Nat Genet︱GWAS analysis reveals a new gene (new protein) that has a clear causal relationship with Alzheimer's disease

And using rigorous academic and logical thinking to explore the mysteries of neuroscience.
Written by Wang Sizhen, edited by Wang Sizhen, Genome-Wide Association Studies (GWAS) refers to the study of the association between genes and diseases at the whole genome level.
This is a research method to find genetic factors related to complex diseases by performing genome-wide high-density genetic marker typing of large-scale population DNA samples, and comprehensively reveal genetic genes related to disease occurrence, development and treatment.

 Alzheimer’s disease (AD for short), commonly known as Alzheimer’s disease, as the name suggests, is one of the most common degenerative diseases of the central nervous system that occurs in the elderly, with an insidious onset and a chronic and progressive course [1].
There is no effective treatment.

 At present, through GWAS, many risk sites of AD genes have been identified, but we do not know how these risk sites affect AD [2-3].

Therefore, an in-depth understanding of their disease impact mechanisms will help us accurately recognize and treat AD.

 On January 28, 2021, Nature Genetics published online the latest research results of the Thomas S.
Wingo and Aliza P.
Wingo team of Emory University School of Medicine in the United States, entitled Integrating human brain proteomes with genome- wide association data implicates new proteins in Alzheimer's disease pathogenesis (Aliza Wingo is the first author of the article).

The research aims to identify new genes and new proteins in the occurrence of AD disease through human brain proteomics and GWAS analysis.

First, the author performed an integrated analysis of the AD GWAS results of Iris E.
Jansen et al.
(n=455,258) [2] and the human brain proteomic results (n=376), and found that 13 of them are significantly related to AD.
Genes (Table 1).

Then through Bayesian colocalization COLOC and Mendelian randomization (SMR) experiments, it was found that CTSH, DOC2A, ICA1L, LACTB, PLEKHA1, SNX32, STX4, ACE, CARHSP1, RTFDC1 and STX, these 11 genes are in cis It regulates the protein abundance in the brain and has obvious causal relationship with AD (Table 2).
At the same time, these 9 genes, namely CTSH, DOC2A, ICA1L, LACTB, SNX32, STX4, ACE, CARHSP1 and STX, are very good GWAS results repeatability (replication) (Table 3).

Table 1 Analysis of AD PWAS results showed that 13 genes were significantly related to AD (Table quoted from: Wingo, AP, Liu, Y.
, Gerasimov, ES et al.
.
Nat Genet 2021; 53: 143–146) Among the currently known AD risk genes, the APOE e4 allele has a strong correlation with AD, so the author further studied its influence on the results of PWAS.

It is found that the PWAS results are not affected by the APOE e4 gene, that is, the AD PWAS results have nothing to do with APOE e4, which also shows the objectivity of the PWAS results.

Table 2 Analysis of COLOC and SMR results showed that 11 genes have obvious causal relationship with AD (Table quoted from: Wingo, AP, Liu, Y.
, Gerasimov, ES et al.
.
Nat Genet 2021; 53: 143–146) Then How specific are these AD PWAS results? In other words, how representative or indicative of these results? The authors found that these AD PWAS results can represent 75% of clinical AD, 0% of amyotrophic lateral sclerosis (ALS, commonly known as gradual freezing), 5.
9% of Parkinson's (PD), 2.
8% of neuroticism, 1.
7% height, 1.
5% body mass index, and 0.
4% waist-to-hip ratio.

These results indicate the specificity of AD PWAS results.

(Supplement: Neuroticism, also known as neuroticism or emotional instability.
Neurotic people are more likely to be anxious, melancholy, angry, sad, and nervous than ordinary people; they will always be suddenly depressed, and suddenly become bad.
Return to normal) Table 3 Summary of relevant information about 11 genes that are causally related to AD (Table quoted from: Wingo, AP, Liu, Y.
, Gerasimov, ES et al.
.
Nat Genet 2021; 53: 143–146) These 11 genes have obvious causal relationship with AD.
So, is there a unified or corresponding relationship between their protein level and transcription level? The author found that ACE, CARHSP1, SNX32, STX4 and STX6, the protein levels of these five genes have a certain corresponding relationship with their transcription levels.
In other words, these five genes not only have a significant causal relationship with AD at the transcription level, but also At its protein level, there is also an obvious causal relationship with AD (Table 3).

 In addition, the analysis results also showed that DOC2A, ICA1L, PLEKHA1 and SNX32 are mainly enriched in excitatory neurons, CARHSP1 is mainly enriched in oligodendrocytes, and CTSH is mainly enriched in astrocytes and microglia.
There is obvious enrichment (Figure 1). Figure 1 Gene specific expression analysis in different cell types (picture quoted from: Wingo, AP, Liu, Y.
, Gerasimov, ES et al.
.
Nat Genet 2021; 53: 143–146) Conclusion and discussion In this study, through the analysis of AD brain protein abundance and AD PWAS analysis, 13 genes (or proteins) that affect the risk of AD were identified, 11 of which have obvious causal relationships with the onset of AD.

Moreover, this study provides new insights into the pathogenesis of AD, and provides a reference for further mechanism research and drug treatment.

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et al.
Alzheimer's disease.
Lancet 377, 1019–1031 (2011) [2] Jansen, IE et al.
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.
Nat.
Genet.
51,404–413 (2019).
[3] Kunkle, BW et al.
Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Nat.
Genet.
51, 414–430 (2019).
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