Nat Neurosci︱ Down-regulation of neuroimmunity and synapse-related pathways in the amygdala and anterior cingulate gyrus in patients with bipolar disorder

Written by ︱Tong editor ︱Sizhen Wang Bipolar disorder (BD) is a highly heritable serious mental illness, and its heritability is as high as 80%[1]
.

A recent study by the Psychiatric Genomics Consortium reported 31 genome-wide significant loci and 850 potential loci [2]
.

However, the variants identified by genome-wide association study (GWAS) analysis were mainly at common loci, which could only explain the effect of a small number of genes on BD, and the mechanisms by which these genes increase the risk of BD are still unclear
.

 On March 7, 2022, Thomas M.
Hyde's team at the Johns Hopkins School of Medicine in the United States published an article entitled "Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways" in Nature Neuroscience, A series of transcriptomic analysis of RNA-seq was performed on human BD samples, and it was found that biological processes related to neuroimmunity and synaptic signaling were down-regulated in BD patients, which provided an evidence base for subsequent molecular biology studies [3]
.

 The researchers collected a total of 511 samples of the anterior cingulate cortex (sACC) and amygdala from 295 individuals (138 in the experimental group and 157 in the control group) to study two brain regions, the anterior cingulate cortex.
268 samples and 243 amygdala samples
.

 First, the authors tested differences in gene, transcript, exon, and connectivity expression profiles in two brain regions between BD patients and neural normal controls
.

962 genes showed significant differences in expression between the two groups (Fig.
1a), of which 86.
8% were protein-coding genes, and the rest were long non-coding RNA (IncRNA) (6%) and other non-coding sequences, but Only a few differential genes (41) were expressed in both sACC and amygdala (Fig.
1a–b)
.

Figure 1 Differentially expressed genes in BD patients (Source: Zandi, et al.
, Nat Neurosci, 2022) In order to further study the biological significance of these genes, the researchers used weighted gene co-expression network analysis (WGCNA) to study the relationship between these genes and the relationship between BDs
.

The module consisting of 579 genes was significantly associated with BD, and its genes were generally down-regulated (Fig.
2a).
This module contained the enrichment of microglia-specific genes (such as P2RY12), and the GO analysis results showed that this module was in the Enriched in many immune- and inflammation-related pathways (Fig.
2b)
.

This module also includes genes related to Alzheimer's disease (such as A2M, TREM2, CTSB, PLCG2), and genes related to NF-κB (CD4, IKBKB, CX3CR1, PYCARD, NFKBID, SYK, BLNK, TNFAIP8L2) (Fig.
2c)
.

Another BD-related module consisted of 224 genes, which were down-regulated in BD, and GO analysis showed that the genes of this module were mainly enriched in synapse-related pathways (Fig.
2d–f)
.

Figure 2 WGCNA analysis results of differential genes (source: Zandi, et al.
, Nat Neurosci, 2022) Transcriptomic differences between BD patients and control groups may be related to the etiology or consequence of the disease, in order to further study may lead to the occurrence of BD Quantitative trait loci (QTL), including cis-expressed QTL (cis eQTL) or splicing QTL (sQTL), were analyzed at BD loci previously associated with GWASs. .

Similar to the transcriptomic differential expression analysis, there were more significant QTLs in the sACC than in the amygdala, but there was a large overlap in the two brain regions
.

Among the 881 GWAS loci, 172 loci (33.
2%) have significant cis eQTL and sQTL in at least one brain region, of which 16 (51.
6%) are genome-wide significant loci, suggesting that there are 156 loci (32.
0%)
.

Table 1 shows the results for 9 single genes involved in 16 genomically important loci
.

Two of these genes, SCN2A and GRIN2A, are associated with synaptic membrane channels
.

Table 1 cis eQTL of significant loci in GWAS (FDR < 1%) (Table source: Zandi, et al.
, Nat Neurosci, 2022) The gene SCN2A currently contains 18 annotated transcript isoforms, of which 9 encode proteins transcript (Fig.
3a), the alternative allele rs17183814[G:A] of the major SNP site at this locus is a missense coding variant, that is, the R19K0 variant causes the arginine at position 19 of the normal SCN2A protein to be replaced by Lysine substitution, this variant is associated with a reduced risk of BD
.

Another gene, GRIN2A, had 15 transcript mutants in the genome database, including seven protein-coding transcripts (Fig.
3b), and these transcript mutants were associated with reduced expression of exon 11 of its normal transcript
.

Figure 3.
SNP loci with significant eQTL or sQTL and gene visualization map of accompanying SNP signatures (Source: Zandi, et al.
, Nat Neurosci, 2022) Finally, the researchers evaluated the genes by transcriptome association study analysis (TWAS).
Whether expression levels correlate with BD
.

Among 13,822 genes, we identified 247 genes (155 in sACC and 125 in amygdala) that were significantly associated with BD disorder (FDR < 5%) (Fig.
4)
.

Figure 4 Scatter plot of ACC and amygdala gene TWAS results (Source: Zandi, et al.
, Nat Neurosci, 2022) Conclusion and discussion, inspiration and prospect BD) related human brain sample library, through the analysis of differential genes in large samples and quantitative trait locus (QTL) analysis, the changes in the transcriptome of BD patients have been comprehensively explored, which is helpful for further elucidating the mechanism of BD occurrence and development.
Transcriptome changes of these genes are instructive in the risk of BD and provide a more solid basis for BD treatment
.

 But at the same time, this work is only at the stage of data analysis, and the researchers have not conducted further research
.

For example, there are microglia-specific genes among the differential genes they found.
What role do microglia play in the occurrence and development of BD? How is the NF-κB signaling pathway involved in BD? These are for further study
.

Link to the original text: https://doi.
org/10.
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2-3 Tencent Online) References (swipe up and down to view) [1] Craddock N, Sklar P.
Genetics of bipolar disorder [J].
The Lancet, 2013, 381(9878): 1654-62.
[2]Stahl EA, Breen G, Forstner AJ, et al.
Genome-wide association study identifies 30 loci associated with bipolar disorder [J].
Nature Genetics, 2019, 51(5): 793-803.
[3]Zandi PP, Jaffe AE, Goes FS, et al.
Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways [J].
Nat Neurosci, 2022, 25(3): 381-9.
Edition ︱Sizhen Wang End of this paper