Professor Jianping Jia’s team from Xuanwu Hospital discovered four new risk gene loci in China’s first large-sample Alzheimer’s disease whole-genome association analysis (GWAS) and constructed an incidence prediction model based on them

In November 2020, the team of Professor Jianping Jia from Xuanwu Hospital published a paper entitled “Prediction of Alzheimer’s disease using multi-variants from a Chinese genome-wide association study” in “Brain” (IF: 11.337).Through China’s first large-sample genome-wide association study (GWAS) study, four new risk gene loci related to Alzheimer’s disease (AD) were discovered. And using these risk sites to establish a predictive model, verified in a cohort study, can effectively predict the incidence of AD. This not only provides East Asian data for global AD-related GWAS research, but also provides new genetic markers for early AD screening. The first author of the article is Jia Longfei, deputy chief physician of Xuanwu Hospital of Capital Medical University, and the corresponding author is Professor Jia Jianping.

AD is the most common type of Alzheimer’s, with greater genetic complexity. The GWAS study can find risk genes related to AD through case-control analysis. These genes affect the pathological changes and disease process of AD, including lipid metabolism, inflammation, innate immunity, production and removal of β-amyloid, etc., which are predictive AD has important meaning. However, most of the AD-related GWAS studies reported in the past were conducted in European and American countries, and China is still blank in this field. Not only that, the AD-related risk genes found abroad are rarely verified in the Chinese population, so there is a lack of predictive models that can predict the genetic risk of AD in Chinese.

This study conducted a two-stage GWAS study on a total of 11506 subjects (including 3,913 AD patients and 7,593 normal cognitive subjects) from multiple research centers across the country. In the first stage, 4187 subjects were genotyped for the whole genome, and in the second stage, 34 loci of 7319 subjects were genotyped. After Bonferroni correction, 13 sites finally reached the P cutoff value and passed the heterogeneity test. Further meta-analysis was performed on the first and second stages of 13 points, and the results all reached the GWAS significance threshold (P <5.0 × 10−8), which was further verified in the longitudinal cohort data. The two-phase GWAS study found 13 sites including 4 new sites (rs3777215, rs6859823, rs234434, and rs2255835) (Figure 1) and 9 sites in the APOE region. The results show that there is a large genetic heterogeneity between Chinese and Westerners. This study reveals the risk sites of AD with Chinese characteristics and provides important data for the prevention of AD in Chinese.

Figure 1. Regional association plots.

In order to further apply the discovered loci in the clinic, the study used 13 loci in different combinations to establish an AD genetic risk prediction model to obtain the best prediction effect with the least number of loci. In the end, it was found that 4 sites could be used to predict AD for APOE e4-negative population , and the area under the curve reached 0.73. This model can carry out genetic screening of young people, and provide early warning to APOE e4-positive population , which has important clinical significance for preventing the occurrence of AD.

This study was supported by the Key Project of the National Natural Science Foundation of China (81530036); the National Key Scientific Instrument and Equipment Development Project (31627803); Mission Program of Beijing Municipal Administration of Hospitals (SML20150801); Beijing Scholars Program; Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016, Z201100005520017, Z161100000216137); Project for Outstanding Doctor with Combined Ability of Western and Chinese Medicine; and Beijing Municipal Commission of Health and Family Planning (PXM2019_026283_000003) .

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