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Article ; Online: Concerted Genetic Function in Blood Traits.

Kim-Hellmuth, Sarah / Lappalainen, Tuuli

2016 Volume 167, Issue 5, Page(s) 1167–1169

Abstract: The hematopoietic system plays a major role in human health. Two studies by Astle et al. and Chen et al. published in this issue of Cell use genome-wide association and functional genomics approaches to provide deep insights into the role of genetic ... ...

Abstract	The hematopoietic system plays a major role in human health. Two studies by Astle et al. and Chen et al. published in this issue of Cell use genome-wide association and functional genomics approaches to provide deep insights into the role of genetic variants in hematological traits. We discuss these discoveries and future strategies toward completing our understanding of the genetic basis for variation in human traits.
MeSH term(s)	Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Phenotype ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2016-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review ; Comment
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.10.055
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Article ; Online: Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

American journal of human genetics

2024 Volume 111, Issue 1, Page(s) 133–149

Abstract: Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs ( ... ...

Abstract	Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
MeSH term(s)	Humans ; Quantitative Trait Loci/genetics ; Gene Expression Regulation ; Genotype ; Phenotype
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2023.11.013
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Article: Concerted Genetic Function in Blood Traits

Kim-Hellmuth, Sarah / Tuuli Lappalainen

Cell. 2016 Nov. 17, v. 167

2016

Abstract: The hematopoietic system plays a major role in human health. Two studies by Astle etÂ al. and ChenÂ etÂ al. published in this issue of Cell use genome-wide association and functional genomics approaches to provide deep insights into the role of genetic ... ...

Abstract	The hematopoietic system plays a major role in human health. Two studies by Astle etÂ al. and ChenÂ etÂ al. published in this issue of Cell use genome-wide association and functional genomics approaches to provide deep insights into the role of genetic variants in hematological traits. WeÂ discuss these discoveries and future strategies toward completing our understanding of the genetic basis for variation in human traits.
Keywords	blood ; genetic variation ; genomics ; human health ; humans
Language	English
Dates of publication	2016-1117
Size	p. 1167-1169.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.10.055
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Article ; Online: Transcription factor regulation of eQTL activity across individuals and tissues.

Flynn, Elise D / Tsu, Athena L / Kasela, Silva / Kim-Hellmuth, Sarah / Aguet, Francois / Ardlie, Kristin G / Bussemaker, Harmen J / Mohammadi, Pejman / Lappalainen, Tuuli

PLoS genetics

2022 Volume 18, Issue 1, Page(s) e1009719

Abstract: Tens of thousands of genetic variants associated with gene expression (cis-eQTLs) have been discovered in the human population. These eQTLs are active in various tissues and contexts, but the molecular mechanisms of eQTL variability are poorly understood, ...

Abstract	Tens of thousands of genetic variants associated with gene expression (cis-eQTLs) have been discovered in the human population. These eQTLs are active in various tissues and contexts, but the molecular mechanisms of eQTL variability are poorly understood, hindering our understanding of genetic regulation across biological contexts. Since many eQTLs are believed to act by altering transcription factor (TF) binding affinity, we hypothesized that analyzing eQTL effect size as a function of TF level may allow discovery of mechanisms of eQTL variability. Using GTEx Consortium eQTL data from 49 tissues, we analyzed the interaction between eQTL effect size and TF level across tissues and across individuals within specific tissues and generated a list of 10,098 TF-eQTL interactions across 2,136 genes that are supported by at least two lines of evidence. These TF-eQTLs were enriched for various TF binding measures, supporting with orthogonal evidence that these eQTLs are regulated by the implicated TFs. We also found that our TF-eQTLs tend to overlap genes with gene-by-environment regulatory effects and to colocalize with GWAS loci, implying that our approach can help to elucidate mechanisms of context-specificity and trait associations. Finally, we highlight an interesting example of IKZF1 TF regulation of an APBB1IP gene eQTL that colocalizes with a GWAS signal for blood cell traits. Together, our findings provide candidate TF mechanisms for a large number of eQTLs and offer a generalizable approach for researchers to discover TF regulators of genetic variant effects in additional QTL datasets.
MeSH term(s)	Alleles ; Binding Sites ; Gene Knockdown Techniques ; Gene-Environment Interaction ; Genome-Wide Association Study ; Humans ; Interferon Regulatory Factor-1/genetics ; Models, Genetic ; Phenotype ; Quantitative Trait Loci ; Transcription Factors/metabolism ; Transcription Factors/physiology
Chemical Substances	IRF1 protein, human ; Interferon Regulatory Factor-1 ; Transcription Factors
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1009719
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Article: Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

bioRxiv : the preprint server for biology

2023

Abstract: Bulk tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, while context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs ( ... ...

