scholarly journals Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

2020 ◽  
pp. jmedgenet-2020-107095
Author(s):  
William Schierding ◽  
Julia A Horsfield ◽  
Justin M O'Sullivan
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Genes Encoding ◽  
Full Complement ◽  
Transcriptional Changes ◽  
Robust Regulation

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.

scholarly journals Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

2020 ◽  
Author(s):  
William Schierding ◽  
Julia Horsfield ◽  
Justin O’Sullivan
Keyword(s):  
Regulatory Elements ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Transcriptional Variation ◽  
Genes Encoding ◽  
Full Complement ◽  
Transcriptional Changes ◽  
Matrix Production ◽  
Dna Regulatory Elements ◽  
Robust Regulation

AbstractVariants in DNA regulatory elements can alter the regulation of distant genes through spatial-regulatory connections. In humans, these spatial-regulatory connections are largely set during early development, when the cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components are often sufficient to produce a disease phenotype. The implication that genes encoding the cohesin complex and cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci, including linking their expression to that of other genes. Connections that centre on the cohesin ring subunits (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A and PDS5B), and CTCF provide evidence of coordinated regulation that has little tolerance for perturbation. We identified transcriptional changes across a set of genes co-regulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are co-regulated with cohesin loci are themselves intolerant to loss-of-function. The results highlight the importance of robust regulation of cohesin genes, indicating novel pathways that may be important in the human cohesinopathy disorders.

scholarly journals Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

2020 ◽  
Vol 9 (4) ◽  
pp. 1096
Author(s):  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Marco Bruno Morelli ◽  
John Ferrara ◽  
Gaetano Santulli
Keyword(s):  
Human Disease ◽  
Calcium Release ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Inositol 1,4,5 Trisphosphate ◽  
Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

scholarly journals Regulatory Variants and Disease: The E-Cadherin −160C/A SNP as an Example

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Gongcheng Li ◽  
Tiejun Pan ◽  
Dan Guo ◽  
Long-Cheng Li
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Regulate Gene Expression ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Regulatory Snps ◽  
E Cadherin

Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter −160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs.

scholarly journals Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

2019 ◽  
Author(s):  
Madison L. Doolittle ◽  
Gina M Calabrese ◽  
Larry D. Mesner ◽  
Dana A. Godfrey ◽  
Robert D. Maynard ◽  
...  
Keyword(s):  
Bone Formation ◽  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Mineral Density ◽  
Osteoblast Activity ◽  
Genome Wide ◽  
Increased Risk

ABSTRACTOsteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

scholarly journals Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

2018 ◽  
Author(s):  
Satish K Nandakumar ◽  
Sean K McFarland ◽  
Laura Marlene Mateyka ◽  
Caleb A Lareau ◽  
Jacob C Ulirsch ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Target Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Causal Variants ◽  
Genomic Regions

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding genomic regions and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

Polymorphisms Affecting Trace Element Bioavailability

2010 ◽  
Vol 80 (45) ◽  
pp. 314-318 ◽  
Author(s):  
John C. Mathers ◽  
Catherine Méplan ◽  
John E. Hesketh
Keyword(s):  
Trace Element ◽  
Individual Variation ◽  
Association Studies ◽  
Copy Number Variants ◽  
Micro Rna ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Complex Interactions ◽  
Genome Wide ◽  
Genes Encoding

This review outlines the nature of inter-individual variation in trace element bioavailability, focusing on genetic and epigenetic determinants. We note that pathogenic mutations responsible for dangerously high (or low) status for the micronutrient are unlikely to make large contributions to variability in bioavailability among the general population. Prospective genotyping (for variants in genes encoding selenoproteins) of participants in human studies illustrate one approach to understanding the complex interactions between genotype and trace element supply, which determine the functional bioavailability of selenium. Rapid advances in technological and bioinformatics tools; e. g., as used in Genome-Wide Association Studies, are opening new avenues for research on the genetic determinants of inter-individual variation in trace element bioavailability. This may include copy number variants in addition to the more widely studied polymorphisms. Future research on trace element bioavailability should encompass studies of epigenetic variants, including the role of non-coding (micro) RNA.

scholarly journals LPCAT1 controls phosphate homeostasis in a zinc-dependent manner

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mushtak Kisko ◽  
Nadia Bouain ◽  
Alaeddine Safi ◽  
Anna Medici ◽  
Robert C Akkers ◽  
...  
Keyword(s):  
Allelic Variation ◽  
Association Studies ◽  
Essential Elements ◽  
Zn Deficiency ◽  
Genome Wide Association Studies ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Living Organisms

