More than 60 independent single-nucleotide polymorphisms (SNPs) have been associated with Alzheimer's disease risk by genome-wide association studies in European.
Objective
We aimed to confirm these SNPs in Chinese Han populations and investigate the utility of these genetic markers.
Methods
Altogether 1595 late-onset Alzheimer's disease (LOAD) patients and 2474 controls from Chinese population were recruited. We replicated the association of 68 SNPs with LOAD and established polygenetic risk score (PRS) prediction model using significant SNPs. Meta-analysis for MS4A6A rs610932 and PICALM rs3851179 were performed.
Results
According to our findings, 14 out of 68 SNPs are validated significantly associated with LOAD (adjusted p < 0.05) after adjusting age and sex in the Chinese population. Besides, after stratification by APOE ε4 status, almost all SNPs retain markedly relationship with LOAD in APOE ε4 noncarriers. However, few loci retain correlation in APOE ε4 carriers. Furthermore, the area under the receiver operating characteristic curve prediction model for distinguishing LOAD patients from normal subjects were 0.614 for PRS and 0.689 for PRS and APOE. In addition, meta-analysis including this study of East Asian populations confirmed that rs610932 and rs3851179 were dramatically related to the LOAD (OR = 0.85, 95% CI = 0.74-0.97; OR = 0.87, 95% CI = 0.83-0.91).
Conclusions
Despite genetic heterogeneity, there are still common loci among different races. PRS based on AD risk-associated SNPs may supplement APOE for better assessing individual risk for AD in Chinese. Besides, interactions between genes and gene environment affect the impact of risk allele on diverse populations.
World Health Organization. Global status report on the public health response to dementia. Geneva: World Health Organization, 2021.
2.
JiaLDuYChuL, et al.Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health2020; 5: e661–e671.
3.
HarmanD. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci2006; 1067: 454–460.
4.
NajACSchellenbergGD. Genomic variants, genes, and pathways of Alzheimer's disease: an overview. Am J Med Genet B Neuropsychiatr Genet2016; 174: 5–26.
5.
GatzMReynoldsCAFratiglioniL, et al.Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry2006; 63: 168–174.
6.
JiaLXuHChenS, et al.The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease. Alzheimers Dement2020; 16: 1613–1623.
7.
QinWLiWWangQ, et al.Race-related association between APOE genotype and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis2021; 83: 897–906.
8.
KunkleBWGrenier-BoleyBSimsR, et al.Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet2019; 51: 414–430.
9.
HollingworthPHaroldDSimsR, et al.Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet2011; 43: 429–435.
10.
WightmanDPJansenIESavageJE, et al.A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet2021; 53: 1276–1282.
11.
AlmeidaJFFdos SantosLRTrancozoM, et al.Updated meta-analysis of BIN1, CR1, MS4A6A, CLU, and ABCA7 variants in Alzheimer’s disease. J Mol Neurosci2018; 64: 471–477.
12.
HaroldDAbrahamRHollingworthP, et al.Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet2009; 41: 1088–1093.
13.
HaoXWangALiC, et al.Genetic association of BIN1 and GAB2 in Alzheimer's disease: a meta-analysis and systematic review. Geriatr Gerontol Int2020; 21: 185–191.
14.
YiH-CYouZ-HHuangD-S, et al.A deep learning framework for robust and accurate prediction of ncRNA-protein interactions using evolutionary information. Mol Ther Nucleic Acids2018; 11: 337–344.
15.
BaoWJiangZHuangD-S. Novel human microbe-disease association prediction using network consistency projection. BMC Bioinformatics2017; 18: 543.
16.
BellenguezCKüçükaliFJansenIE, et al.New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet2022; 54: 412–436.
17.
MiyashitaAKoikeAJunG, et al.SORL1 Is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One2013; 8: e58618.
18.
TanLYuJTZhangW, et al.Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population. Alzheimers Dement2012; 9: 546–553.
WangH-ZBiRHuQ-X, et al.Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations. Mol Neurobiol2014; 53: 379–390.
21.
SchultzLMMerikangasAKRuparelK, et al.Stability of polygenic scores across discovery genome-wide association studies. HGG Adv2022; 3: 100091.
22.
BrayneCDesikanRSFanCC, et al.Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med2017; 14: e1002258.
23.
JiaLLiFWeiC, et al.Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study. Brain2021; 144: 924–937.
24.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer's disease: recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 263–269.
25.
McKhannGDrachmanDFolsteinM, et al.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. Neurology1984; 34: 939–944.
26.
ChangCCChowCCTellierLCAM, et al.Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience2015; 4: 7.
27.
NasiriHForouzandehMRasaeeMJ, et al.Modified salting-out method: high-yield, high-quality genomic DNA extraction from whole blood using laundry detergent. J Clin Lab Anal2005; 19: 229–232.
28.
SangerFNicklenSCoulsonAR. DNA Sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA1977; 72: 5463–5467.
29.
LiFXieSCuiJ, et al.Polygenic risk score reveals genetic heterogeneity of Alzheimer’s disease between the Chinese and European populations. J Prev Alzheimers Dis2024; 11: 701–709.