Abstract	Bulk tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, while context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell type proportions, we demonstrate that cell type iQTLs could be considered as proxies for cell type-specific QTL effects. The interpretation of age iQTLs, however, warrants caution as the moderation effect of age on the genotype and molecular phenotype association may be mediated by changes in cell type composition. Finally, we show that cell type iQTLs contribute to cell type-specific enrichment of diseases that, in combination with additional functional data, may guide future functional studies. Overall, this study highlights iQTLs to gain insights into the context-specificity of regulatory effects.
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.26.546528
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Article: Systematic visualisation of molecular QTLs reveals variant mechanisms at GWAS loci.

bioRxiv : the preprint server for biology

2023

Abstract: Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation ... ...

Abstract	Splicing quantitative trait loci (QTLs) have been implicated as a common mechanism underlying complex trait associations. However, utilising splicing QTLs in target discovery and prioritisation has been challenging due to extensive data normalisation which often renders the direction of the genetic effect as well as its magnitude difficult to interpret. This is further complicated by the fact that strong expression QTLs often manifest as weak splicing QTLs and vice versa, making it difficult to uniquely identify the underlying molecular mechanism at each locus. We find that these ambiguities can be mitigated by visualising the association between the genotype and average RNA sequencing read coverage in the region. Here, we generate these QTL coverage plots for 1.7 million molecular QTL associations in the eQTL Catalogue identified with five quantification methods. We illustrate the utility of these QTL coverage plots by performing colocalisation between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. We find that while visually confirmed splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases. All our association summary statistics and QTL coverage plots are freely available at https://www.ebi.ac.uk/eqtl/.
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.06.535816
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Article ; Online: eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs.

PLoS genetics

2023 Volume 19, Issue 9, Page(s) e1010932

Abstract: The eQTL Catalogue is an open database of uniformly processed human molecular quantitative trait loci (QTLs). We are continuously updating the resource to further increase its utility for interpreting genetic associations with complex traits. Over the ... ...

Abstract	The eQTL Catalogue is an open database of uniformly processed human molecular quantitative trait loci (QTLs). We are continuously updating the resource to further increase its utility for interpreting genetic associations with complex traits. Over the past two years, we have increased the number of uniformly processed studies from 21 to 31 and added X chromosome QTLs for 19 compatible studies. We have also implemented Leafcutter to directly identify splice-junction usage QTLs in all RNA sequencing datasets. Finally, to improve the interpretability of transcript-level QTLs, we have developed static QTL coverage plots that visualise the association between the genotype and average RNA sequencing read coverage in the region for all 1.7 million fine mapped associations. To illustrate the utility of these updates to the eQTL Catalogue, we performed colocalisation analysis between vitamin D levels in the UK Biobank and all molecular QTLs in the eQTL Catalogue. Although most GWAS loci colocalised both with eQTLs and transcript-level QTLs, we found that visual inspection could sometimes be used to distinguish primary splicing QTLs from those that appear to be secondary consequences of large-effect gene expression QTLs. While these visually confirmed primary splicing QTLs explain just 6/53 of the colocalising signals, they are significantly less pleiotropic than eQTLs and identify a prioritised causal gene in 4/6 cases.
MeSH term(s)	Humans ; Quantitative Trait Loci/genetics ; Genotype ; Multifactorial Inheritance ; Base Sequence ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2023-09-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010932
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Article ; Online: Systematic evaluation of transcriptomics-based deconvolution methods and references using thousands of clinical samples.

Nadel, Brian B / Oliva, Meritxell / Shou, Benjamin L / Mitchell, Keith / Ma, Feiyang / Montoya, Dennis J / Mouton, Alice / Kim-Hellmuth, Sarah / Stranger, Barbara E / Pellegrini, Matteo / Mangul, Serghei

Briefings in bioinformatics

2021 Volume 22, Issue 6

Abstract: Estimating cell type composition of blood and tissue samples is a biological challenge relevant in both laboratory studies and clinical care. In recent years, a number of computational tools have been developed to estimate cell type abundance using gene ... ...

