Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

AbstractInsomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia complaints. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.

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Genome-wide analyses point to differences in genetic architecture of BMI between tall and short people

10.1101/2020.09.24.312181 ◽

2020 ◽

Author(s):

Bochao D. Lin ◽

Benjamin H. Mullin ◽

Scott G. Wilson ◽

John P. Walsh ◽

Yue Li ◽

...

Keyword(s):

Genetic Architecture ◽

Genetic Correlations ◽

Portion Size ◽

Mineral Density ◽

Genome Wide ◽

Biological Insight ◽

Specific Locus ◽

Insight Into

AbstractTo examine differences in the genetic architecture of BMI between tall and short people, we conducted genome-wide and follow-up analyses using UK Biobank data. We identify 57 loci as height-specific, detect differences in SNP-based heritability between tall and short people and show how genetic correlations between the two rises during the lifespan. Using phenome-wide analyses (PHEWAS), a significant association between a short people-specific locus on MC4R and energy portion size was detected. We identify one locus (GPC5-GPC6) with different effect directions on BMI in short and tall people. PHEWAS indicates this locus is associated with bone mineral density. Transcriptome-wide analyses hint that genes differentially associated with BMI in short vs tall people are enriched in brain tissue. Our findings highlight the role of height in the genetic underpinnings of BMI, provide biological insight into mechanisms underlying height-dependent differences in BMI and show that in short and tall people obesity is a risk factor that differentially increases susceptibility for disease.

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Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor

Molecular Endocrinology ◽

10.1210/me.2003-0476 ◽

2004 ◽

Vol 18 (8) ◽

pp. 2035-2048 ◽

Cited By ~ 62

Author(s):

Bukhtiar H. Shah ◽

Akin Yesilkaya ◽

J. Alberto Olivares-Reyes ◽

Hung-Dar Chen ◽

László Hunyady ◽

...

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Types ◽

Specific Cell ◽

Heparin Binding ◽

Epidermal Growth

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Type 2 Diabetes (T2D) Associated Polymorphisms Regulate Expression of Adjacent Transcripts in Transformed Lymphocytes, Adipose, and Muscle from Caucasian and African-American Subjects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-1754 ◽

2011 ◽

Vol 96 (2) ◽

pp. E394-E403 ◽

Cited By ~ 11

Author(s):

Neeraj K. Sharma ◽

Kurt A. Langberg ◽

Ashis K. Mondal ◽

Steven C. Elbein ◽

Swapan K. Das

Keyword(s):

Genome Wide Association ◽

Small Subset ◽

Nucleotide Polymorphisms ◽

Healthy Individuals ◽

Allelic Expression Imbalance ◽

Single Nucleotide ◽

Metabolic Traits ◽

Genome Wide

abstract Context: Genome-wide association scans (GWAS) have identified novel single nucleotide polymorphisms (SNPs) that increase T2D susceptibility and indicated the role of nearby genes in T2D pathogenesis. Objective: We hypothesized that T2D-associated SNPs act as cis-regulators of nearby genes in human tissues and that expression of these transcripts may correlate with metabolic traits, including insulin sensitivity (SI). Design, Settings, and Patients: Association of SNPs with the expression of their nearest transcripts was tested in adipose and muscle from 168 healthy individuals who spanned a broad range of SI and body mass index (BMI) and in transformed lymphocytes (TLs). We tested correlations between the expression of these transcripts in adipose and muscle with metabolic traits. Utilizing allelic expression imbalance (AEI) analysis we examined the presence of other cis-regulators for those transcripts in TLs. Results: SNP rs9472138 was significantly (P = 0.037) associated with the expression of VEGFA in TLs while rs6698181 was detected as a cis-regulator for the PKN2 in muscle (P = 0.00027) and adipose (P = 0.018). Significant association was also observed for rs17036101 (P = 0.001) with expression of SYN2 in adipose of Caucasians. Among 19 GWAS-implicated transcripts, expression of VEGFA in adipose was correlated with BMI (r = −0.305) and SI (r = 0.230). Although only a minority of the T2D-associated SNPs were validated as cis-eQTLs for nearby transcripts, AEI analysis indicated presence of other cis-regulatory polymorphisms in 54% of these transcripts. Conclusions: Our study suggests that a small subset of GWAS-identified SNPs may increase T2D susceptibility by modulating expression of nearby transcripts in adipose or muscle.

