Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci

Dudding, Tom; Haworth, Simon; Lind, Penelope A.; Sathirapongsasuti, J. Fah; Tung, Joyce Y.; Mitchell, Ruth; Colodro‐Conde, Lucía; Medland, Sarah E.; Gordon, Scott D.; Elsworth, Benjamin; Paternoster, Lavinia; Franks, Paul W.; Thomas, Steven J.; Martin, Nicholas G.; Timpson, Nicholas J.

doi:10.1038/s41467-019-08923-6

Cited by 62 publications

(87 citation statements)

References 75 publications

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“…Host immunogenetics likely play a critical role in the pathogenesis of oral mucosal inflammatory disease as recently confirmed by a genome‐wide association study which identified 97 genetic variants independently associated with recurrent aphthous stomatitis (Dudding et al., 2019). Future studies should investigate how these genetic variants relate to the structure of the oral microbiota.…”

Section: Discussionmentioning

confidence: 89%

Oral bacterial diversity is inversely correlated with mucosal inflammation

et al. 2020

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Objective We investigated the relationship amongst the oral mucosal bacterial community, clinical severity and inflammatory markers in the two most common immune‐mediated oral mucosal diseases, namely recurrent aphthous stomatitis (RAS) and oral lichen planus (LP). Methods Patients with RAS (n = 15) and LP (n = 18) and healthy controls (n = 13) were recruited using criteria to reduce the effect of factors that influence the microbiota structure independently of oral mucosal disease. Clinical severity was quantified using validated scoring methods. DNA was extracted from oral mucosal swabs for 16S rRNA gene high‐throughput sequencing. Salivary cytokines were measured using cytometric bead assays. Correlation studies were conducted amongst microbial diversity, clinical scores and cytokine concentrations. Results We observed a significant reduction of bacterial diversity in LP and RAS patients compared to controls (p = .021 and .044, respectively). Reduced bacterial diversity in LP and RAS correlated with increased clinical scores of the two conditions (⍴ = −0.551 to −0.714). A negative correlation was observed between microbial diversity and salivary interferon‐γ, interleukin‐17A and interleukin‐1β (⍴ = −0.325 to −0.449). Conclusions This study reports reduced oral microbial diversity in the context of increased mucosal inflammation and supports the role for microbial diversity as a marker or contributor to oral mucosal inflammatory disease activity and development.

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Section: Discussionmentioning

confidence: 89%

Oral bacterial diversity is inversely correlated with mucosal inflammation

et al. 2020

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“…The genotyping and quality control (QC) protocol for the target sample have been described previously 34,45 . Briefly, standard protocols for DNA collection and extraction were used.…”

Section: Prs Target Sample the Target Sample Consisted Of Individualmentioning

confidence: 99%

Genetic aetiology of self-harm ideation and behaviour

Campos

Verweij

Statham

et al. 2020

Sci Rep

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Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. in the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (pRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. Snp heritability (h snp 2) estimates were ~10%, and both traits were highly genetically correlated (LDSC r g > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant. Every year nearly one million people take their own lives 1 , making suicide a pressing issue of considerable social and economic burden. Moreover, self-harm behaviours are now recognized by the American Psychiatric Association as independent conditions for further study. Namely, non-suicidal self-injury and suicidal behaviour disorder were recently introduced in the section 3 of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) 2. The lifetime prevalence estimate for suicide thoughts is ~10%, while suicide attempt and non-suicidal self-harm (NSSH) affect ~2.5 and ~5% of the population, respectively 3-5. Higher rates have been reported amongst children and adolescents 6. The key difference between suicidal and non-suicidal self-harm is that the former implies an intent to die as a consequence of the act. Non-suicidal self-harm acts include equally dangerous behaviours such as cutting, burning or poisoning, but are underlined by a different motivation such as seeking attention or the desire to feel pain. Twin and family studies indicate that NSSH, suicide thoughts and suicide attempt are moderately heritable 7,8. Multiple studies have documented that the presence of a psychiatric disorder considerably increases the risk for both suicidal and non-...

