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Article ; Online: ColocQuiaL: a QTL-GWAS colocalization pipeline.

Chen, Brian Y / Bone, William P / Lorenz, Kim / Levin, Michael / Ritchie, Marylyn D / Voight, Benjamin F

2022 Volume 38, Issue 18, Page(s) 4409–4411

Abstract: Summary: Identifying genomic features responsible for genome-wide association study (GWAS) signals has proven to be a difficult challenge; many researchers have turned to colocalization analysis of GWAS signals with expression quantitative trait loci ( ... ...

Abstract	Summary: Identifying genomic features responsible for genome-wide association study (GWAS) signals has proven to be a difficult challenge; many researchers have turned to colocalization analysis of GWAS signals with expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) to connect GWAS signals to candidate causal genes. The ColocQuiaL pipeline provides a framework to perform these colocalization analyses at scale across the genome and returns summary files and locus visualization plots to allow for detailed review of the results. As an example, we used ColocQuiaL to perform colocalization between a recent type 2 diabetes GWAS and Genotype-Tissue Expression (GTEx) v8 single-tissue eQTL and sQTL data. Availability and implementation: ColocQuiaL is primarily written in R and is freely available on GitHub: https://github.com/bvoightlab/ColocQuiaL.
MeSH term(s)	Humans ; Genome-Wide Association Study/methods ; Quantitative Trait Loci ; Diabetes Mellitus, Type 2/genetics ; Genomics ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease
Language	English
Publishing date	2022-07-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btac512
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Article ; Online: Evaluating the Contribution of Cell Type-Specific Alternative Splicing to Variation in Lipid Levels.

Gawronski, Katerina A B / Bone, William P / Park, YoSon / Pashos, Evanthia E / Wenz, Brandon M / Dudek, Max F / Wang, Xiao / Yang, Wenli / Rader, Daniel J / Musunuru, Kiran / Voight, Benjamin F / Brown, Christopher D

Circulation. Genomic and precision medicine

2023 Volume 16, Issue 3, Page(s) 248–257

Abstract: Background: Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of ... ...

Abstract	Background: Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait variation. Consequently, identifying genetic loci that associate with alternative splicing in disease-relevant cell types and determining the degree to which these loci are informative for lipid biology is of broad interest. Methods: We analyze gene splicing in 83 sample-matched induced pluripotent stem cell (iPSC) and hepatocyte-like cell lines (n=166), as well as in an independent collection of primary liver tissues (n=96) to perform discovery of splicing quantitative trait loci (sQTLs). Results: We observe that transcript splicing is highly cell type specific, and the genes that are differentially spliced between iPSCs and hepatocyte-like cells are enriched for metabolism pathway annotations. We identify 1384 hepatocyte-like cell sQTLs and 1455 iPSC sQTLs at a false discovery rate of <5% and find that sQTLs are often shared across cell types. To evaluate the contribution of sQTLs to variation in lipid levels, we conduct colocalization analysis using lipid genome-wide association data. We identify 19 lipid-associated loci that colocalize either with an hepatocyte-like cell expression quantitative trait locus or sQTL. Only 2 loci colocalize with both a sQTL and expression quantitative trait locus, indicating that sQTLs contribute information about genome-wide association studies loci that cannot be obtained by analysis of steady-state gene expression alone. Conclusions: These results provide an important foundation for future efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing both cardiovascular disease risk and complex traits in general.
MeSH term(s)	Humans ; Alternative Splicing ; Genome-Wide Association Study/methods ; RNA Splicing ; Quantitative Trait Loci ; Lipids
Chemical Substances	Lipids
Language	English
Publishing date	2023-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2574-8300
ISSN (online)	2574-8300
DOI	10.1161/CIRCGEN.120.003249
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Article ; Online: Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations.

Temprano-Sagrera, Gerard / Sitlani, Colleen M / Bone, William P / Martin-Bornez, Miguel / Voight, Benjamin F / Morrison, Alanna C / Damrauer, Scott M / de Vries, Paul S / Smith, Nicholas L / Sabater-Lleal, Maria

Journal of thrombosis and haemostasis : JTH

2022 Volume 20, Issue 6, Page(s) 1331–1349

Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively ... ...

