Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

Rao, Shuquan; Yao, Yao; Bauer, Daniel E.

doi:10.1186/s13073-021-00857-3

Cited by 49 publications

(28 citation statements)

References 147 publications

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“…Consistently, clinical trials targeting IL-1β in UC pancolitis are currently in progress today [49]. Functional genetics could substantially facilitate the assessment of clinical implication of IBD-associated genetic variation, thus contributing to the urging need for redefining of this entity [50,51]; hopefully, these latter have been the topics of two recently published studies [52,53].…”

Section: Discussionmentioning

confidence: 96%

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

Papadopoulos

Antoniadou

Ritis

et al. 2022

JGLD

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Background and Aims: Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease (IBD) patients. We aimed to provide further evidence regarding a potential correlation between MEFV gene mutations and IBD by identifying all relevant studies and analyzing their results. Methods: EMBASE, PubMed/MEDLINE, and Google Scholar were used to identify all studies that published until January 2021 and reported MEFV mutation patterns in patients with ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC) with or without a control group. The Newcastle-Ottawa quality assessment scale was used to appraise the quality of the included studies. Results: Thirteen observational studies, including 937 patients and 977 controls, were analyzed. MEFV mutation rate in IBD patients was 0.238 (95%CI: 0.209-0.270; I 2 =95%); MEFV mutated alleles were more frequent in IBD patients when compared with controls (p=0.03 for UC, p=0.01 for CD and IC). Subgroup analysis indicated that MEFV mutations were increased in patients with IC when compared with UC and CD (I 2 =91%, p<0.001). Patients with extra-intestinal manifestations and pancolitis had 2.57 (95%CI 1.07-6.14; p=0.03) and 2.02 (95%CI: 1.01-4.04, P=0.049) odds ratios to carry MEFV mutant genotypes, respectively. Exon 10 mutations had the most serious impact. No source of heterogeneity was detected. Conclusions: MEFV mutations are common in IBD and are linked with the presence of extra-intestinal manifestations and pancolitis. Further research to assess the clinical significance and evolutionary significance of MEFV mutations in IBD patients is warranted.

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Section: Discussionmentioning

confidence: 96%

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

Papadopoulos

Antoniadou

Ritis

et al. 2022

JGLD

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“…The field of genetics as applied to complex traits has started to move beyond the identification of genetic associations and toward the elucidation of the mechanisms through which genetic variants confer risk (34, 35). However, a significant impediment to accomplishing this task is the fact that a strength GWAS studies, which leverage LD to identify regions conferring genetic risk, is also a weakness, in that the SNPs that tag genetic risk loci are in LD with dozens, sometimes hundreds, of other SNPs, most of which have no influence at all on disease risk.…”

Section: Discussionmentioning

confidence: 99%

“…Another important limitation to this approach is the fact that MPRA may not detect effects as they would occur in native chromatin (35, 39). This limitation may lead to both false positives and false negatives.…”

Section: Discussionmentioning

confidence: 99%

A Systematic Strategy for Identifying Causal Single Nucleotide Polymorphisms and Their Target Genes on Juvenile Arthritis Risk Haplotypes

Jiang

Liu

Kales

et al. 2022

Preprint

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Introduction: Although genome-wide association studies (GWAS) multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes. Methods: We used a massively parallel reporter assay (MPRA) in myeloid K562 cells to query the effects of 5,226 SNPs in non-coding regions on JIA risk haplotypes for their ability to alter gene expression when compared to the common allele. The assay relies on 180 bp oligonucleotide reporters (oligos) in which the allele of interest is flanked by its cognate genomic sequence. Barcodes were added randomly by PCR to each oligo to achieve >20 barcodes per oligo to provide a quantitative read-out of gene expression for each allele. Assays were performed in both unstimulated K562 cells and cells stimulated overnight with interferon gamma (IFNg). As proof of concept, we then used CRISPRi to demonstrate the feasibility of identifying the genes regulated by enhancers harboring expression-altering SNPs. Results: We identified 553 expression-altering SNPs in unstimulated K562 cells and an additional 490 in cells stimulated with IFNg. We further filtered the SNPs to identify those plausibly situated within functional chromatin, using open chromatin and H3K27ac ChIPseq peaks in unstimulated cells and open chromatin plus H3K4me1 in stimulated cells. These procedures yielded 42 unique SNPs (total = 84) for each set. Using CRISPRi, we demonstrated that enhancers harboring MPRA-screened variants in the TRAF1 and LNPEP/ERAP2 loci regulated multiple genes, suggesting complex influences of disease-driving variants. Conclusion: Using MPRA and CRISPRi, JIA risk haplotypes can be queried to identify plausible candidates for disease-driving variants. Once these candidate variants are identified, target genes can be identified using CRISPRi informed by the 3D chromatin structures that encompass the risk haplotypes.

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“…The majority of GWAS reports on variants found in intergenic and intronic regions, limiting their interpretability [15 52]. Identifying a gene from the variant(s) in GWAS necessitates additional evidence such as physical distances between the variants and the transcript start site, the location of regulatory regions (e.g., enhancers, chromatin), and other factors [38]. In fact, with over 1100 loci with leading SNPs, the transcriptome-wide summary statistics-based Mendelian randomization (TWMR) method [39] showed that 71% of the genes closest to that SNP do not show significant association with the tested phenotype.…”

Section: Discussionmentioning

confidence: 99%

Recessive and sex-dependent genetic effects in primary hypertension

Zucker

Linial

2022

Preprint

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BackgroundEssential hypertension is a polygenic disease that affects almost half of the adult population in the USA. It is a major risk factor for renal, cerebrovascular, and cardiovascular diseases. Previous studies used UK-Biobank (UKB) GWAS results for hypertension to create a polygenic risk score (PRS), with the top and bottom 5% of the PRS translating to a 4-fold difference in the estimated risk. The heritability of hypertension is estimated to be high (30–60%), yet the underlying mechanisms and the associated genes are largely unknown.MethodsIn this study, we used a gene-based method, the proteome-wide association study (PWAS), to detect associations mediated by the effects of variants on protein function. PWAS was applied to individuals of European ancestry from the UKB, with 74,090 cases of clinical diagnosis of essential (primary) hypertension (ICD-10, I10) and 200,734 controls. PWAS aggregates the signal from all variants affecting each coding gene and provides scores for dominant, recessive, and hybrid genetic heritability.ResultsPWAS identified 70 statistically significant associated genes (FDR-q-value <0.05) and 127 genes with a weaker threshold (FDR-q-value <0.1). The overlap with GWAS summary statistics (total 1,362 genes) is only partial, with 23 and 62 genes identified exclusively by PWAS from a total of 70 and 127 genes, respectively), among them 18% were assigned recessive inheritance. Furthermore, PWAS analysis, separately performed on females and males from UKB genotyping imputed data, revealed sex-dependent genetics. There are 22 genes unique in females, with only 2 in males. We identified 6 female-specific genes that were not identified by PWAS for the entire group (70 genes). Only one associated gene (SH2B3) is shared between the sexes. Many of the female-significant genes from PWAS are enriched in cellular immunity functions.ConclusionsWe conclude that hypertension displays sex-dependent genetics with an overlooked recessive inheritance, postulating that the underlying mechanism is substantially different for males and females. Studying hypertension by a gene-based association method improves interpretability and clinical utility.

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Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

Cited by 49 publications

References 147 publications

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

A Systematic Strategy for Identifying Causal Single Nucleotide Polymorphisms and Their Target Genes on Juvenile Arthritis Risk Haplotypes

Recessive and sex-dependent genetic effects in primary hypertension

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