8:133. doi:10.3389/fnbeh.2014.00133
Yamamoto-Katayama S, Ariyoshi M, Ishihara K, Hirano T, Jingami H, Morikawa K (2002) Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities. J Mol Biol 316(3):711–723. doi:10.1006/jmbi.2001.5386
Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM (2012) mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486(7404):490–495. doi:10.1038/nature11163
Poehler AM, Xiang W, Spitzer P, May VE, Meixner H, Rockenstein E, Chutna O, Outeiro TF, Winkler J, Masliah E, Klucken J (2014) Autophagy modulates SNCA/alpha-synuclein release, thereby generating a hostile microenvironment. Autophagy 10(12):2171–2192. doi:10.4161/auto.36436
Byers B, Cord B, Nguyen HN, Schule B, Fenno L, Lee PC, Deisseroth K, Langston JW, Pera RR, Palmer TD (2011) SNCA triplication Parkinson’s patient’s iPSC-derived DA neurons accumulate alpha-synuclein and are susceptible to oxidative stress. PLoS One 6(11):e26159. doi:10.1371/journal.pone.0026159
Sposito T, Preza E, Mahoney CJ, Seto-Salvia N, Ryan NS, Morris HR, Arber C, Devine MJ, Houlden H, Warner TT, Bushell TJ, Zagnoni M, Kunath T, Livesey FJ, Fox NC, Rossor MN, Hardy J, Wray S (2015) Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet 24(18):5260–5269. doi:10.1093/hmg/ddv246
Chen S, Townsend K, Goldberg TE, Davies P, Conejero-Goldberg C (2010) MAPT isoforms: differential transcriptional profiles related to 3R and 4R splice variants. J Alzheimers Dis 22(4):1313–1329. doi:10.3233/JAD-2010-101155
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39(1):17–23. doi:10.1038/ng1934
Ramanan VK, Saykin AJ (2013) Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am J Neurodegener Dis 2(3):145–175
Dachsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67(5):542–547. doi:10.1001/archneurol.2010.79
Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilarino-Guell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case–control study. Lancet Neurol 10(10):898–908. doi:10.1016/S1474-4422(11)70175-2
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607. doi:10.1016/j.neuron.2004.11.005
Lee E, Hui S, Ho G, Tan EK, Chen CP (2006) LRRK2 G2019S and I2020T mutations are not common in Alzheimer’s disease and vascular dementia. Am J Med Genet B Neuropsychiatr Genet 141B(5):549–550. doi:10.1002/ajmg.b.30305
Santos-Reboucas CB, Abdalla CB, Baldi FJ, Martins PA, Correa JC, Goncalves AP, Cunha MS, Borges MB, Pereira JS, Laks J, Pimentel MM (2008) Co-occurrence of sporadic parkinsonism and late-onset Alzheimer’s disease in a Brazilian male with the LRRK2 p.G2019S mutation. Genet Test 12(4):471–473. doi:10.1089/gte.2008.0042
Tan EK, Lee J, Chen CP, Wong MC, Zhao Y (2009) Case control analysis of LRRK2 Gly2385Arg in Alzheimer’s disease. Neurobiol Aging 30(3):501–502. doi:10.1016/j.neurobiolaging.2007.07.010
Zhao Y, Ho P, Yih Y, Chen C, Lee WL, Tan EK (2011) LRRK2 variant associated with Alzheimer’s disease. Neurobiol Aging 32(11):1990–1993. doi:10.1016/j.neurobiolaging.2009.11.019
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278(16):1349–1356
Chang TY, Kuo HC, Lu CS, Wu-Chou YH, Huang CC (2010) Analysis of the LRRK2 Gly2385Arg variant in Alzheimer’s disease in Taiwan. Parkinsonism Relat Disord 16(1):28–30. doi:10.1016/j.parkreldis.2009.06.009
Bi R, Zhao L, Zhang C, Lu W, Feng JQ, Wang Y, Ni J, Zhang J, Li GD, Hu QX, Wang D, Yao YG, Li T (2014) No association of the LRRK2 genetic variants with Alzheimer’s disease in Han Chinese individuals. Neurobiol Aging 35(2):444. doi:10.1016/j.neurobiolaging.2013.08.013, e445-449>
Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, de Andrade M, West A, de Silva R, Hardy J, Hernandez D (2001) alpha-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 10(17):1847–1851
Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T, Berg D, Wullner U, Meitinger T, Gasser T (2005) Multiple regions of alpha-synuclein are associated with Parkinson’s disease. Ann Neurol 57(4):535–541. doi:10.1002/ana.20438
Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y, Nagai Y, Oka A, Inoko H, Fukae J, Saito Y, Sawabe M, Murayama S, Yamamoto M, Hattori N, Murata M, Toda T (2006) Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson’s disease. Hum Mol Genet 15(7):1151–1158. doi:10.1093/hmg/ddl030
Peuralinna T, Oinas M, Polvikoski T, Paetau A, Sulkava R, Niinisto L, Kalimo H, Hernandez D, Hardy J, Singleton A, Tienari PJ, Myllykangas L (2008) Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein. Ann Neurol 64(3):348–352. doi:10.1002/ana.21446
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (81471309, 81571245, 81501103), the Shandong Provincial Outstanding Medical Academic Professional Program, Qingdao Key Health Discipline Development Fund, Qingdao Outstanding Health Professional Development Fund, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, and the Innovation Project for Postgraduates of Jiangsu province (to XCZ (KYLX15_0958)).
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Xi-Chen Zhu and Lei Cao contributed equally to this work.
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Zhu, XC., Cao, L., Tan, MS. et al. Association of Parkinson’s Disease GWAS-Linked Loci with Alzheimer’s Disease in Han Chinese. Mol Neurobiol 54, 308–318 (2017). https://doi.org/10.1007/s12035-015-9649-5
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DOI: https://doi.org/10.1007/s12035-015-9649-5