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A Weighted Genetic Risk Score Based on Four APOE-Independent Alzheimer’s Disease Risk Loci May Supplement APOE E4 for Better Disease Prediction

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Abstract

Recent genome-wide association studies (GWAS) in European descent population have identified more than 30 independent single-nucleotide polymorphisms (SNPs) associated with Alzheimer’s disease (AD). In the present study, we genotyped 39 AD-risk SNPs in 499 sporadic AD patients and 760 matched healthy controls of Mongolian ethnicity from the Inner Mongolia, China. Further, we investigated whether genetic risk score (GRS) combining multiple AD-risk loci confirmed in our study population could improve AD prediction. Two approaches were used for GRS calculation: a simple risk allele count (cGRS) and a weighted approach (wGRS). The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory ability of the GRS models. Seven SNPs were confirmed associated with AD and four SNPs were associated with AD risk independent of APOE genotypes in our population. GRS based on either seven SNPs or four APOE-independent SNPs were significantly associated with AD risk (P = 2.3E−17~2.0E−6). The AUC for wGRS was significantly greater than for cGRS (0.6416 versus 0.6339, P = 0.0049 for seven SNPs; 0.5857 versus 0.5765, P = 0.0047 for four APOE-independent SNPs). Furthermore, we found that wGRS combining four APOE-independent SNPs and APOE E4 genotypes reached AUC 0.7023, significantly better than the discriminate ability of APOE E4 genotypes alone (AUC = 0.6699, P = 0.0379). The combined model, with an AUC of 0.6989, significantly higher than that of APOE E4 alone (0.6529) (P = 0.0284), for subjects in a validation cohort comprising 250 cases and 380 controls, randomly selected from our original cohort. In summary, we found that wGRS based on four APOE-independent AD risk SNPs may supplement APOE E4 for better assessing individual risk for AD in Mongolian population in China.

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References

  • Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, Dowzell K, Cichon S, Hillmer AM, O'Donovan MC, Williams J, Owen MJ, Kirov G (2008) A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Med Genet 1:44. https://doi.org/10.1186/1755-8794-1-44

    Article  CAS  Google Scholar 

  • American Psychiatric A, American Psychiatric A, Task Force on D-I (2011) Diagnostic and statistical manual of mental disorders : DSM-IV-TR. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Antunez C et al (2011) The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer’s disease. Genome Med 3:33. https://doi.org/10.1186/gm249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ashford JW, Mortimer JA (2002) Non-familial Alzheimer’s disease is mainly due to genetic factors. J Alzheimers Dis: JAD 4:169–177

    Article  PubMed  Google Scholar 

  • Bekris LM, Yu C-E, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227. https://doi.org/10.1177/0891988710383571

    Article  PubMed  PubMed Central  Google Scholar 

  • Carrasquillo MM, Crook JE, Pedraza O, Thomas CS, Pankratz VS, Allen M, Nguyen T, Malphrus KG, Ma L, Bisceglio GD, Roberts RO, Lucas JA, Smith GE, Ivnik RJ, Machulda MM, Graff-Radford NR, Petersen RC, Younkin SG, Ertekin-Taner N (2015) Late-onset Alzheimer’s risk variants in memory decline, incident mild cognitive impairment, and Alzheimer’s disease. Neurobiol Aging 36:60–67. https://doi.org/10.1016/j.neurobiolaging.2014.07.042

    Article  PubMed  Google Scholar 

  • Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4:7. https://doi.org/10.1186/s13742-015-0047-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, Mullan M (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–846. https://doi.org/10.1038/353844a0

    Article  CAS  PubMed  Google Scholar 

  • Chaudhury S et al (2017) Polygenic risk score in post-mortem diagnosed sporadic early onset Alzheimer’s disease. Neurobiol Aging 62:S0197458017303408

