SOBIR1/EVR prevents precocious initiation of fiber differentiation during wood development through a mechanism involving BP and ERECTA

In plants, secondary growth results in radial expansion of stems and roots, generating large amounts of biomass in the form of wood. Using genome-wide association studies (GWAS)-guided reverse genetics inArabidopsis thaliana, we discoveredSOBIR1/EVR, previously known to control plant immunoresponses and abscission, as a regulator of secondary growth. We present anatomical, genetic, and molecular evidence indicating that SOBIR1/EVR prevents the precocious differentiation of xylem fiber, a key cell type for wood development. SOBIR1/EVR acts through a mechanism that involves BREVIPEDICELLUS (BP) and ERECTA (ER), 2 proteins previously known to regulate xylem fiber development. We demonstrate that BP bindsSOBIR1/EVRpromoter and thatSOBIR1/EVRexpression is enhanced inbpmutants, suggesting a direct, negative regulation of BP overSOBIR1/EVRexpression. We show that SOBIR1/EVR physically interacts with ER and that defects caused by thesobir1/evrmutation are aggravated by mutatingER, indicating that SOBIR1/EVR and ERECTA act together in the control of the precocious formation of xylem fiber development.

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Partitioning heritability by functional category using GWAS summary statistics

10.1101/014241 ◽

2015 ◽

Cited By ~ 9

Author(s):

Hilary Kiyo Finucane ◽

Brendan Bulik-Sullivan ◽

Alexander Gusev ◽

Gosia Trynka ◽

Yakir Reshef ◽

...

Keyword(s):

Association Studies ◽

Smoking Behavior ◽

Complex Diseases ◽

New Method ◽

Age At Menarche ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Cell Type ◽

Genome Wide ◽

Cell Type Specific

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

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Inferring relevant tissues and cell types for complex traits in genome-wide association studies

10.1101/2021.06.09.447805 ◽

2021 ◽

Author(s):

Rujin Wang ◽

Danyu Lin ◽

Yuchao Jiang

Keyword(s):

Single Cell ◽

Complex Traits ◽

Association Studies ◽

Cell Types ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Cell Type ◽

Disease Etiology ◽

Genome Wide ◽

Cell Type Specific

More than a decade of genome-wide association studies (GWASs) have identified genetic risk variants that are significantly associated with complex traits. Emerging evidence suggests that the function of trait-associated variants likely acts in a tissue- or cell-type-specific fashion. Yet, it remains challenging to prioritize trait-relevant tissues or cell types to elucidate disease etiology. Here, we present EPIC (cEll tyPe enrIChment), a statistical framework that relates large-scale GWAS summary statistics to cell-type-specific omics measurements from single-cell sequencing. We derive powerful gene-level test statistics for common and rare variants, separately and jointly, and adopt generalized least squares to prioritize trait-relevant tissues or cell types while accounting for the correlation structures both within and between genes. Using enrichment of loci associated with four lipid traits in the liver and enrichment of loci associated with three neurological disorders in the brain as ground truths, we show that EPIC outperforms existing methods. We extend our framework to single-cell transcriptomic data and identify cell types underlying type 2 diabetes and schizophrenia. The enrichment is replicated using independent GWAS and single-cell datasets and further validated using PubMed search and existing bulk case-control testing results.

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Bench Research Informed by GWAS Results

Cells ◽

10.3390/cells10113184 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3184

Author(s):

Nikolay V. Kondratyev ◽

Margarita V. Alfimova ◽

Arkadiy K. Golov ◽

Vera E. Golimbet

Keyword(s):

Complex Traits ◽

Genetic Architecture ◽

Reverse Genetics ◽

Genetic Factors ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they are usually ‘highly polygenic’. The study of such traits presents a challenge for researchers, as the complex genetic architecture of such traits makes it nearly impossible to utilise many of the usual methods of reverse genetics, which often focus on specific genes. In recent years, thousands of genome-wide association studies (GWAS) were undertaken to explore the relationships between complex traits and a large number of genetic factors, most of which are characterised by tiny effects. In this review, we aim to familiarise ‘wet biologists’ with approaches for the interpretation of GWAS results, to clarify some issues that may seem counterintuitive and to assess the possibility of using GWAS results in experiments on various complex traits.

