Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus

Khunsriraksakul, Chachrit; Li, Qinmengge; Markus, Havell; Patrick, Matthew; Sauteraud, Renan; McGuire, Daniel; Wang, Xianyou; Wang, Chen; Wang, Lida; Chen, Siyuan; Shenoy, Ganesh; Li, Bingshan; Zhong, Xue; Olsen, Nancy J.; Carrel, Laura; Tsoi, L.C.; Jiang, Bibo; Liu, Dajiang

doi:10.1038/s41467-023-36306-5

Cited by 27 publications

(18 citation statements)

References 131 publications

(179 reference statements)

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“…Both mouse and human studies corroborate the role of T cells as central players in RA pathogenesis (21–23). Similarly, for systemic lupus erythematosus (SLE), studies have identified an enrichment of B cell-specific putative regulatory elements and gene expression in SLE risk loci (19,20,24,25) consistent with the well-established role of B cells in SLE pathogenesis (26,27). Hence, there is precedence that the integration of GWAS with functional genomics datasets can identify cellular drivers in inflammatory diseases with complex pathogenesis.…”

Section: Introductionmentioning

confidence: 63%

Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Chiñas,

Fernandez-Salinas,

Aguiar

et al. 2023

Preprint

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ObjectiveMultiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased integrative functional genomics approach.MethodsWe integrated GWAS data with epigenomic and transcriptomic datasets of immune cells in healthy humans. To quantify enrichment of cell type-specific open chromatin regions or gene expression in AS risk loci, we used three published methods which have identified cell types for other diseases. Additionally, we performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes of AS risk variants.ResultsNatural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Expression levels of AS-associated genes, such asRUNX3,TBX21,TNFRSF1A, andNPEPPS, were found to be highest in NK cells compared to five T cell subsets. Using the human Space-Time Gut Cell Atlas we found significant upregulation of AS-associated genes predominantly in NK cells. Co-localization analysis revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci,ERAP1 and TNFRSF1A, and two under-studied loci,ENTR1(akaSDCCAG3) andB3GNT2.ConclusionOur results point to NK cells as potential key drivers in the development of AS and highlight four putative target genes for functional follow-up in NK cells.

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Section: Introductionmentioning

confidence: 63%

Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Chiñas,

Fernandez-Salinas,

Aguiar

et al. 2023

Preprint

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“…When we performed the colocalization at increasing tertiles of the perturbation score within the NP-state (NP T1 -NP T3 ) and P-state (P T1 -P T3 ) ( METHODS ), we found that the eQTL signal for PXK colocalized in the lowest tertile of the NP cells (colocalization Pr NPT1 =53.1% Figure 5 f ). PXK encodes a sorting nexin (SNX) protein important for receptor internalization, organelle trafficking including endosomal trafficking 31 , and it has been previously implicated in the risk of SLE 32,33 . Our results shows that genetic regulation of PXK is particularly strong in lowly perturbed cell states.…”

Section: Resultsmentioning

confidence: 99%

Modeling heterogeneity in single-cell perturbation states enhances detection of response eQTLs

Valencia,

Nathan,

Kang

et al. 2024

Preprint

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Identifying response expression quantitative trait loci (reQTLs) can help to elucidate mechanisms of disease associations. Typically, such studies model the effect of perturbation as discrete conditions. However, perturbation experiments usually affect perturbed cells heterogeneously. We demonstrated that modeling of per-cell perturbation state enhances power to detect reQTLs. We use public single-cell peripheral blood mononuclear cell (PBMC) data, to study the effect of perturbations withInfluenza A virus(IAV),Candida albicans(CA),Pseudomonas aeruginosa(PA), andMycobacterium tuberculosis(MTB) on gene regulation. We found on average 36.9% more reQTLs by accounting for single cell heterogeneity compared to the standard discrete reQTL model. For example, we detected a decrease in the eQTL effect of rs11721168 forPXKin IAV. Furthermore, we found that on average of 25% reQTLs have cell-type-specific effects. For example, in IAV the increase of the eQTL effect of rs10774671 forOAS1was stronger in CD4+T and B cells. Similarly, in all four perturbation experiments, the reQTL effect forRPS26was stronger in B cells. Our work provides a general model for more accurate reQTL identification and underscores the value of modeling cell-level variation.

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“…Additionally, the long non-coding RNA C5orf56 (5q31) has been identified for its protective role in IBD [ 97 ]. SCHIP1 (3q25) has been associated with SLE [ 98 ], while RNASET2 (6q27) has been identified as a risk gene for both vitiligo [ 99 ] and GD [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis

Yu,

Chen,

Chen

et al. 2024

BMC Med

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Background To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. Methods Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. Results Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10–8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. Conclusions Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

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Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus

Cited by 27 publications

References 131 publications

Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Modeling heterogeneity in single-cell perturbation states enhances detection of response eQTLs

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis

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