30.
ZhouYZhouBPacheL, et al.Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun2019; 10: 1523.
31.
DengY-LLiuL-HWangY, et al.The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer’s disease. Hum Genet2012; 131: 1245–1249.
32.
JuanH. Association analysis of eight gene variations with Alzheimer's disease susceptibility in Northern Chinese populations. Thesis, Ningxia Medical University, China, 2014.
33.
XiaoyanL. Association analysis of late-onset Alzheimer's disease and susceptibility genes in Chinese Han population. Thesis, Central South University, China, 2014.
34.
LixiaW. The association of PICALM gene rs541458 and rs3851179 polymorphisms study for Alzheimer disease in different ethnic groups of Dali district. Thesis, Dali University, China,2015.
35.
OharaTNinomiyaTHirakawaY, et al.Association study of susceptibility genes for late-onset Alzheimer’s disease in the Japanese population. Psychiatr Genet2012; 22: 290–293.
36.
YuJ-TSongJ-HMaT, et al.Genetic association of PICALM polymorphisms with Alzheimer's disease in Han Chinese. J Neurol Sci2011; 300: 78–80.
37.
LiH-LShiS-SGuoQ-H, et al.PICALM And CR1 variants are not associated with sporadic Alzheimer's disease in Chinese patients. J Alzheimers Dis2011; 25: 111–117.
38.
JiaoBLiuXZhouL, et al.Polygenic analysis of late-onset Alzheimer’s disease from Mainland China. PLoS One2015; 10: e0144898.
39.
ChenLHKaoPYPFanYH, et al.Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population. Neurobiol Aging2012; 33: 210.e211–210.e217.
40.
DingD. Population-based prevalence survey and genetic epidemiology of cognitive impairment among elderly. Thesis, Fudan University, China,2012.
41.
XiaoQLiuZJTaoS, et al.Risk prediction for sporadic Alzheimer's disease using genetic risk score in the Han Chinese population. Oncotarget2015; 6: 36955–36964.
42.
LewisCMVassosE. Polygenic risk scores: from research tools to clinical instruments. Genome Med2020; 12: 44.
43.
DehghaniNBrasJGuerreiroR. How understudied populations have contributed to our understanding of Alzheimer’s disease genetics. Brain2021; 144: 1067–1081.
44.
ZhuZYangYXiaoZ, et al.TOMM40 And APOE variants synergistically increase the risk of Alzheimer’s disease in a Chinese population. Aging Clin Exp Res2020; 33: 1667–1675.
45.
JiangTTanLChenQ, et al.A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging2016; 42: 217.e211–217.e213.
46.
JiaLFuYShenL, et al.PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement2020; 16: 178–191.
47.
HanZWangTTianR, et al.BIN1 Rs744373 variant shows different association with Alzheimer’s disease in Caucasian and Asian populations. BMC Bioinformatics2019; 20: 691.
48.
ZhouXChenYMokKY, et al.Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis. Proc Natl Acad Sci U S A2018; 115: 1697–1706.
49.
FrickEAEmilssonVJonmundssonT, et al.Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease. Nat Aging2024; 4: 1446–1464.
50.
LiY-QTanM-SWangH-F, et al.Common variant in PTK2B is associated with late-onset Alzheimer’s disease: a replication study and meta-analyses. Neurosci Lett2016; 621: 83–87.
51.
KarahanHSmithDCKimB, et al.The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies. Front Immunol2023; 14: 1102530.
52.
BalesKRVerinaTCumminsDJ, et al.Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A1999; 96: 15233–15238.
53.
HouTLiuKFaW, et al.Association of polygenic risk scores with Alzheimer's disease and plasma biomarkers among Chinese older adults: a community-based study. Alzheimers Dement2024; 20: 6669–6681.
54.
KikuchiMMiyashitaAHaraN, et al.Polygenic effects on the risk of Alzheimer’s disease in the Japanese population. Alzheimers Res Ther2024; 16: 45.
55.
Escott-PriceVSimsRBannisterC, et al.Common polygenic variation enhances risk prediction for Alzheimer’s disease. Brain2015; 138: 3673–3684.
56.
LeonenkoGBakerEStevenson-HoareJ, et al.Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores. Nat Commun2021; 12: 4506.
57.
StockerHPernaLWeiglK, et al.Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years. Mol Psychiatry2020; 26: 5812–5822.
58.
LicherSAhmadSKaramujić-ČomićH, et al.Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat Med2019; 25: 1364–1369.
59.
DengSPZhuLHuangDS. Predicting hub genes associated with cervical cancer through gene co-expression networks. IEEE/ACM Trans Comput Biol Bioinform2016; 13: 27–35.
60.
RamirezLMGoukasianNPoratS, et al.Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy. Neurobiol Aging2016; 39: 82–89.
61.
LiuGXuYJiangY, et al.PICALM Rs3851179 variant confers susceptibility to Alzheimer’s disease in Chinese population. Mol Neurobiol2016; 54: 3131–3136.
62.
AndoKNagarajSKüçükaliF, et al.PICALM And Alzheimer’s disease: an update and perspectives. Cells2022; 11: 3994.
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