Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Wu, Yiming; Gettler, Kyle; Kars, Meltem Ece; Giri, Mamta; Li, Dalin; Bayrak, Çiğdem Sevim; Zhang, Peng; Jain, Aayushee; Maffucci, Patrick; Sabic, Ksenija; Vleck, Tielman Van; Nadkarni, Girish N.; Denson, Lee A.; Ostrer, Harry; Levine, Adam P.; Schiff, Elena R.; Segal, Anthony W.; Kugathasan, Subra; Stenson, Peter D.; Cooper, David Neil; Schumm, L. Philip; Snapper, Scott B.; Daly, Mark J.; Haritunians, Talin; Duerr, Richard H.; Silverberg, Mark S.; Rioux, John D.; Brant, Steven R.; McGovern, Dermot P.; Cho, Judy H.; Itan, Yuval

doi:10.1038/s41467-023-37849-3

Cited by 6 publications

(2 citation statements)

References 69 publications

(75 reference statements)

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“…To examine the genes that have a close biological relationship to the known IBD and PD genes, we generated sets of known genes. The set of 157 known IBD genes was generated based on studies of IBD, CD, and UC [ 35 , 36 ] following the methodology described in our previous study [ 37 ]. We included 142 genes from the merged signals of the genome-wide significant loci ( P < 5 × 10 −8 ) from Jostins et al [ 36 ], as well as 15 genes from the 95% credible set of the fine-mapping results by Huang et al [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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Background Inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. Methods We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. Results The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein–protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. Conclusions Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

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Section: Methodsmentioning

confidence: 99%

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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“…This obstacle was removed with the development of single-cell RNA sequencing (scRNA-seq), which has revolutionized transcriptome exploration on a single-cell resolution [ 35 ]. Moreover, studies deploying scRNA-seq technology in anti-TNFα IBD research are already driving in the direction of discovery to provide insights into the unique functional roles of individual cells in a high-dimensional space of data and contribute to a more complex understanding of biological processes and disease mechanisms [ 32 , 36 , 37 ]. However, these studies are being focused on tissues.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn’s Disease

Gorenjak,

Gole,

Goričan

et al. 2024

Pharmaceutics

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Background: The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn’s disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation.

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A novel Sagittaria sagittifolia L. polysaccharides mitigate DSS-induced colitis via modulation of gut microbiota and MAPK/NF-κB signaling pathways

Feng,

Chen,

Song

et al. 2024

International Journal of Biological Macromolecules

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Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Cited by 6 publications

References 69 publications

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn’s Disease

A novel Sagittaria sagittifolia L. polysaccharides mitigate DSS-induced colitis via modulation of gut microbiota and MAPK/NF-κB signaling pathways

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