In this study, 478 ET patients and 505 controls of Chinese origin were screened for 25 anxiety-related risk variants. Six SNPs (rs1187280, rs16879771, rs3807866, rs708012, rs7309727 and rs78602344) were identified as being associated with ET in the dominant model and/or recessive model. Among them, four SNPs of rs1187280, rs3807866, rs6557168 and rs708012 were associated with the occurrence of ET in the eastern China by allelic analysis. All of them presented compelling support for a genetic overlap between ET and anxiety disorders.
The frequency of rs1187280 T allele was significantly lower in the ET patients compared to age-matched controls, indicating a protective role. This SNP is located in an intron of the protein coding gene Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2), which encodes the TrkB protein and mainly expressed in the central nervous system. Brain derived neurotrophic factor (BDNF) is one member of the neurotrophin family of secreted growth factors19. NTRK2 (formerly TrkB) is one of its receptor20. They have also been associated with a multitude of pathologies including but not limited to Alzheimer’s disease, Parkinson’s disease, epileptic encephalopathy and depression21, 22. Pathologically, circadian control of BDNF-mediated nuclear factor-E2-related factor 2 (Nrf2) activation via the truncated form of TrkB in astrocytes protects dopaminergic neurons from ferroptosis23. In addition, MPTP-induced reduction of tyrosine hydroxylase (TH) in the striatum and substantia nigra (SNr) was attenuated by administration of (R)-ketamine via TrkB activation24. Genetically, patients with epilepsy exhibit a higher prevalence of the T/T genotype in NTRK2 rs10868235 compared to controls24. Until now, there is no evidence to support the role of NTRK2 polymorphisms in ET, thus further investigations with larger sample sizes and diverse ancestries are warranted to validate this finding.
On the contrary, the frequency of rs3807866 T allele in TMEM106B (Transmembrane Protein 106B) gene was significantly higher in the ET patients than age-matched controls, suggesting a risk factor. The TMEM106B gene encodes a type II transmembrane glycoprotein24. In 2010, SNPs of rs1020004, rs6966915, and rs1990622 (top SNP) in TMEM106B were identified to be associated with frontal temporal dementia (FTD)28. Then, it was also demonstrated that the p.T185S coding variant was associated with FTLD-TDP risk by regulating TMEM106B protein levels29. Recently, the rs1990622T allele has been identified as a potential contributor to progressive cognitive decline in individuals with PD30. Aged TMEM106B knockout (KO) mice displayed different behavioral deficits including motor impairment accompanied by Purkinje cells and reactive gliosis in the cerebellum. Although the involvement of TMEM106B in PD has been established, its potential role in ET remains uncertain. A more extensive sample and further pathological research of ET are recommanded.
Similar to TMEM106B rs3807866, a higher proportion of ET patients exhibited the minor allele of ESR1 rs6557168 compared to controls (38.3% vs. 33.3%; p<0.05). ESR1 encodes oestrogen receptor alpha (ERα) that mediates the physiological effects of estradiol-17-β including neuroprotective and antiapoptotic effects32. As it is well-established, there exists an association between ESR1 and the risk of PD. Some ESR1 polymorphism, such as rs3798577, rs1709183, rs9322335, rs6912184, rs2347923, have been significantly associated with altered risk of PD since 2010.33, 34. Additionally, ESR1 rs6557168 was shown to be related to anxiety disorders through GWAS analysis in 2019. Our study also demonstrated the significant role of ESR1 rs6557168 in ET. However, further functional study of the SNP and additional supporting evidence from diverse ethnic populations are imperative for comprehensive understanding.
The association of rs708012 with ET was found to be significantly in both the dominant and recessive models. And the frequency of rs708012 C allele was significantly lower in ET patients compared to age-matched controls, indicating a potential protective role. MTCH1 and FGD2 were two of genes that near rs708012. The mitochondrial carrier 1 (MTCH1) is a protein-coding gene and originally described as the interactor of presenilin 1. It is also referred to as presenilin 1-associated protein (PSAP)36. Interestingly, genetic studies have identified the potential pathogenic variants within specific PSAP domains in PD, like rs4747203 and rs88582837. However, the role of rs708012 in ET needs to be further studied.
To the best of our knowledge, this study represents the first attempt to investigate whether patients with ET exhibit a genetic predisposition to anxiety. However, it is important to acknowledge certain limitations in this study. Firstly, the sample size of the ET population was relatively small and only 47.28% had a documented family history of the condition. Additionally, we solely relied on the HAMA to assess anxiety levels in these patients and most not having a diagnosed anxiety disorder at the time of evaluation. Secondly, our analysis focused exclusively on risk variants associated with anxiety disorders that have been identified through linkage studies, WES, WGS, and GWAS. Given that research on genetic factors contributing to anxiety remains limited overall, our understanding of potential genetic overlaps between ET and anxiety is inherently constrained as well. Nevertheless, this study offers preliminary evidence supporting a possible genetic association between ET and anxiety.
In conclusion, our data show that rs3807866 in the TMEM106B gene and rs6557168 in ESR1 increases the risk for ET in the eastern China and that the other two SNPs of rs1187280 (in NTRK2) and rs708012 (near MTCH1 and FDG2) show a protective role. Our study is the first to explore the relationship between anxiety and ET through genetic analysis. However, the limited sample size and racial heterogeneity have hindered the robustness of these associations. Further replication analyses are required to completely elucidate the potential involvement of anxiety-related SNPs in ET.