Abstract	Estimating cell type composition of blood and tissue samples is a biological challenge relevant in both laboratory studies and clinical care. In recent years, a number of computational tools have been developed to estimate cell type abundance using gene expression data. Although these tools use a variety of approaches, they all leverage expression profiles from purified cell types to evaluate the cell type composition within samples. In this study, we compare 12 cell type quantification tools and evaluate their performance while using each of 10 separate reference profiles. Specifically, we have run each tool on over 4000 samples with known cell type proportions, spanning both immune and stromal cell types. A total of 12 of these represent in vitro synthetic mixtures and 300 represent in silico synthetic mixtures prepared using single-cell data. A final 3728 clinical samples have been collected from the Framingham cohort, for which cell populations have been quantified using electrical impedance cell counting. When tools are applied to the Framingham dataset, the tool Estimating the Proportions of Immune and Cancer cells (EPIC) produces the highest correlation, whereas Gene Expression Deconvolution Interactive Tool (GEDIT) produces the lowest error. The best tool for other datasets is varied, but CIBERSORT and GEDIT most consistently produce accurate results. We find that optimal reference depends on the tool used, and report suggested references to be used with each tool. Most tools return results within minutes, but on large datasets runtimes for CIBERSORT can exceed hours or even days. We conclude that deconvolution methods are capable of returning high-quality results, but that proper reference selection is critical.
MeSH term(s)	Algorithms ; Computational Biology/methods ; Computer Simulation ; Gene Expression Profiling/methods ; Humans ; Transcriptome
Language	English
Publishing date	2021-08-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2068142-2
ISSN	1477-4054 ; 1467-5463
ISSN (online)	1477-4054
ISSN	1467-5463
DOI	10.1093/bib/bbab265
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Article ; Online: An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?

Brandt, Margot / Kim-Hellmuth, Sarah / Ziosi, Marcello / Gokden, Alper / Wolman, Aaron / Lam, Nora / Recinos, Yocelyn / Daniloski, Zharko / Morris, John A / Hornung, Veit / Schumacher, Johannes / Lappalainen, Tuuli

PLoS genetics

2021 Volume 17, Issue 7, Page(s) e1009684

Abstract: Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for ... ...

Abstract	Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56, affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect specific to IRF1 is active under early immune stimulus, with a large number of trans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that perturbation of the SNP locus downregulates IRF1 and causes widespread transcriptional effects. Genome editing by CRISPR had suggestive recapitulation of the LPS-specific trans-eQTL signal and lent support for the rs17622517 site being functional. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1. For this autoimmune GWAS locus, our work provides evidence of the functional variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatory trans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.
MeSH term(s)	Adult ; Autoimmune Diseases/genetics ; Autoimmune Diseases/metabolism ; Chromosome Mapping/methods ; DNA, Antisense/genetics ; Female ; Gene Expression/genetics ; Gene Expression Profiling/methods ; Gene Expression Regulation/genetics ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; HEK293 Cells ; Humans ; Immunity/genetics ; Interferon Regulatory Factor-1/genetics ; Interferon Regulatory Factor-1/metabolism ; Male ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Risk Factors
Chemical Substances	DNA, Antisense ; IRF1 protein, human ; Interferon Regulatory Factor-1
Language	English
Publishing date	2021-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1009684
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: SARS-CoV-2 Triggering Severe Acute Respiratory Distress Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-Old Child With Down Syndrome.

Kim-Hellmuth, Sarah / Hermann, Matthias / Eilenberger, Julia / Ley-Zaporozhan, Julia / Fischer, Marcus / Hauck, Fabian / Klein, Christoph / Haas, Nikolaus / Kappler, Matthias / Huebner, Johannes / Jakob, André / von Both, Ulrich

Journal of the Pediatric Infectious Diseases Society

2020 Volume 10, Issue 4, Page(s) 543–546

Abstract: Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here, we report a pediatric DS patient with coronavirus disease 2019 (COVID-19) who developed a hyperinflammatory syndrome, severe acute respiratory distress ... ...

Abstract	Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here, we report a pediatric DS patient with coronavirus disease 2019 (COVID-19) who developed a hyperinflammatory syndrome, severe acute respiratory distress syndrome, and secondary hemophagocytic lymphohistiocytosis requiring pediatric intensive care unit admission and treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19 and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated complications warrant systematic clinical and scientific studies. We report a pediatric Down syndrome patient with coronavirus disease 2019 (COVID-19) who developed secondary hemophagocytic lymphohistiocytosis requiring treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19-associated complications warrant systematic clinical and scientific studies.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/therapeutic use ; Alanine/analogs & derivatives ; Alanine/therapeutic use ; Antiviral Agents/therapeutic use ; COVID-19/complications ; COVID-19/diagnosis ; COVID-19/drug therapy ; COVID-19/virology ; COVID-19 Testing ; Child, Preschool ; Critical Care ; Down Syndrome/complications ; Genetic Predisposition to Disease ; Glucocorticoids/therapeutic use ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/drug therapy ; Lymphohistiocytosis, Hemophagocytic/virology ; Male ; Prednisolone/therapeutic use ; SARS-CoV-2 ; Systemic Inflammatory Response Syndrome/diagnosis ; Systemic Inflammatory Response Syndrome/drug therapy ; Systemic Inflammatory Response Syndrome/virology
Chemical Substances	Antiviral Agents ; Glucocorticoids ; Immunoglobulins, Intravenous ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Prednisolone (9PHQ9Y1OLM) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-11-13
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	2668791-4
ISSN	2048-7207 ; 2048-7193
ISSN (online)	2048-7207
ISSN	2048-7193
DOI	10.1093/jpids/piaa148
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