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Comprehensive Genomic Discovery of Non-Coding Transcriptional Enhancers in the African Malaria Vector Anopheles coluzzii

Frontiers in Genetics ◽

10.3389/fgene.2021.785934 ◽

2022 ◽

Vol 12 ◽

Author(s):

Inge Holm ◽

Luisa Nardini ◽

Adrien Pain ◽

Emmanuel Bischoff ◽

Cameron E. Anderson ◽

...

Keyword(s):

Malaria Vector ◽

Regulatory Elements ◽

Specific Cell ◽

Insect Vector ◽

Anopheles Coluzzii ◽

Gene Promoters ◽

Transcriptional Enhancers ◽

Genome Wide ◽

A Genome

Almost all regulation of gene expression in eukaryotic genomes is mediated by the action of distant non-coding transcriptional enhancers upon proximal gene promoters. Enhancer locations cannot be accurately predicted bioinformatically because of the absence of a defined sequence code, and thus functional assays are required for their direct detection. Here we used a massively parallel reporter assay, Self-Transcribing Active Regulatory Region sequencing (STARR-seq), to generate the first comprehensive genome-wide map of enhancers in Anopheles coluzzii, a major African malaria vector in the Gambiae species complex. The screen was carried out by transfecting reporter libraries created from the genomic DNA of 60 wild A. coluzzii from Burkina Faso into A. coluzzii 4a3A cells, in order to functionally query enhancer activity of the natural population within the homologous cellular context. We report a catalog of 3,288 active genomic enhancers that were significant across three biological replicates, 74% of them located in intergenic and intronic regions. The STARR-seq enhancer screen is chromatin-free and thus detects inherent activity of a comprehensive catalog of enhancers that may be restricted in vivo to specific cell types or developmental stages. Testing of a validation panel of enhancer candidates using manual luciferase assays confirmed enhancer function in 26 of 28 (93%) of the candidates over a wide dynamic range of activity from two to at least 16-fold activity above baseline. The enhancers occupy only 0.7% of the genome, and display distinct composition features. The enhancer compartment is significantly enriched for 15 transcription factor binding site signatures, and displays divergence for specific dinucleotide repeats, as compared to matched non-enhancer genomic controls. The genome-wide catalog of A. coluzzii enhancers is publicly available in a simple searchable graphic format. This enhancer catalogue will be valuable in linking genetic and phenotypic variation, in identifying regulatory elements that could be employed in vector manipulation, and in better targeting of chromosome editing to minimize extraneous regulation influences on the introduced sequences.Importance: Understanding the role of the non-coding regulatory genome in complex disease phenotypes is essential, but even in well-characterized model organisms, identification of regulatory regions within the vast non-coding genome remains a challenge. We used a large-scale assay to generate a genome wide map of transcriptional enhancers. Such a catalogue for the important malaria vector, Anopheles coluzzii, will be an important research tool as the role of non-coding regulatory variation in differential susceptibility to malaria infection is explored and as a public resource for research on this important insect vector of disease.

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CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment

Frontiers in Oncology ◽

10.3389/fonc.2021.722916 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiakang Jin ◽

Jinti Lin ◽

Ankai Xu ◽

Jianan Lou ◽

Chao Qian ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cell Types ◽

Host Cells ◽

Specific Cell ◽

Tumor Patients ◽

Multiple Tumor ◽

Inflammatory Monocytes ◽

Immunosuppressive Cell ◽

Tumor Types

Tumor microenvironment (TME) formation is a major cause of immunosuppression. The TME consists of a considerable number of macrophages and stromal cells that have been identified in multiple tumor types. CCL2 is the strongest chemoattractant involved in macrophage recruitment and a powerful initiator of inflammation. Evidence indicates that CCL2 can attract other host cells in the TME and direct their differentiation in cooperation with other cytokines. Overall, CCL2 has an unfavorable effect on prognosis in tumor patients because of the accumulation of immunosuppressive cell subtypes. However, there is also evidence demonstrating that CCL2 enhances the anti-tumor capability of specific cell types such as inflammatory monocytes and neutrophils. The inflammation state of the tumor seems to have a bi-lateral role in tumor progression. Here, we review works focusing on the interactions between cancer cells and host cells, and on the biological role of CCL2 in these processes.