All living organisms require a variety of essential elements for their basic biological functions. While the homeostasis of nutrients is highly intertwined, the molecular and genetic mechanisms of these dependencies remain poorly understood. Here, we report a discovery of a molecular pathway that controls phosphate (Pi) accumulation in plants under Zn deficiency. Using genome-wide association studies, we first identified allelic variation of the Lyso-PhosphatidylCholine (PC) AcylTransferase 1 (LPCAT1) gene as the key determinant of shoot Pi accumulation under Zn deficiency. We then show that regulatory variation at the LPCAT1 locus contributes significantly to this natural variation and we further demonstrate that the regulation of LPCAT1 expression involves bZIP23 TF, for which we identified a new binding site sequence. Finally, we show that in Zn deficient conditions loss of function of LPCAT1 increases the phospholipid Lyso-PhosphatidylCholine/PhosphatidylCholine ratio, the expression of the Pi transporter PHT1;1, and that this leads to shoot Pi accumulation.

scholarly journals Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

2016 ◽  
Vol 48 (11) ◽  
pp. 1418-1424 ◽  
Author(s):  
Ying Jin ◽  
Genevieve Andersen ◽  
Daniel Yorgov ◽  
Tracey M Ferrara ◽  
Songtao Ben ◽  
...  
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Autoimmune Vitiligo ◽  
Key Pathways

scholarly journals Personality traits and polymorphisms of genes coding neurotransmitter receptors or transporters: review of single gene and genome-wide association studies

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Szymon Zmorzyński ◽  
Wojciech Styk ◽  
Waldemar Klinkosz ◽  
Justyna Iskra ◽  
Agata Anna Filip
Keyword(s):  
Personality Traits ◽  
Five Factor Model ◽  
Association Studies ◽  
Genome Wide Association ◽  
Cochrane Library ◽  
Neurotransmitter Receptors ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genes Encoding ◽  
The Relationship

Abstract Background The most popular tool used for measuring personality traits is the Five-Factor Model (FFM). It includes neuroticism, extraversion, openness, agreeableness and conscientiousness. Many studies indicated the association of genes encoding neurotransmitter receptors/transporters with personality traits. The relationship connecting polymorphic DNA sequences and FFM features has been described in the case of genes encoding receptors of cannabinoid and dopaminergic systems. Moreover, dopaminergic system receives inputs from other neurotransmitters, like GABAergic or serotoninergic systems. Methods We searched PubMed Central (PMC), Science Direct, Scopus, Cochrane Library, Web of Science and EBSCO databases from their inception to November 19, 2020, to identify original studies, as well as peer-reviewed studies examining the FFM and its association with gene polymorphisms affecting the neurotransmitter functions in central nervous system. Results Serotonin neurons modulate dopamine function. In gene encoding serotonin transporter protein, SLC6A4, was found polymorphism, which was correlated with openness to experience (in Sweden population), and high scores of neuroticism and low levels of agreeableness (in Caucasian population). The genome-wide association studies (GWASs) found an association of 5q34-q35, 3p24, 3q13 regions with higher scores of neuroticism, extraversion and agreeableness. However, the results for chromosome 3 regions are inconsistent, which was shown in our review paper. Conclusions GWASs on polymorphisms are being continued in order to determine and further understand the relationship between the changes in DNA and personality traits.

scholarly journals Natural selection influenced the genetic architecture of brain structure, behavioral and neuropsychiatric traits

2020 ◽  
Author(s):  
Frank R Wendt ◽  
Gita A Pathak ◽  
Cassie Overstreet ◽  
Daniel S Tylee ◽  
Joel Gelernter ◽  
...  
Keyword(s):  
Natural Selection ◽  
Complex Traits ◽  
Association Studies ◽  
Model Fit ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Risk Alleles ◽  
Genome Wide ◽  
Improved Model

AbstractNatural selection has shaped the phenotypic characteristics of human populations. Genome-wide association studies (GWAS) have elucidated contributions of thousands of common variants with small effects on an individual’s predisposition to complex traits (polygenicity), as well as wide-spread sharing of risk alleles across traits in the human phenome (pleiotropy). It remains unclear how the pervasive effects of natural selection influence polygenicity in brain-related traits. We investigate these effects by annotating the genome with measures of background (BGS) and positive selection, indications of Neanderthal introgression, measures of functional significance including loss-of-function (LoF) intolerant and genic regions, and genotype networks in 75 brain-related traits. Evidence of natural selection was determined using binary annotations of top 2%, 1%, and 0.5% of selection scores genome-wide. We detected enrichment (q<0.05) of SNP-heritability at loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and LoF-intolerant regions (67 phenotypes). BGS (top 2%) significantly predicted effect size variance for trait-associated loci (σ2 parameter) in 75 brain-related traits (β=4.39×10−5, p=1.43×10−5, model r2=0.548). By including the number of DSM-5 diagnostic combinations per psychiatric disorder, we substantially improved model fit (σ2 ~ BTop2% × Genic × diagnostic combinations; model r2=0.661). We show that GWAS with larger variance in risk locus effect sizes are collectively predicted by the effects of loci under strong BGS and in regulatory regions of the genome. We further show that diagnostic complexity exacerbates this relationship and perhaps dampens the ability to detect psychiatric risk loci.

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