Functional Characterization of Genetic Variant Effects on Expression

Flynn, Elise; Lappalainen, Tuuli

doi:10.1146/annurev-biodatasci-122120-010010

Cited by 13 publications

(11 citation statements)

References 172 publications

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“…One way to connect GWAS-reported genetic variants with effects on gene function is to associate the genetic polymorphisms with eQTLs. [81] eQTLs with a higher probability to directly impact gene expression variation tend to be found in open chromatin regions, such as promoters and enhancers, [82] supporting the hypothesis of a possible effect through changes on regulatory mechanisms. Studies of natural genetic variation through eQTLs thus provide important insights into the mechanisms of specific diseases and gene control, and can point to the possible gene regulatory function of specific sequences based on their allelic associations with gene expression.…”

Section: Genetic Variation At Epromoters Might Have Pleiotropic Rolesmentioning

confidence: 86%

Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Malfait,

Wan,

Spicuglia

2023

BioEssays

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Precise spatiotemporal control of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis‐regulatory elements. Recent studies have reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opened novel questions regarding the complexity of our genome and raises the possibility that genetic variation within Epromoters has pleiotropic effects on various physiological and pathological traits by differentially impacting multiple proximal and distal genes. Here, we discuss the different observations pointing to an important role of Epromoters in the regulatory landscape and summarize the evidence supporting a pleiotropic impact of these elements in disease. We further hypothesize that Epromoter might represent a major contributor to phenotypic variation and disease.

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Section: Genetic Variation At Epromoters Might Have Pleiotropic Rolesmentioning

confidence: 86%

Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Malfait,

Wan,

Spicuglia

2023

BioEssays

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“…ISG15 rs4615788 C/G (5′‐UTR), rs1921 G/A (Exon 2), and rs8997 A/G (Exon 2) polymorphisms were genotyped. SNPs distributed in different gene regions such as promoters, exons, and introns as well as 5′‐ and 3′‐untranslated regions (UTRs) can affect gene expression and function 28 . Since these investigated polymorphisms resided in 5′‐UTR and exons of the ISG15 gene may play a pivotal role in gene functions, it is possible that these SNPs might affect the ISG15 gene expression and immune responses.…”

Section: Methodsmentioning

confidence: 99%

Interferon‐stimulated gene 15 polymorphisms are associated with spontaneous preterm birth in Taiwanese women

Chang,

Wang,

Kuo

et al. 2023

American J Rep Immunol

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ProblemImmune and inflammatory responses are known to be major causes of preterm birth (PTB). The maternal genetic background plays an important role in the development of PTB. Interferon‐stimulated gene 15 (ISG15) is an interferon‐induced protein which can modulate immune cell activation and function. We aim to study if polymorphisms in the ISG15 gene are associated with spontaneous PTB (sPTB) risk in Taiwanese women.Method of studyISG15 rs4615788 C/G, rs1921 G/A, and rs8997 A/G polymorphisms were genotyped in a hospital‐based study of 112 women with sPTB and 1120 term controls. The plasma concentrations of ISG15 were determined by enzyme‐linked immunosorbent assay.ResultsWe found the ISG15 rs1921 G‐rs8997 A haplotype was associated with decreased risk for PTB (χ2 = 6.26, p = .01, pc = .04). The A/G genotype of ISG15 rs8997 polymorphism might have the potential to confer reduced risk of PTB women (χ2 = 4.09, p = .04, pc = .08). Spontaneous PTB women displayed higher plasma ISG15 levels compared to term controls (p < .001). The plasma ISG15 levels among pregnant women with rs8997 A/G genotype were found significantly lower compared to G/G genotype (p = .03).ConclusionsWomen with the ISG15 rs1921 G‐rs8997 A haplotype may associate with spontaneous PTB. These findings provide new insights into the etiology of preterm birth.

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“…Genome-wide association studies (GWASs) have successfully linked tens of thousands of loci to complex human traits and diseases 1,2 , providing a glimpse into the biological underpinnings of these phenotypes and motivating the development of targeted therapeutics 2–7 . Pinpointing the exact causal variant at each locus, a critical step for understanding how individual variants and genes contribute to genetic risk 8–11 , has proven a more elusive task 12,13 . Unlike classical Mendelian disease genetics, the majority of loci associated with complex human traits have individually small effect sizes 14,15 and do not directly modify the sequences governing the splicing of an mRNA transcript or the amino acid composition of a protein.…”

Section: Mainmentioning

confidence: 99%

Functional dissection of complex and molecular trait variants at single nucleotide resolution

Siraj,

Castro,

Dewey

et al. 2024

Preprint

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Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

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Functional Characterization of Genetic Variant Effects on Expression

Cited by 13 publications

References 172 publications

Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Interferon‐stimulated gene 15 polymorphisms are associated with spontaneous preterm birth in Taiwanese women

Functional dissection of complex and molecular trait variants at single nucleotide resolution

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