Multiple Causal Variants Underlie Genetic Associations in Humans

DeGorter, Marianne K.; Gloudemans, Michael J.; Greenwald, Emily; Smith, Kevin S.; He, Zihuai; Montgomery, S

doi:10.1101/2021.05.24.445471

Cited by 22 publications

(32 citation statements)

References 72 publications

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“…The remarkable complexity in causal variants we uncovered underscores the challenge of predicting variant effects on UPS protein degradation. Similar to recent results 47, 85 , each of the four QTL regions we fine-mapped contained multiple causal variants in a single gene (Figures 3/4). In the case of NTA1 , we observed that the effect of the D111E variant was likely masked during QTL mapping by the larger effect of the E129G variant (Figure 4C), highlighting the need to test individual variants in isolation.…”

Section: Discussionsupporting

confidence: 85%

“…Previous efforts to understand how genetic variation influences gene expression have revealed considerable discrepancies between genetic effects on mRNA versus protein abundance [40][41][42][43][44][45][46][47][48] . Many gene expression QTLs alter protein abundance without detectable effects on mRNA levels.…”

Section: Protein-specific Effects Of Ubr1 -469a>t On Gene Expressionmentioning

confidence: 99%

“…Finally, we do not know how ge-netic effects on UPS activity influence other traits. For example, many genetic effects on gene expression influence protein levels without altering mRNA abundance for the same gene [40][41][42][43][44][45][46][47][48] . These protein-specific effects could arise through differences in UPS activity, but there have been no efforts to understand how natural variation that alters UPS activity influences global protein abundance.…”

Section: Introductionmentioning

confidence: 99%

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Variation in Ubiquitin System Genes Creates Substrate-Specific Effects on Proteasomal Protein Degradation

Collins

Mekonnen

Albert

2021

Preprint

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The ubiquitin-proteasome system (UPS) is the cell's primary pathway for targeted protein degradation. Although the molecular mechanisms controlling UPS activity are well-characterized, we have almost no knowledge of how these mechanisms are shaped by heritable genetic variation. To address this limitation, we developed an approach that combines fluorescent UPS activity reporters with a statistically powerful genetic mapping framework to comprehensively characterize genetic influences on UPS activity in the yeast Saccharomyces cerevisiae. We applied this approach to substrates of the UPS N-end rule, which relates a protein's degradation rate to the identity of its N-terminal amino acid ("N-degron") through the Arg/N-end and Ac/N-end pathways. Genetic influences on UPS activity were numerous and complex, comprising 149 loci influencing UPS activity across the 20 N-degrons. Many loci specifically affected individual pathways or degrons and multiple loci exerted divergent effects on distinct UPS pathways. One Arg/N-end pathway-specific locus resulted from multiple causal variants in the promoter, open reading frame, and terminator of the UBR1 E3 ubiquitin ligase gene. These variants differentially affected substrates bound by the Type 1 and Type 2 recognition sites of Ubr1p. Collectively, our results provide the first systematic characterization of genetic influences on UPS activity and a generalizable approach for mapping genetic effects on protein degradation with high statistical power and quantitative precision.

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Section: Discussionsupporting

confidence: 85%

Section: Protein-specific Effects Of Ubr1 -469a>t On Gene Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Variation in Ubiquitin System Genes Creates Substrate-Specific Effects on Proteasomal Protein Degradation

Collins

Mekonnen

Albert

2021

Preprint

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“…Our analysis shows that several credible set variants overlap either with transcription start sites or enhancer regions, providing additional support for potential causal variants. Considering recent studies, it is plausible that there are several tightly linked causal variants in each locus 55 and functional studies are needed for further fine-mapping.…”