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“…For these 89 lead SNPs, we found one stop gained variant, one splice region variant, one non-coding transcript exon variant, three missense variants, five untranslated region variants, 14 regulatory region variants, 24 intergenic variants, and 40 intron variants ( Supplementary Table 4). Dudding et al conducted GWAS of oral ulcers based on the UK Biobank Project, and found 97 independent lead variants 4 . There were 37 lead SNPs which we also found in comparison with the 97 variants discovered by Dudding et al (Supplementary Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…The genetic data of European populations in 1000G phase3 21 were viewed as reference data to conduct LD analyses. Besides, 24 SNPs reported by Dudding and colleagues 4 which reached GWA significant P-values and displayed the same effect directions in different independent populations were defined as lead SNPs, as shown in Supplementary Table 2.…”

Section: Identification Of Genes and Their Roles In Oral Ulcers Usingmentioning

confidence: 99%

Gene mapping and functional annotation of GWAS of oral ulcers using FUMA software

Jin

Wang

Zhang

et al. 2020

Sci Rep

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Oral ulcers not only influence the physical health of patients, but they also interfere with their quality of life. However, the exact etiology of oral ulcers is not clear. To explore the roles of genetic factors in oral ulcers, a genome-wide association study of the condition in European individuals was re-evaluated by the FUMA v1.3.5e online tool. A total of 380 independent significant single nucleotide polymorphisms (SNPs) and 89 lead SNPs were identified in 34 genomic risk loci. Out of these identified genomic risk loci, 280 possible causal genes were pinpointed by positional mapping and expression quantitative trait locus mapping. Among these genes, 216 novel genes were identified. Furthermore, some genomic loci were mapped to a single gene. Functional annotation of these prioritized genes revealed that the immune response pathway was implicated in the onset of oral ulcers. Overall, our findings revealed novel possible causal genes and demonstrated that the immune response has a crucial role in the occurrence of oral ulcers. The oral ulcer is an ulcer that occurs on the mucous membrane of the oral cavity. Nearly one-quarter of young adults and many children are affected by this condition 1,2. Recurrent aphthous stomatitis (RAS) refers to a chronic inflammatory, ulcerative condition of the oral cavity. RAS is characterized by the recurrent outbreak of ulcers and erosions 1. It is one of the most common causes of oral ulcers, and its prevalence in populations is 5-20% 3. Even though several factors have been implicated in RAS (e.g., trauma, bacterial/viral infections, anaphylaxis, autoimmune diseases), the exact etiology of this condition is not clear. Dudding and colleagues stated that immune regulation exerts important influences on RAS onset 4. Besides, family-based studies have revealed that genetic factors also have pivotal roles in RAS etiopathogenesis 5-7. Genome-wide association studies can be used to assess associations between SNPs and traits/diseases by detecting a multitude of genetic variants in individuals with different phenotypes. Also, it is beneficial to discern possible causal variants and the genetic architecture of the disease of interest. Dudding et al. re-analyzed data of GWAS of oral ulcers in the UK Biobank Project. They found some genetic variants associated with oral ulcers. Then, they replicated these variants in another novel cohort and assessed the effects of these variants in other populations 4. Overall, they revealed that 97 variants were related to RAS risk, and that T cell regulation was implicated in RAS 4. Even though GWAS can provide many disease-associated genetic loci, it may be difficult to determine possible causal mutations because identified genetic variants may be situated in non-coding regions 8 , or be in complete linkage disequilibrium (LD) with unknown causal variants 9. Recently, researchers have started to focus on roles of the non-coding regulatory regions in the etiopathogenesis of complex diseases. For example, by assessing mRNA expression data in zebrafish...

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Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci

Cited by 62 publications

References 75 publications

Oral bacterial diversity is inversely correlated with mucosal inflammation

Oral bacterial diversity is inversely correlated with mucosal inflammation

Genetic aetiology of self-harm ideation and behaviour

Gene mapping and functional annotation of GWAS of oral ulcers using FUMA software

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