Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia

Li, Quan‐Lin; Chen, Weifeng; Wang, Cheng; Liu, Zuqiang; Gu, Yayun; Xu, Xiaoyue; Xu, Jiaxing; Jiang, Tao; Xu, Mei‐Dong; Wang, Yifeng; Chen, Congcong; Zhong, Yun‐Shi; Zhang, Yiqun; Yao, Ling; Jin, Guangfu; Hu, Zhibin; Zhou, Ping‐Hong

doi:10.1016/j.ajhg.2021.06.004

Cited by 10 publications

(15 citation statements)

References 52 publications

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“…[44][45][46] Vackova et al 47 performed the first genotype-phenotype analysis to investigate the frequency of an insertion variant (rs28688207) in HLA-DQB1, and found that the distribution of the insertion was significantly different across the HRM subtypes, being the most prevalent in type I, followed by type II and III. A whole-exome sequencing study conducted by Li et al 48 also identified a missense variant (rs1126511) in the HLA region in patients with achalasia. The protein tyrosine phosphatase N22 (PTPN22) gene, another immune-related gene, which encodes a lymphoid-specific phosphatase that downregulates T cell activation, 49 is associated with systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases.…”

Section: Genetic Association Analysis Studiesmentioning

confidence: 99%

“… 44 - 46 Vackova et al 47 performed the first genotype-phenotype analysis to investigate the frequency of an insertion variant (rs28688207) in HLA-DQB1, and found that the distribution of the insertion was significantly different across the HRM subtypes, being the most prevalent in type I, followed by type II and III. A whole-exome sequencing study conducted by Li et al 48 also identified a missense variant (rs1126511) in the HLA region in patients with achalasia.…”

Section: Pathogenesismentioning

confidence: 99%

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Achalasia: The Current Clinical Dilemma and Possible Pathogenesis

Jia

Chen

Zhuang

et al. 2023

J Neurogastroenterol Motil

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Achalasia is a primary esophageal motility disorder manifested by dysphagia and chest pain that impair patients' quality of life, and it also leads to chronic esophageal inflammation by food retention and increases the risk of esophageal cancer. Although achalasia has long been reported, the epidemiology, diagnosis and treatment of achalasia are not fully understood. The current clinical dilemma of achalasia is mainly due to its unclear pathogenesis. In this paper, epidemiology, diagnosis treatment, as well as possible pathogenesis of achalasia will be reviewed and summarized. The proposed hypothesis on the pathogenesis of achalasia is that genetically susceptible populations potentially have a higher risk of infection with viruses, triggering autoimmune and inflammation responses to inhibitory neurons in lower esophageal sphincter.

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Section: Genetic Association Analysis Studiesmentioning

confidence: 99%

Section: Pathogenesismentioning

confidence: 99%

Achalasia: The Current Clinical Dilemma and Possible Pathogenesis

Jia

Chen

Zhuang

et al. 2023

J Neurogastroenterol Motil

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“…DEGs for the Dormant (O1) subcluster encompass Ankrd36, whose mutation has been implicated in diminished ovarian reserve [33], as well as Pm20d1, which has been noted for its potential involvement in the pathogenesis of polycystic ovary syndrome [34,35] (Fig 5D). DEGs for the Activated-Ctrl (O2) subcluster contain famous oocyte-specific genes typically found in mature oocytes like Dppa5a, Kpna7, Khdc3 and Nlrp4a [36][37][38][39], whereas the Activated-cKO (O3) subcluster showed lower expression of these genes (Fig 5D).…”

Section: Transcriptomic Consequences In Oocytes That Are Impacted By ...mentioning

confidence: 99%

Transcriptomic Signatures of WNT-Driven Pathways and Granulosa Cell-Oocyte Interactions during Primordial Follicle Activation