    Google Scholar 

  • Chauhan G, Adams HHH, Bis JC, Weinstein G, Yu L, Töglhofer AM, Smith AV, van der Lee SJ, Gottesman RF, Thomson R, Wang J, Yang Q, Niessen WJ, Lopez OL, Becker JT, Phan TG, Beare RJ, Arfanakis K, Fleischman D, Vernooij MW, Mazoyer B, Schmidt H, Srikanth V, Knopman DS, Jack CR Jr, Amouyel P, Hofman A, DeCarli C, Tzourio C, van Duijn CM, Bennett DA, Schmidt R, Longstreth WT Jr, Mosley TH, Fornage M, Launer LJ, Seshadri S, Ikram MA, Debette S (2015) Association of Alzheimer’s disease GWAS loci with MRI markers of brain aging. Neurobiol Aging 36:1765.e1767. https://doi.org/10.1016/j.neurobiolaging.2014.12.028

    Article  CAS  Google Scholar 

  • Che R, Motsinger-Reif AA (2013) Evaluation of genetic risk score models in the presence of interaction and linkage disequilibrium. Front Genet 4:138. https://doi.org/10.3389/fgene.2013.00138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H et al. (2011a) A genetic risk score combining ten psoriasis risk loci improves disease prediction vol 6. doi:https://doi.org/10.1371/journal.pone.0019454

  • Chen LH et al (2011b) Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer’s disease in a southern Chinese population. Alzheimer's & Dementia: Alzheimers Dement Alzheimer’s Association 7:S181–S181

    Article  Google Scholar 

  • Chen LH, Kao PYP, Fan YH, Ho DTY, Chan CSY, Yik PY, Ha JCT, Chu LW, Song YQ (2012) Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer’s disease in a southern Chinese population. Neurobiol Aging 33:210.e211–210.e217. https://doi.org/10.1016/j.neurobiolaging.2011.09.016

    Article  CAS  Google Scholar 

  • Deng YL, Liu LH, Wang Y, Tang HD, Ren RJ, Xu W, Ma JF, Wang LL, Zhuang JP, Wang G, Chen SD (2012) The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer’s disease. Hum Genet 131:1245–1249. https://doi.org/10.1007/s00439-012-1154-6

    Article  CAS  PubMed  Google Scholar 

  • Ebbert MT et al (2014) Population-based analysis of Alzheimer’s disease risk alleles implicates genetic interactions. Biol Psychiatry 75:732–737. https://doi.org/10.1016/j.biopsych.2013.07.008

    Article  CAS  PubMed  Google Scholar 

  • Escott-Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E, Badarinarayan N, GERAD/PERADES, IGAP consortia, Morgan K, Passmore P, Holmes C, Powell J, Brayne C, Gill M, Mead S, Goate A, Cruchaga C, Lambert JC, van Duijn C, Maier W, Ramirez A, Holmans P, Jones L, Hardy J, Seshadri S, Schellenberg GD, Amouyel P, Williams J (2015) Common polygenic variation enhances risk prediction for Alzheimer’s disease. Brain J Neurol 138:3673–3684. https://doi.org/10.1093/brain/awv268

    Article  Google Scholar 

  • Escott-Price V, Myers AJ, Huentelman M, Hardy J (2017) Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann Neurol 82:311–314. https://doi.org/10.1002/ana.24999

    Article  PubMed  PubMed Central  Google Scholar 

  • Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Tan MS, Wang HF, Zhang W, Wang ZX, Jiang T, Yu JT, Tan L (2016) ZCWPW1 is associated with late-onset Alzheimer’s disease in Han Chinese: a replication study and meta-analyses. Oncotarget 7:20305–20311. https://doi.org/10.18632/oncotarget.7945

    Article  PubMed  PubMed Central  Google Scholar 

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706. https://doi.org/10.1038/349704a0

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez Murcia JD et al (2013) Assessment of TREM2 rs75932628 association with Alzheimer’s disease in a population-based sample: the Cache County Study. Neurobiol Aging 34:2889.e2811–2889.e2883. https://doi.org/10.1016/j.neurobiolaging.2013.06.004

    Article  CAS  Google Scholar 

  • Hall TO et al (2013) Risk prediction for complex diseases: application to Parkinson disease. Genet Med 15:361–367. https://doi.org/10.1038/gim.2012.109

    Article  CAS  PubMed  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics science (New York, NY) 297:353–356 doi:https://doi.org/10.1126/science.1072994

  • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JSK, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, de Deyn PP, van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J (2009a) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease, and shows evidence for additional susceptibility genes. Nat Genet 41:1088–1093. https://doi.org/10.1038/ng.440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JSK, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, de Deyn PP, van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J (2009b) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. https://doi.org/10.1038/ng.440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison TM, Mahmood Z, Lau EP, Karacozoff AM, Burggren AC (2016) An Alzheimer’s disease genetic risk score predicts longitudinal thinning of hippocampal complex subregions in healthy older adults 3 doi:https://doi.org/10.1523/eneuro.0098-16.2016

  • He Y et al. (2016) Meta-analysis of the rs2075650 polymorphism and risk of Alzheimer disease 28:805–811 doi:https://doi.org/10.1007/s40520-015-0489-y

  • Herold C, Hooli BV, Mullin K, Liu T, Roehr JT, Mattheisen M, Parrado AR, Bertram L, Lange C, Tanzi RE (2016) Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer’s disease with OSBPL6, PTPRG, and PDCL3. Mol Psychiatry 21:1608–1612. https://doi.org/10.1038/mp.2015.218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hollingworth P et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435. https://doi.org/10.1038/ng.803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Zhao J, Xu B, Ma X, Dai Q, Li T, Xue F, Chen B (2016) The TOMM40 gene rs2075650 polymorphism contributes to Alzheimer’s disease in Caucasian, and Asian populations. Neurosci Lett 628:142–146. https://doi.org/10.1016/j.neulet.2016.05.050

    Article  CAS  PubMed  Google Scholar 

  • Jiao B, Liu X, Zhou L, Wang MH, Zhou Y, Xiao T, Zhang W, Sun R, Waye MMY, Tang B, Shen L (2015) Polygenic analysis of late-onset Alzheimer’s disease from mainland China. PLoS One 10:e0144898. https://doi.org/10.1371/journal.pone.0144898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin G, Zhu M, Yin R, Shen W, Liu J, Sun J, Wang C, Dai J, Ma H, Wu C, Yin Z, Huang J, Higgs BW, Xu L, Yao Y, Christiani DC, Amos CI, Hu Z, Zhou B, Shi Y, Lin D, Shen H (2015) Low-frequency coding variants at 6p21.33 and 20q11.21 are associated with lung cancer risk in Chinese populations. Am J Hum Genet 96:832–840. https://doi.org/10.1016/j.ajhg.2015.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116. https://doi.org/10.1056/NEJMoa1211103

    Article  CAS  PubMed  Google Scholar 

  • Jun G et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein 21:108–117 doi:https://doi.org/10.1038/mp.2015.23

  • Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, Buxbaum JD, Byrd GS, Carrasquillo MM, Crane PK, Cruchaga C, de Jager P, Ertekin-Taner N, Evans D, Fallin MD, Foroud TM, Friedland RP, Goate AM, Graff-Radford NR, Hendrie H, Hall KS, Hamilton-Nelson KL, Inzelberg R, Kamboh MI, Kauwe JSK, Kukull WA, Kunkle BW, Kuwano R, Larson EB, Logue MW, Manly JJ, Martin ER, Montine TJ, Mukherjee S, Naj A, Reiman EM, Reitz C, Sherva R, St. George-Hyslop PH, Thornton T, Younkin SG, Vardarajan BN, Wang LS, Wendlund JR, Winslow AR, Haines J, Mayeux R, Pericak-Vance MA, Schellenberg G, Lunetta KL, Farrer LA, Adams PM, Albert MS, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Barmada MM, Barnes LL, Beach TG, Becker JT, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cribbs DH, Crocco EA, Cruchaga C, de Jager PL, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Doody RS, Duara R, Ertekin-Taner N, Faber KM, Fairchild TJ, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Graff-Radford NR, Green RC, Growdon JH, Hakonarson H, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huebinger RM, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Karydas A, Kauwe JSK, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lin CF, Lopez OL, Lyketsos CG, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Mukherjee S, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Partch A, Paulson HL, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reisch JS, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Royall DR, Sager MA, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, van Deerlin VM, van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Wu CK, Yu CE, Yu L, Zhang X (2017) Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimers Association 13:727–738. https://doi.org/10.1016/j.jalz.2016.12.012