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Neural Foundations of Variability in Attachment

The Cultural Nature of Attachment ◽

10.7551/mitpress/9780262036900.003.0010 ◽

2017 ◽

Author(s):

Allyson J. Bennett ◽

William D. Hopkins ◽

Ruth Feldman ◽

Valeria Gazzola ◽

Jay Giedd ◽

...

Keyword(s):

Brain Development ◽

Animal Studies ◽

Experimental Studies ◽

Theory Development ◽

Single Type ◽

Negative Consequences ◽

Cultural Contexts ◽

The Social ◽

Insight Into

Neuroscience offers insight into processes that support the development of the social brain within the cultural contexts that permit attachment relationships to form. Both human and nonhuman animal studies are critical to inform theory development and hypothesis testing via descriptive and experimental studies. A scientifically valid evolutionary theory is necessary to account for the remarkable diversity of parenting systems across human and many nonhuman animals. This chapter examines the neural foundations of attachment and poses critical questions that relate to the initiation of this relationship: How does attachment interface with brain development? What is the interplay between attachment and brain development (including elements of bidirectionality)? Are there negative consequences associated with variation in attachment, and are they reversible? Rather than conceptualizing attachment in terms of a single type of relationship, or a rigid developmental channel, this chapter proposes that an expanded consideration of variation is necessary to understand the neural foundations of infant-caregiver relationships, and the role of those relationships in developing competence across the life span. This approach will permit identification of common neurobiological elements of attachment as well as the remarkable plasticity and diversity within and across individuals, cultures, and species.

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Functional Genomics for the Identification of Modulators of Platelet-Dependent Thrombus Formation

TH Open ◽

10.1055/s-0038-1670630 ◽

2018 ◽

Vol 02 (03) ◽

pp. e272-e279

Author(s):

Elien Vermeersch ◽

Benedicte Nuyttens ◽

Claudia Tersteeg ◽

Katleen Broos ◽

Simon De Meyer ◽

...

Keyword(s):

Functional Genomics ◽

Platelet Reactivity ◽

Thrombus Formation ◽

Cell Types ◽

Correlative Analysis ◽

Genome Expression ◽

Genome Wide ◽

Whole Genome Expression

AbstractDespite the absence of the genome in platelets, transcription profiling provides important insights into platelet function and can help clarify abnormalities in platelet disorders. The Bloodomics Consortium performed whole-genome expression analysis comparing in vitro–differentiated megakaryocytes (MKs) with in vitro–differentiated erythroblasts and different blood cell types. This allowed the identification of genes with upregulated expression in MKs compared with all other cell lineages, among the receptors BAMBI, LRRC32, ESAM, and DCBLD2. In a later correlative analysis of genome-wide platelet RNA expression with interindividual human platelet reactivity, LLRFIP and COMMD7 were additionally identified. A functional genomics approach using morpholino-based silencing in zebrafish identified various roles for all of these selected genes in thrombus formation. In this review, we summarize the role of the six identified genes in zebrafish and discuss how they correlate with subsequently performed mouse experiments.

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The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2017/4826724 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 72

Author(s):

Joshua A. David ◽

William J. Rifkin ◽

Piul S. Rabbani ◽

Daniel J. Ceradini

Keyword(s):

Diabetes Mellitus ◽

Oxidative Damage ◽

Therapeutic Target ◽

Type Ii Diabetes ◽

Animal Studies ◽

Cell Types ◽

Type Ii Diabetes Mellitus ◽

Type Ii ◽

And Oxidative Stress

Despite improvements in awareness and treatment of type II diabetes mellitus (TIIDM), this disease remains a major source of morbidity and mortality worldwide, and prevalence continues to rise. Oxidative damage caused by free radicals has long been known to contribute to the pathogenesis and progression of TIIDM and its complications. Only recently, however, has the role of the Nrf2/Keap1/ARE master antioxidant pathway in diabetic dysfunction begun to be elucidated. There is accumulating evidence that this pathway is implicated in diabetic damage to the pancreas, heart, and skin, among other cell types and tissues. Animal studies and clinical trials have shown promising results suggesting that activation of this pathway can delay or reverse some of these impairments in TIIDM. In this review, we outline the role of oxidative damage and the Nrf2/Keap1/ARE pathway in TIIDM, focusing on current and future efforts to utilize this relationship as a therapeutic target for prevention, prognosis, and treatment of TIID.

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