Takase,

Mishina,

Hayashi

et al. 2024

Preprint

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Primordial follicle activation (PFA) is a pivotal event in female reproductive biology, coordinating the transition from quiescent to growing follicles. This study employed comprehensive single-cell RNA sequencing to gain insights into the detailed regulatory mechanisms governing the synchronized dormancy and activation between granulosa cells (GCs) and oocytes with the progression of the PFA process.Wntless(Wls) conditional knockout (cKO) mice served as a unique model, suppressing the transition from pre-GCs to GCs, and disrupting somatic cell-derived WNT signaling in the ovary. Our data revealed immediate transcriptomic changes in GCs post-PFA inWlscKO mice, leading to a divergent trajectory, while oocytes exhibited modest transcriptomic alterations. Subpopulation analysis identified the molecular pathways affected by WNT signaling on GC maturation, along with specific gene signatures linked to dormant and activated oocytes. Despite minimal evidence of continuous up-regulation of dormancy-related genes in oocytes, the loss of WNT signaling in (pre-)GCs impacted gene expression in oocytes even before PFA, subsequently influencing them globally. The infertility observed inWlscKO mice was attributed to compromised GC-oocyte molecular crosstalk and the microenvironment for oocytes. Our study highlights the pivotal role of the WNT-signaling pathway and its molecular signature, emphasizing the importance of intercellular crosstalk between (pre-)GCs and oocytes in orchestrating folliculogenesis.Author summaryIn mammalian ovaries, primordial follicles protect dormant oocytes from wasteful consumption. We explored the complex molecular dynamics of the critical process of primordial follicle activation (PFA) that underlies female reproductive health, with a focus on the role of WNT signaling. By utilizing a unique mouse model with disrupted WNT signaling, our study reveals novel insights into the regulatory dynamics of granulosa cells (GCs) and oocytes during PFA. Single-cell transcriptome profiling uncovered distinct cell populations and highlighted the impact of WNT signaling on ovarian cell types. This study reveals distinct transcriptomic changes in GCs post-PFA, which affects their differentiation trajectories and highlights the critical role of WNT signaling in establishing GC function. We further examined the consequences of disrupted microenvironments on oocytes and GC-oocyte interactions, which elucidated altered oocyte subclusters and potential links to infertility. These findings provide a foundation for understanding the connections between WNT signaling and ovarian function. Our comprehensive analysis contributes valuable knowledge to reproductive biology, emphasizing the clinical relevance of WNT signaling in female fertility.

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“…We next built a disease-associated list of genes for each DGBI by combining the genes annotated to significant SNPs (category 1), z-score filtered genes/transcripts from gene-based testing (category 2), and previously published GWAS results for related GI disorders 24,25,[27][28][29][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] (category 3)(Figure 2B-D). The published category contained an expanded list of other potentially related disease categories, including achalasia, constipation, Hirschsprung's disease and IBS (Figure 2D).…”

Section: Identification Of Genetic Variants and Genes Associated With...mentioning

confidence: 99%

Combined GWAS and single cell transcriptomics uncover the underlying genes and cell types in disorders of gut-brain interaction

Majd

Richter

Samuel

et al. 2023

Preprint

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Disorders of gut-brain interaction (DGBIs), formerly known as functional gastrointestinal disorders, are extremely common and historically difficult to manage. This is largely because their cellular and molecular mechanisms have remained poorly understood and understudied. One approach to unravel the molecular underpinnings of complex disorders such as DGBIs is performing genome wide association studies (GWASs). However, due to the heterogenous and non-specific nature of GI symptoms, it has been difficult to accurately classify cases and controls. Thus, to perform reliable studies, we need to access large patient populations which has been difficult to date. Here, we leveraged the UK Biobank (UKBB) database, containing genetic and medical record data of over half a million individuals, to perform GWAS for five DGBI categories: functional chest pain, functional diarrhea, functional dyspepsia, functional dysphagia, and functional fecal incontinence. By applying strict inclusion and exclusion criteria, we resolved patient populations and identified genes significantly associated with each condition. Leveraging multiple human single-cell RNA-sequencing datasets, we found that the disease associated genes were highly expressed in enteric neurons, which innervate and control GI functions. Further expression and association testing-based analyses revealed specific enteric neuron subtypes consistently linked with each DGBI. Furthermore, protein-protein interaction analysis of each of the disease associated genes revealed protein networks specific to each DGBI, including hedgehog signaling for functional chest pain and neuronal function and neurotransmission for functional diarrhea and functional dyspepsia. Finally, through retrospective medical record analysis we found that drugs that inhibit these networks are associated with an increased disease risk, including serine/threonine kinase 32B drugs for functional chest pain, solute carrier organic anion transporter family member 4C1, mitogen-activated protein kinase 6, and dual serine/threonine and tyrosine protein kinase drugs for functional dyspepsia, and serotonin transporter drugs for functional diarrhea. This study presents a robust strategy for uncovering the tissues, cell types, and genes involved in DGBIs, presenting novel predictions of the mechanisms underlying these historically intractable and poorly understood diseases.

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Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia

Cited by 10 publications

References 52 publications

Achalasia: The Current Clinical Dilemma and Possible Pathogenesis

Achalasia: The Current Clinical Dilemma and Possible Pathogenesis

Transcriptomic Signatures of WNT-Driven Pathways and Granulosa Cell-Oocyte Interactions during Primordial Follicle Activation

Combined GWAS and single cell transcriptomics uncover the underlying genes and cell types in disorders of gut-brain interaction

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