Abstract	Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10 Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
MeSH term(s)	Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/genetics ; Factor XI/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Hemostasis/genetics ; Hemostatics ; Humans ; Phenotype ; Polymorphism, Single Nucleotide ; Tissue Plasminogen Activator/genetics
Chemical Substances	Hemostatics ; Factor XI (9013-55-2) ; Tissue Plasminogen Activator (EC 3.4.21.68)
Language	English
Publishing date	2022-03-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15698
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Article ; Online: Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.

Bone, William P / Siewert, Katherine M / Jha, Anupama / Klarin, Derek / Damrauer, Scott M / Chang, Kyong-Mi / Tsao, Philip S / Assimes, Themistocles L / Ritchie, Marylyn D / Voight, Benjamin F

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 34

Abstract: Background: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous ... ...

Abstract	Background: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Conclusion: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
MeSH term(s)	Alzheimer Disease/genetics ; Cardiovascular Diseases ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Humans ; Phenotype ; Polymorphism, Single Nucleotide/genetics
Language	English
Publishing date	2021-02-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-021-00773-z
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Article ; Online: Large-scale genomic analyses reveal insights into pleiotropy across circulatory system diseases and nervous system disorders.

Nature communications

2022 Volume 13, Issue 1, Page(s) 3428

Abstract: Clinical and epidemiological studies have shown that circulatory system diseases and nervous system disorders often co-occur in patients. However, genetic susceptibility factors shared between these disease categories remain largely unknown. Here, we ... ...

Abstract	Clinical and epidemiological studies have shown that circulatory system diseases and nervous system disorders often co-occur in patients. However, genetic susceptibility factors shared between these disease categories remain largely unknown. Here, we characterized pleiotropy across 107 circulatory system and 40 nervous system traits using an ensemble of methods in the eMERGE Network and UK Biobank. Using a formal test of pleiotropy, five genomic loci demonstrated statistically significant evidence of pleiotropy. We observed region-specific patterns of direction of genetic effects for the two disease categories, suggesting potential antagonistic and synergistic pleiotropy. Our findings provide insights into the relationship between circulatory system diseases and nervous system disorders which can provide context for future prevention and treatment strategies.
MeSH term(s)	Cardiovascular Diseases/genetics ; Genetic Pleiotropy ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomics ; Humans ; Nervous System Diseases/genetics ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2022-06-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-30678-w
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Article: Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.

Frontiers in genetics

2022 Volume 12, Page(s) 787545

Abstract: Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci ...

Abstract	Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the
Language	English
Publishing date	2022-02-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.787545
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Article ; Online: Natural human genetic variation determines basal and inducible expression of

Benson, Kiara K / Hu, Wenxiang / Weller, Angela H / Bennett, Alexis H / Chen, Eric R / Khetarpal, Sumeet A / Yoshino, Satoshi / Bone, William P / Wang, Lin / Rabinowitz, Joshua D / Voight, Benjamin F / Soccio, Raymond E

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 46, Page(s) 23232–23242

Abstract: PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) ... ...

Abstract	PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce
MeSH term(s)	Adipocytes/metabolism ; Adipose Tissue/metabolism ; Amidohydrolases/genetics ; Amidohydrolases/metabolism ; Animals ; Gene Expression ; Gene Expression Regulation ; Genetic Variation ; Humans ; Male ; Mice ; Obesity/genetics ; PPAR gamma/metabolism ; Phenotype ; Thiazolidinediones
Chemical Substances	PPAR gamma ; Thiazolidinediones ; 2,4-thiazolidinedione (AA68LXK93C) ; Amidohydrolases (EC 3.5.-) ; PM20D1 protein, human (EC 3.5.-)
Language	English
Publishing date	2019-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1913199116
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Article ; Online: Explorations to improve the completeness of exome sequencing.

Du, Chen / Pusey, Barbara N / Adams, Christopher J / Lau, C Christopher / Bone, William P / Gahl, William A / Markello, Thomas C / Adams, David R

BMC medical genomics

2016 Volume 9, Issue 1, Page(s) 56

Abstract: Background: Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These ...