    Article  Google Scholar 

  • Kamboh MI et al (2012) Genome-wide association study of Alzheimer’s disease. Transl Psychiatry 2:e117. https://doi.org/10.1038/tp.2012.45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keogh-Brown MR, Jensen HT, Arrighi HM, Smith RD (2016) The impact of Alzheimer’s disease on the Chinese economy. EBioMedicine 4:184–190. https://doi.org/10.1016/j.ebiom.2015.12.019

    Article  PubMed  Google Scholar 

  • Lambert JC et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099. https://doi.org/10.1038/ng.439

    Article  CAS  PubMed  Google Scholar 

  • Lambert JC et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li YQ, Tan MS, Wang HF, Tan CC, Zhang W, Zheng ZJ, Kong LL, Wang ZX, Tan L, Jiang T, Tan L, Yu JT (2016) Common variant in PTK2B is associated with late-onset Alzheimer’s disease: a replication study and meta-analyses. Neurosci Lett 621:83–87. https://doi.org/10.1016/j.neulet.2016.04.020

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Song Y (2010) Building genetic scores to predict risk of complex diseases in humans: is it possible? Diabetes 59:2729–2731. https://doi.org/10.2337/db10-1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu C-C, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nat Rev Neurol 9:106–118. https://doi.org/10.1038/nrneurol.2012.263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu LH, Xu J, Deng YL, Tang HD, Wang Y, Ren RJ, Xu W, Ma JF, Wang G, Chen SD (2014) A complex association of ABCA7 genotypes with sporadic Alzheimer disease in Chinese Han population. Alzheimer Dis Assoc Disord 28:141–144. https://doi.org/10.1097/wad.0000000000000000

    Article  PubMed  Google Scholar 

  • Liu G, Xu Y, Jiang Y, Zhang L, Feng R, Jiang Q (2017) PICALM rs3851179 variant confers susceptibility to Alzheimer's disease in Chinese population. Mol Neurobiol 54:3131–3136. https://doi.org/10.1007/s12035-016-9886-2

    Article  CAS  PubMed  Google Scholar 

  • Lu H et al. (2016) Lack of association between SLC24A4 polymorphism and late-onset Alzheimer’s disease in Han Chinese Aging clinical and experimental research 13:239–243 doi:https://doi.org/10.1007/s40520-015-0489-y

  • Lu R-C, Yang W, Tan L, Sun FR, Tan MS, Zhang W, Wang HF, Tan L (2017) Association of HLA-DRB1 polymorphism with Alzheimer’s disease: a replication and meta-analysis. Oncotarget 8:93219–93226. https://doi.org/10.18632/oncotarget.21479

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma JF, Liu LH, Zhang Y, Wang Y, Deng YL, Huang Y, Wang G, Xu W, Cui PJ, Fei QZ, Ding JQ, Tang HD, Chen SD (2011) Association study of clusterin polymorphism rs11136000 with late onset Alzheimer’s disease in Chinese Han population. Am J Alzheimers Dis Other Dement 26:627–630. https://doi.org/10.1177/1533317511432735

    Article  Google Scholar 

  • Ma XY, Yu JT, Wu ZC, Zhang Q, Liu QY, Wang HF, Wang W, Tan L (2012) Replication of the MTHFD1L gene association with late-onset Alzheimer’s disease in a Northern Han Chinese population. J Alzheimers Dis: JAD 29:521–525. https://doi.org/10.3233/jad-2011-111847

    Article  PubMed  Google Scholar 

  • Ma XY, Yu JT, Wang W, Wang HF, Liu QY, Zhang W, Tan L (2013) Association of TOMM40 polymorphisms with late-onset Alzheimer’s disease in a Northern Han Chinese population. NeuroMolecular Med 15:279–287. https://doi.org/10.1007/s12017-012-8217-7

    Article  CAS  PubMed  Google Scholar 

  • Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TFC, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753. https://doi.org/10.1038/nature08494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marden JR, Walter S, Tchetgen Tchetgen EJ, Kawachi I, Glymour MM (2014) Validation of a polygenic risk score for dementia in black and white individuals. Brain Behav 4:687–697. https://doi.org/10.1002/brb3.248