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Transethnic meta-analysis of genome-wide association studies identifies three new loci and characterizes population-specific differences for coronary artery disease

10.1101/739979 ◽

2019 ◽

Author(s):

Hiroshi Matsunaga ◽

Kaoru Ito ◽

Masato Akiyama ◽

Atsushi Takahashi ◽

Satoshi Koyama ◽

...

Keyword(s):

Adrenal Glands ◽

Association Studies ◽

Meta Analysis ◽

Enrichment Analysis ◽

Tissue Cell ◽

Genome Wide Association Studies ◽

Diverse Populations ◽

Cell Type ◽

Genome Wide ◽

Artery Disease

AbstractBackgroundGenome-wide association studies (GWAS) provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. GWAS in diverse populations have the potential to advance our understanding of CAD.Methods and ResultsWe conducted two GWAS for CAD in the Japanese population, which included 12,494 cases and 28,879 controls, and 2,808 cases and 7,261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the CARDIoGRAMplusC4D 1000 Genomes meta-analysis with UK Biobank. We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands and fat tissues in the development of CAD. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies, and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans.ConclusionsWe identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

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Pediatric Germ Cell Tumors: A Developmental Perspective

Advances in Urology ◽

10.1155/2018/9059382 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Joshua L. Pierce ◽

A. Lindsay Frazier ◽

James F. Amatruda

Keyword(s):

Germ Cell ◽

Cancer Susceptibility ◽

Association Studies ◽

Germ Cell Tumors ◽

Molecular Evidence ◽

Genome Wide Association Studies ◽

Germ Cell Differentiation ◽

Genome Wide ◽

Sequencing Studies ◽

Adolescents And Adults

Germ cell tumors (GCTs) arising in infants, children, and adolescents present a set of special challenges. GCTs make up about 3% of malignancies in children aged 0–18 and nearly 15% of cancers in adolescents. Epidemiologic and molecular evidence suggests that GCTs in young children likely represent a distinct biologic group as compared to GCTs of older adolescents and adults. Despite this difference, pediatric GCTs are typically treated with cisplatin-based multiagent regimens similar to those used in adults. There is evidence that children are particularly vulnerable to late effects of conventional therapy, including ototoxicity, pulmonary abnormalities, and secondary malignancies, motivating the search for molecular targets for novel therapies. Evidence is accumulating that the genes and mechanisms controlling normal germ cell development are particularly relevant to the understanding of germ cell tumorigenesis. Perturbations in the epigenetic program of germ cell differentiation, with resulting effects on the regulation of pluripotency, may contribute to the marked histologic variability of GCTs. Perturbations in the KIT receptor signaling pathway have been identified via next-generation sequencing studies and in genome-wide association studies of testicular cancer susceptibility. Here, we review these and other biological insights that may fuel further translational and clinical research in childhood GCTs.

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Identification of novel seed longevity genes related to oxidative stress and seed coat by genome‐wide association studies and reverse genetics

Plant Cell & Environment ◽

10.1111/pce.13822 ◽

2020 ◽

Vol 43 (10) ◽

pp. 2523-2539 ◽

Cited By ~ 1

Author(s):

Joan Renard ◽

Regina Niñoles ◽

Irene Martínez‐Almonacid ◽

Beatriz Gayubas ◽

Rubén Mateos‐Fernández ◽

...

Keyword(s):

Oxidative Stress ◽

Seed Coat ◽

Reverse Genetics ◽

Association Studies ◽

Seed Longevity ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Longevity Genes

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Parkinson’s Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes

10.1101/2020.08.17.254276 ◽

2020 ◽

Author(s):

Alix Booms ◽

Steven E. Pierce ◽

Gerhard A. Coetzee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cell Type ◽

Genome Wide ◽

Risk Snps ◽

A Cell ◽

Regulatory Dna

AbstractGenome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinson’s disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 ‘SNPs of interest’ from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at the SLC50A1, SNCA, BAG3, FBXL19, SETD1A, and NUCKS1 loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for PD.