Section: Discussionmentioning

confidence: 99%

GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

Koel

Võsa

Lepamets

et al. 2021

Preprint

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Background The uterine cervix has an important role in female reproductive health, but not much is known about the genetic determinants of cervical biology and pathology. Genome-wide association studies (GWAS) with increasing sample sizes have reported a few genetic associations for cervical cancer. However, GWAS is only the first step in mapping the genetic susceptibility and thus, the underlying biology in cervical cancer and other cervical phenotypes is still not entirely understood. Here, we use data from large biobanks to characterise the genetics of cervical phenotypes (including cervical cancer) and leverage latest computational methods and gene expression data to refine the association signals for cervical cancer. Methods Using Estonian Biobank and FinnGen data, we characterise the genetic signals associated with cervical ectropion (10,162 cases/151,347 controls), cervicitis (19,285/185,708) and cervical dysplasia (14,694/150,563). We present the results from the largest trans-ethnic GWAS meta-analysis of cervical cancer, including up to 9,229 cases and 490,304 controls from Estonian Biobank, the FinnGen study, the UK Biobank and Biobank Japan. We combine GWAS results with gene expression data and chromatin regulatory annotations in HeLa cervical carcinoma cells to propose the most likely candidate genes and causal variants for every locus associated with cervical cancer. We further dissect the HLA association with cervical pathology using imputed data on alleles and amino acid polymorphisms. Results We report a single associated locus on 2q13 for both cervical ectropion (rs3748916, p=5.1 x 10-16) and cervicitis (rs1049137, p=3.9 x 10-10), and five signals for cervical dysplasia - 6p21.32 (rs1053726, p=9.1 x 10-9; rs36214159, 1.6 x 10-22), 2q24.1 (rs12611652, p=3.2 x 10-9) near DAPL1, 2q13 ns1049137, p=6.4 x 10-9) near PAX8, and 5p15.33 (rs6866294, p=2.1 x 10-9), downstream of CLPTM1L. We identify five loci associated with cervical cancer in the trans-ethnic meta-analysis: 1p36.12 (rs2268177, p= 3.1 x 10-8), 2q13 (rs4849177, p=9.4 x 10-15), 5p15.33 (rs27069, p=1.3 x 10-14), 17q12 (rs12603332, p=1.2 x 10-9), and 6p21.32 (rs35508382, p=1.0 x 10-39). Joint analysis of dysplasia and cancer datasets revealed an association on chromosome 19 (rs425787, p=3.5 x 10-8), near CD70. Conclusions Our results map PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1, HLA-B, and GSDMB as the most likely candidate genes for cervical cancer, which provides novel insight into cervical cancer pathogenesis and supports the role of genes involved in reproductive tract development, immune response and cellular proliferation/apoptosis. We further show that PAX8/PAX8-AS1 has a central role in cervical biology and pathology, as it was associated with all analysed phenotypes. The detailed characterisation of association signals, together with mapping of causal variants and genes offers valuable leads for further functional studies.

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“…[6][7][8] However, linkage disequilibrium (LD) within each locus along with the presence of multiple causal alleles within or between cell types may skew the quantification of sharing of genetic effects between tissues and impede our ability to identify causal variants. Indeed, recent research has demonstrated that multiple causal variants are often present in many eQTL and complex-trait-associated loci, 9,10 suggesting that allelic heterogeneity may be more com-mon than previously anticipated and underscoring the importance of disentangling causal signals in high-LD regions. These complex patterns could hinder the identification of regulatory effects for disease-associated genetic variants, potentially obscuring both the relevant cell type and target gene.…”

Section: Introductionmentioning

confidence: 99%

Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity

Arvanitis

Tayeb

Strober

et al. 2022

The American Journal of Human Genetics

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Uncovering the functional impact of genetic variation on gene expression is important in understanding tissue biology and the pathogenesis of complex traits. Despite large efforts to map expression quantitative trait loci (eQTLs) across many human tissues, our ability to translate those findings to understanding human disease has been incomplete, and the majority of disease loci are not explained by association with expression of a target gene. Cell-type specificity and the presence of multiple independent causal variants for many eQTLs are potential confounders contributing to the apparent discrepancy with disease loci. In this study, we investigate the tissue specificity of genetic effects on gene expression and the overlap with disease loci while considering the presence of multiple causal variants within and across tissues. We find evidence of pervasive tissue specificity of eQTLs, often masked by linkage disequilibrium that misleads traditional meta-analytic approaches. We propose CAFEH (colocalization and fine-mapping in the presence of allelic heterogeneity), a Bayesian method that integrates genetic association data across multiple traits, incorporating linkage disequilibrium to identify causal variants. CAFEH outperforms previous approaches in colocalization and fine-mapping. Using CAFEH, we show that genes with highly tissue-specific genetic effects are under greater selection, enriched in differentiation and developmental processes, and more likely to be involved in human disease. Last, we demonstrate that CAFEH can efficiently leverage the widespread allelic heterogeneity in genetic regulation of gene expression to prioritize the target tissue in genome-wide association complex trait loci, thereby improving our ability to interpret complex trait genetics.

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Multiple Causal Variants Underlie Genetic Associations in Humans

Cited by 22 publications

References 72 publications

Variation in Ubiquitin System Genes Creates Substrate-Specific Effects on Proteasomal Protein Degradation

Variation in Ubiquitin System Genes Creates Substrate-Specific Effects on Proteasomal Protein Degradation

GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity

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