    Article  PubMed  PubMed Central  Google Scholar 

  • Martiskainen H, Helisalmi S, Viswanathan J, Kurki M, Hall A, Herukka SK, Sarajärvi T, Natunen T, Kurkinen KMA, Huovinen J, Mäkinen P, Laitinen M, Koivisto AM, Mattila KM, Lehtimäki T, Remes AM, Leinonen V, Haapasalo A, Soininen H, Hiltunen M (2015) Effects of Alzheimer’s disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach. J Alzheimers Dis 43:565–573. https://doi.org/10.3233/jad-140777

    Article  CAS  PubMed  Google Scholar 

  • Naj AC, Beecham GW, Martin ER, Gallins PJ, Powell EH, Konidari I, Whitehead PL, Cai G, Haroutunian V, Scott WK, Vance JM, Slifer MA, Gwirtsman HE, Gilbert JR, Haines JL, Buxbaum JD, Pericak-Vance MA (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6:e1001130. https://doi.org/10.1371/journal.pgen.1001130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, de Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JSK, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, Green RC, Rogaeva E, George-Hyslop PS, Arnold SE, Barber R, Beach T, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Cummings JL, DeCarli C, DeKosky ST, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman AP, Lopez OL, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Parisi JE, Perl DP, Peskind E, Petersen RC, Poon WW, Quinn JF, Rajbhandary RA, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, van Deerlin VM, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Cantwell LB, Dombroski BA, Beekly D, Lunetta KL, Martin ER, Kamboh MI, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43:436–441. https://doi.org/10.1038/ng.801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nasreddine ZS, Phillips NA, Bédirian Vé, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H (2005) The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695–699. https://doi.org/10.1111/j.1532-5415.2005.53221.x

    Article  PubMed  Google Scholar 

  • Pericak-Vance MA, Haines JL (1995) Genetic susceptibility to Alzheimer disease. Trends Genet 11:504–508

    Article  CAS  PubMed  Google Scholar 

  • Qianyi X et al (2015) Risk prediction for sporadic Alzheimer’s disease using genetic risk score in the Han Chinese population. Oncotarget 6:36955–36964. https://doi.org/10.18632/oncotarget.6271

    Article  Google Scholar 

  • Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RLH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA (2007) GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 54:713–720. https://doi.org/10.1016/j.neuron.2007.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocca WA, Petersen RC, Knopman DS, Hebert LE, Evans DA, Hall KS, Gao S, Unverzagt FW, Langa KM, Larson EB, White LR (2011) Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 7:80–93. https://doi.org/10.1016/j.jalz.2010.11.002

    Article  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Rodriguez E et al (2013) Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer’s disease. J Neural Transm 120:807–812. https://doi.org/10.1007/s00702-012-0920-x

  • Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Piacentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, George-Hyslop PHS (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376:775–778

    Article  CAS  PubMed  Google Scholar 

  • Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S (2016) Van der Flier WM Alzheimer’s disease. Lancet 388:505–517. https://doi.org/10.1016/S0140-6736(15)01124-1

    Article  CAS  PubMed  Google Scholar 

  • Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano A, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT Jr, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn C, Breteler MM, CHARGE Consortium, GERAD1 Consortium, EADI1 Consortium (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. Jama 303:1832–1840. https://doi.org/10.1001/jama.2010.574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760

    Article  CAS  PubMed  Google Scholar 

  • Sherrington R et al (1996) Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet 5:985–988

    Article  CAS  PubMed  Google Scholar 

  • Shi Z, Yu H, Wu Y, Ford M, Perschon C, Wang C, Zheng SL, Xu J (2019) Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer’s disease. Clin Genet 95:302–309. https://doi.org/10.1111/cge.13479

    Article  CAS  PubMed  Google Scholar 

  • Sleegers K, Bettens K, de Roeck A, van Cauwenberghe C, Cuyvers E, Verheijen J, Struyfs H, van Dongen J, Vermeulen S, Engelborghs S, Vandenbulcke M, Vandenberghe R, de Deyn PP, van Broeckhoven C (2015) A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Abeta42. Alzheimers Dement 11:1452–1460. https://doi.org/10.1016/j.jalz.2015.02.013

