doi:10.1093/brain/awaa364 BRAIN 2020: Page 1 of 14 | 1 Prediction of Alzheimer’s disease using Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaa364/5981992 by guest on 15 November 2020 multi-variants from a Chinese genome-wide association study Longfei Jia,1 Fangyu Li,1 Cuibai Wei,1 Min Zhu,1 Qiumin Qu,2 Wei Qin,1 Yi Tang,1 Luxi Shen,1 Yanjiang Wang,3 Lu Shen,4 Honglei Li,5 Dantao Peng,6 Lan Tan,7 Benyan Luo,8 Qihao Guo,9 Muni Tang,10 Yifeng Du,11 Jiewen Zhang,12 Junjian Zhang,13 Jihui Lyu,14 Ying Li,1 Aihong Zhou,1 Fen Wang,1 Changbiao Chu,1 Haiqing Song,1 Liyong Wu,1 Xiumei Zuo,1 Yue Han,1 Junhua Liang,1 Qi Wang,1 Hongmei Jin,1 Wei Wang,1 Yang Lu¨,15 Fang Li,16 Yuying Zhou,17 Wei Zhang,18,19 Zhengluan Liao,20 Qiongqiong Qiu,1 Yan Li,1 Chaojun Kong,1 Yan Li,1 Haishan Jiao,1 Jie Lu21,22 and Jianping Jia1,23,24,25 Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of dis- ease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease –19 and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 Â 10 , 2.49 Â 10–23, 1.35 Â 10–67, and 4.81 Â 10–9, respectively) as well as nine variants in the apolipoprotein E region with genome- wide significance (P 5 5.0 Â 10–8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the develop- ment of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate lon- gitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contri- butions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical appli- cation of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seek- ing genetic consultation. 1 Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China 2 Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, Shaanxi, China 3 Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China 4 Department of Neurology, Xiangya Hospital, Central South University, Changsha, China 5 Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, China 6 Department of Neurology, China-Japan Friendship Hospital, Beijing, China Received February 14, 2020. Revised July 30, 2020. Accepted August 14, 2020. VC The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 2 | BRAIN 2020: Page 2 of 14 L. Jia et al. 7 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong, China 8 Department of Neurology, The First Affiliated Hospital, Zhejiang University, Zhejiang, China 9 Department of Gerontology, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, China 10 Department of Geriatrics, Guangzhou Huiai Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou, China 11 Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China 12 Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan, China 13 Department of Neurology, Zhongnan Hospital, Wuhan University, Hubei, China 14 Center for Cognitive Disorders, Beijing Geriatric Hospital, Beijing, China 15 Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 16 Department of Geriatric, Fuxing Hospital, Capital Medical University, Beijing, China Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaa364/5981992 by guest on 15 November 2020 17 Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China 18 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 19 Center for Cognitive Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 20 Department of Psychiatry, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China 21 Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China 22 Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China 23 Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China 24 Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China 25 Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China Correspondence to: Jianping Jia, MD, PhD Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Changchun Street 45, Xicheng District, Beijing, China, 100053 E-mail: [email protected] Correspondence may also be addressed to: Jie Lu, MD, PhD Department of Radiology, Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Changchun Street 45, Xicheng District, Beijing, China, 100053 E-mail: [email protected] Keywords: Alzheimer’s disease; genome-wide association study; Chinese; predictive model; longitudinal cohort Abbreviations: AUC = area under the curve; eQTL = expression quantitative trait loci; GWAS = genome-wide association study; SNP = single nucleotide polymorphism been identified in the Chinese population (Wang et al., Introduction 2016). A recent whole genome sequencing study in a Alzheimer’s disease is the most common type of dementia Chinese population identified variants in GCH1 and and is genetically complex with an estimated heritability of KCNJ15, in addition to the well-known apolipoprotein E 60–80% (Gatz et al.,1997). Previous genome-wide associ- (APOE) locus; however, the sample size of this study was ation studies (GWASs) of Alzheimer’s disease in Caucasian, relatively small (Zhou et al.,2018). African-American, and Asian populations have identified Recently, genetic predictive models have been established genetic risk variants in ABCA7, BIN1, CASS4, CD2AP, for predicting the onset of Alzheimer’s disease using a poly- CD33, CDK5RAP2, CELF1, CLU, COBL, CR1, genic risk score approach, which was used to reveal polygen- ECHDC3, EPHA1, EXOC3L2, FERMT2, HLA-DRB5, etic contributions to Alzheimer’s disease risk of common HLA-DRB1, HS3ST1, INPP5D, KANSL1, MEF2C, MS4A, single nucleotide polymorphisms (SNPs) that show a disease NME8, PICALM, PM20D1, PTK2B, SLC10A2, SLC24A4, association but fail to meet the accepted P-value threshold SORL1, TREM2,andZCWPW1 (Harold et al.,2009; for genome-wide significance (Escott-Price et al.,2015, Lambert et al., 2009, 2013a; Seshadri et al.,2010; 2017a, b, 2019; Chouraki et al.,2016; Stocker et al.,2018; Hollingworth et al.,2011; Naj et al.,2011; Guerreiro et al., Leonenko et al.,2019). These studies showed variable 2013; Miyashita et al.,2013; Reitz et al.,2013; Desikan results. Specifically, Escott-Price et al. reported that the area et al.,2015; Jun et al.,2016; Lacour et al.,2017; Miron under the curve (AUC) of their predictive models, which et al.,2018; Sanchez-Mut et al.,2018; Kunkle et al.,2019). included APOE, 480 000 SNPs, age, and sex as predictors, These variants affect several Alzheimer’s disease-related was 0.78, whereas in their other study, the AUC of their processes, such as lipid metabolism, inflammation, innate models including 420 000 SNPs and APOE as predictors immunity, production and clearance of amyloid-b,and increased to 0.84 as the included individuals were patho- endosomal vesicle recycling (Selkoe