Abstract	Background: Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis. Such false negatives reflect limitations in experimental design, technical performance, and data analysis. Results: We present examples from our datasets to quantify the analytical performance associated with current practices, and explore strategies to improve the completeness of data analysis. In particular, we focus on patient ascertainment, exome capture, inclusion of intronic variants, and evaluation of medium-sized structural variants. Conclusions: The strategies we present may recover previously-missed, disease causing variants in second-pass exome analysis. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using genome-scale sequencing techniques.
MeSH term(s)	Exome/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Sequence Analysis, DNA/methods
Language	English
Publishing date	2016-08-27
Publishing country	England
Document type	Journal Article
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-016-0216-3
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Article ; Online: Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure.

Levin, Michael G / Tsao, Noah L / Singhal, Pankhuri / Liu, Chang / Vy, Ha My T / Paranjpe, Ishan / Backman, Joshua D / Bellomo, Tiffany R / Bone, William P / Biddinger, Kiran J / Hui, Qin / Dikilitas, Ozan / Satterfield, Benjamin A / Yang, Yifan / Morley, Michael P / Bradford, Yuki / Burke, Megan / Reza, Nosheen / Charest, Brian /

Judy, Renae L / Puckelwartz, Megan J / Hakonarson, Hakon / Khan, Atlas / Kottyan, Leah C / Kullo, Iftikhar / Luo, Yuan / McNally, Elizabeth M / Rasmussen-Torvik, Laura J / Day, Sharlene M / Do, Ron / Phillips, Lawrence S / Ellinor, Patrick T / Nadkarni, Girish N / Ritchie, Marylyn D / Arany, Zoltan / Cappola, Thomas P / Margulies, Kenneth B / Aragam, Krishna G / Haggerty, Christopher M / Joseph, Jacob / Sun, Yan V / Voight, Benjamin F / Damrauer, Scott M

Nature communications

2022 Volume 13, Issue 1, Page(s) 6914

Abstract: Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We ... ...

Abstract	Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.
MeSH term(s)	Humans ; Genome-Wide Association Study/methods ; Phenotype ; Heart Failure/genetics ; Heart ; Gene Expression Profiling ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease
Language	English
Publishing date	2022-11-14
Publishing country	England
Document type	Meta-Analysis ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34216-6
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Article ; Online: Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration.

Davids, Mariska / Kane, Megan S / He, Miao / Wolfe, Lynne A / Li, Xueli / Raihan, Mohd A / Chao, Katherine R / Bone, William P / Boerkoel, Cornelius F / Gahl, William A / Toro, Camilo

Journal of medical genetics

2015 Volume 53, Issue 3, Page(s) 180–189

Abstract: Background: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to ... ...

Abstract	Background: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. Methods: Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization--time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. Results: The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. Conclusions: Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders.
MeSH term(s)	Adult ; Cells, Cultured ; Dystonic Disorders/genetics ; Dystonic Disorders/metabolism ; Dystonic Disorders/pathology ; Female ; Fibroblasts/metabolism ; Fibroblasts/ultrastructure ; Glycosylation ; Golgi Apparatus/metabolism ; Golgi Apparatus/ultrastructure ; Group VI Phospholipases A2/deficiency ; Group VI Phospholipases A2/genetics ; Group VI Phospholipases A2/metabolism ; Humans ; Infant ; Male ; Mutation ; Neuroaxonal Dystrophies/genetics ; Neuroaxonal Dystrophies/metabolism ; Neuroaxonal Dystrophies/pathology ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Parkinsonian Disorders/genetics ; Parkinsonian Disorders/metabolism ; Parkinsonian Disorders/pathology ; Sialyltransferases/metabolism
Chemical Substances	Sialyltransferases (EC 2.4.99.-) ; Group VI Phospholipases A2 (EC 3.1.1.4) ; PLA2G6 protein, human (EC 3.1.1.4)
Language	English
Publishing date	2015-12-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2015-103338
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