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- Bonfiglio, Ferdinando, et al.
(författare)
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GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome
- 2021
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Ingår i: Cell Genomics. - Cambridge, MA, United States : Elsevier. - 2666-979X. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
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- Zheng, Tenghao, et al.
(författare)
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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
- 2024
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Ingår i: Journal of Crohn's and Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 18:3, s. 349-359
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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| 7. |
- Zheng, Tenghao
(författare)
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Identification and functional characterization of irritable bowel syndrome (IBS) risk genes and variants
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As one of the most prevalent functional gastrointestinal disorders (FGIDs), irritable bowel syndrome (IBS) affects more than 10% of the general population worldwide with a higher prevalence in women. The primary clinical manifestation of IBS is chronic abdominal pain or discomfort associated with changes in stool frequency and appearance. IBS is the second leading cause of work absenteeism after colds and has remarkable effects on the socioeconomic system. The pathophysiology of IBS has not been fully clarified yet, including various peripheral and central mechanisms. From the late 1980s, genetic predisposition to IBS has been demonstrated by family and twin studies. Several candidate genes have been linked to IBS susceptibility including TNFSF15, NPSR1, SCN5A, TRPM8, and SI. Moreover, a few underpowered genome-wide association studies (GWAS) have been performed to investigate IBS genetics in population-based cohorts. However, to date, no unequivocal genetic factor has been confirmed yet. In this thesis, we aim to identify risk genes and variants associated with IBS and to characterize their functional roles. The first part focuses on the role of genetic variations in the sucrase-isomaltase (SI) gene and IBS susceptibility. In the second part, the hypothesisfree GWAS approaches are implemented to detect IBS risk genes and variants in large-scale powered cohorts. In Paper I, we have exploited a two-step computational strategy to study the prevalence of SI rare pathogenic variants (SI-RPVs) in 2207 tertiary IBS patients. The prevalence of selected SI-RPVs in all IBS patients is 3.99%, which is significantly higher than the reference population (P=0.00049). This study has provided supporting evidence that links carrying SIRPVs to increased risk of IBS. Paper II has investigated the effects of SI functional variants in the response to dietary intervention in IBS patients. The genotypes of SI hypomorphic variants were obtained for a group of IBS-D patients previously treated with a low FODMAP diet in a clinical trial. After stratifying IBS patients into carriers and non-carriers of SI hypomorphic variants, we have observed significantly lower efficiency of low FODMAP diet in carriers compared to noncarriers (P=0.031). These findings suggest that SI genotype data may contribute to identifying individuals with higher chances to benefit from such dietary interventions. In Paper III, we have performed a GWAS of self-reported IBS exploiting the large population-based UK Biobank. After quality control, the association analysis has been carried out in 9,576 IBS patients and 336,499 controls via logistic regression. Genome-wide significant signals have been identified on chromosome 9q31.2, and sex-stratified analysis suggests this locus is female-specific. This finding has been further supported by replication evidence from analyses in a pooled cohort with multi-national tertiary IBS cases and controls and a Swedish population-based cohort. In the end, IBS GWAS and their meta-analyses have been performed in large-scale multinational tertiary IBS cases and controls from European countries and the US in Paper IV. We have identified two novel genome-wide significant loci in IBS-D meta-analyses, and the results from functional annotation and PheWAS screening have suggested the association of these loci with altered metabolic and immune activities as well as psychiatric conditions. Ion channel biology was also highlighted as plausible pathways linked to IBS. Taken together, this thesis has provided new insight that improves current understanding of genetic predisposition to IBS. In the long run, the discovery of IBS predisposing genes and variants may have a significant impact on IBS management, since it is expected to allow patients stratification and therefore increase the specificity and efficacy of treatment.
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