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Genomic regions influencing aggressive behavior in honey bees are defined by colony allele frequencies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922927117 ◽

2020 ◽

Vol 117 (29) ◽

pp. 17135-17141 ◽

Cited By ~ 2

Author(s):

Arián Avalos ◽

Miaoquan Fang ◽

Hailin Pan ◽

Aixa Ramirez Lluch ◽

Alexander E. Lipka ◽

...

Keyword(s):

Honey Bees ◽

Association Studies ◽

Group Behavior ◽

Individual Behavior ◽

Molecular Evidence ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Group Members ◽

Genomic Regions ◽

Colony Level

For social animals, the genotypes of group members affect the social environment, and thus individual behavior, often indirectly. We used genome-wide association studies (GWAS) to determine the influence of individual vs. group genotypes on aggression in honey bees. Aggression in honey bees arises from the coordinated actions of colony members, primarily nonreproductive “soldier” bees, and thus, experiences evolutionary selection at the colony level. Here, we show that individual behavior is influenced by colony environment, which in turn, is shaped by allele frequency within colonies. Using a population with a range of aggression, we sequenced individual whole genomes and looked for genotype–behavior associations within colonies in a common environment. There were no significant correlations between individual aggression and specific alleles. By contrast, we found strong correlations between colony aggression and the frequencies of specific alleles within colonies, despite a small number of colonies. Associations at the colony level were highly significant and were very similar among both soldiers and foragers, but they covaried with one another. One strongly significant association peak, containing an ortholog of theDrosophilasensory genedpr4on linkage group (chromosome) 7, showed strong signals of both selection and admixture during the evolution of gentleness in a honey bee population. We thus found links between colony genetics and group behavior and also, molecular evidence for group-level selection, acting at the colony level. We conclude that group genetics dominates individual genetics in determining the fatal decision of honey bees to sting.

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Integration of high-resolution promoter profiling assays reveals novel, cell type-specific transcription start sites across 115 human cell and tissue types

Genome Research ◽

10.1101/gr.275723.121 ◽

2021 ◽

pp. gr.275723.121

Author(s):

Jill E Moore ◽

Xiao-Ou Zhang ◽

Shaimae I Elhajjajy ◽

Kaili Fan ◽

Henry E Pratt ◽

...

Keyword(s):

Disease Gene ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Cell Type ◽

Transcription Start ◽

Transcription Start Sites ◽

Genome Wide ◽

Cell Type Specific ◽

Gwas Catalog

Accurate transcription start site (TSS) annotations are essential for understanding transcriptional regulation and its role in human disease. Gene collections such as GENCODE contain annotations for tens of thousands of TSSs, but not all of these annotations are experimentally validated, nor do they contain information on cell type-specific usage. Therefore, we sought to generate a collection of experimentally validated TSSs by integrating RNA Annotation and Mapping of Promoters for the Analysis of Gene Expression (RAMPAGE) data from 115 cell and tissue types, which resulted in a collection of approximately 50 thousand representative RAMPAGE peaks. These peaks were primarily proximal to GENCODE-annotated TSSs and were concordant with other transcription assays. Because RAMPAGE uses paired-end reads, we were then able to connect peaks to transcripts by analyzing the genomic positions of the 3' ends of read mates. Using this paired-end information, we classified the vast majority (37 thousand) of our RAMPAGE peaks as verified TSSs, updating TSS annotations for 20% of GENCODE genes. We also found that these updated TSS annotations were supported by epigenomic and other transcriptomic datasets. To demonstrate the utility of this RAMPAGE rPeak collection, we intersected it with the NHGRI/EBI genome-wide association studies (GWAS) catalog and identified new candidate GWAS genes. Overall, our work demonstrates the importance of integrating experimental data to further refine TSS annotations and provides a valuable resource for the biological community.

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Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

International Journal of Molecular Sciences ◽

10.3390/ijms21186649 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6649 ◽

Cited By ~ 1

Author(s):

Daniel R. Lathen ◽

Collin B. Merrill ◽

Adrian Rothenfluh

Keyword(s):

Candidate Genes ◽

Reverse Genetics ◽

Association Studies ◽

Single Gene ◽

Model Organism ◽

Behavioral Model ◽

Genome Wide Association Studies ◽

Related Function ◽

Genome Wide ◽

Trait Locus

Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

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