    Article  PubMed  Google Scholar 

  • Stocker H, Möllers T, Perna L, Brenner H (2018) The genetic risk of Alzheimer’s disease beyond APOE ε4: systematic review of Alzheimer’s genetic risk scores. Transl Psychiatry 8:166. https://doi.org/10.1038/s41398-018-0221-8

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 9:546–553. https://doi.org/10.1016/j.jalz.2012.08.007

    Article  PubMed  Google Scholar 

  • Tosto G, Fu H, Vardarajan BN, Lee JH, Cheng R, Reyes-Dumeyer D, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Elkind MSV, Wright CB, Sacco RL, Pericak-Vance M, Farrer L, Rogaeva E, St George-Hyslop P, Reitz C, Mayeux R (2015) F-box/LRR-repeat protein 7 is genetically associated with Alzheimer’s disease. Annals of clinical and translation Ann Clin Trans Neurol 2:810–820. https://doi.org/10.1002/acn3.223

  • Tosto G, Bird TD, Tsuang D, Bennett DA, Boeve BF, Cruchaga C, Faber K, Foroud TM, Farlow M, Goate AM, Bertlesen S, Graff-Radford NR, Medrano M, Lantigua R, Manly J, Ottman R, Rosenberg R, Schaid DJ, Schupf N, Stern Y, Sweet RA, Mayeux R (2017) Polygenic risk scores in familial Alzheimer disease. Neurology 88:1180–1186

    Article  PubMed  PubMed Central  Google Scholar 

  • Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016) The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 18:421–430. https://doi.org/10.1038/gim.2015.117

    Article  PubMed  Google Scholar 

  • Vergara IA, Norambuena T, Ferrada E, Slater AW, Melo F (2008) StAR: a simple tool for the statistical comparison of ROC curves. BMC bioinf 9:265–265. https://doi.org/10.1186/1471-2105-9-265

  • Wang HZ, Bi R, Hu QX, Xiang Q, Zhang C, Zhang DF, Zhang W, Ma X, Guo W, Deng W, Zhao L, Ni P, Li M, Fang Y, Li T, Yao YG (2016) Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations. Mol Neurobiol 53:379–390. https://doi.org/10.1007/s12035-014-9015-z

    Article  CAS  PubMed  Google Scholar 

  • Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Backman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC (2004) Mild cognitive impairment--beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. J Intern Med 256:240–246. https://doi.org/10.1111/j.1365-2796.2004.01380.x

    Article  CAS  PubMed  Google Scholar 

  • Yan J, Aliev F, Webb BT, Kendler KS, Williamson VS, Edenberg HJ, Agrawal A, Kos MZ, Almasy L, Nurnberger JI Jr, Schuckit MA, Kramer JR, Rice JP, Kuperman S, Goate AM, Tischfield JA, Porjesz B, Dick DM (2014) Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. Addict Biol 19:708–721. https://doi.org/10.1111/adb.12035

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama JS, Bonham LW, Sears RL, Klein E, Karydas A, Kramer JH, Miller BL, Coppola G (2015) Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease. BMC Neurol 15:47. https://doi.org/10.1186/s12883-015-0304-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We are grateful to all the subjects for participating in our study.

Funding

This project was supported by research grants awarded by the National Natural Science Foundation of China (No. 81360177) and the Inner Mongolia Autonomous Region Natural Science Foundation (No. 2015MS(LH)0813), supported by Inner Mongolia science and technology plan (No. 20130402), and the Inner Mongolia Autonomous Region Natural Science Foundation (No. 2014MS0848).

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    1. Southern Medical University, Guangzhou, China

      Chunyu Zhang & Xiaokun Qi

    2. Neurology Department, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China

      Chunyu Zhang & Xiaokun Qi

    3. Department of Neurology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China

      Chunyu Zhang, Riletemuer Hu, Guohua Zhang, Yan Zhe, Baolige Hu, Juan He & Zhiguang Wang

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    Zhang, C., Hu, R., Zhang, G. et al. A Weighted Genetic Risk Score Based on Four APOE-Independent Alzheimer’s Disease Risk Loci May Supplement APOE E4 for Better Disease Prediction. J Mol Neurosci 69, 433–443 (2019). https://doi.org/10.1007/s12031-019-01372-2

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