scholarly journals Pharmacogenomics of Lithium Response in Bipolar Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 287
Author(s):  
Courtney M. Vecera ◽  
Gabriel R. Fries ◽  
Lokesh R. Shahani ◽  
Jair C. Soares ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Mood Stabilizer ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Lithium Response ◽  
Genetic Loading ◽  
Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

scholarly journals Functional genomics of autoimmune diseases

2021 ◽  
pp. annrheumdis-2019-216794
Author(s):  
Akari Suzuki ◽  
Matteo Maurizio Guerrini ◽  
Kazuhiko Yamamoto
Keyword(s):  
Autoimmune Diseases ◽  
Association Studies ◽  
Linkage Disequilibrium Block ◽  
Causal Variant ◽  
Genome Wide Association Studies ◽  
Coding Region ◽  
Risk Variants ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Long Non Coding Rna

For more than a decade, genome-wide association studies have been applied to autoimmune diseases and have expanded our understanding on the pathogeneses. Genetic risk factors associated with diseases and traits are essentially causative. However, elucidation of the biological mechanism of disease from genetic factors is challenging. In fact, it is difficult to identify the causal variant among multiple variants located on the same haplotype or linkage disequilibrium block and thus the responsible biological genes remain elusive. Recently, multiple studies have revealed that the majority of risk variants locate in the non-coding region of the genome and they are the most likely to regulate gene expression such as quantitative trait loci. Enhancer, promoter and long non-coding RNA appear to be the main target mechanisms of the risk variants. In this review, we discuss functional genetics to challenge these puzzles.

Basic mechanisms of and treatment targets for bipolar disorder

2020 ◽  
pp. 721-734
Author(s):  
Grant C. Churchill ◽  
Nisha Singh ◽  
Michael J. Berridge
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Calcium Signalling ◽  
Cyclic Adenosine Monophosphate ◽  
Mood Stabilizer ◽  
Adenosine Monophosphate ◽  
Genome Wide Association Studies ◽  
Treatment Targets ◽  
Intracellular Signalling Pathways ◽  
Genome Wide

This chapter on basic mechanisms of, and treatment targets for, bipolar disorder examines the cause and treatment of bipolar disorder from the perspective of intracellular signalling pathways implicated by the convergence of evidence from efficacious drugs, pathophysiology, and genetics and concludes that the unifying concept is calcium signalling. It discusses the pathways for cyclic adenosine monophosphate and inositol trisphosphate/calcium in the context of the action of drugs, with emphasis on lithium, the most effective true mood stabilizer. It proposes that the calcium signalling pathway and its components, such as channels, pumps, messengers, and enzymes, can explain both how dysfunction can affect neural activity and how this can be remedied by drugs. It argues for the central role of calcium, based on new evidence for the inositol depletion hypothesis and evidence of calcium dysregulation in peripheral and inducible pluripotent stem cells, as well as genome-wide association studies and drugs implicating a plasma membrane calcium channel.

Η συμβολή των μεγάλων μη-κωδικών (long non-coding) RNAs στην αιτιοπαθογένεια των ΙΦΝΕ

2021 ◽  
Author(s):  
Ειρήνη Ζαχαροπούλου
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Rna Transcripts ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Non Coding Rnas

Ένας αυξανόμενος αριθμός μελετών ευρέως γονιδιώματος (Genome Wide Association Studies, GWAS) έχει αναδείξει εκατοντάδες πολυμορφισμούς που σχετίζονται με τον κίνδυνο εκδήλωσης ιδιοπαθών φλεγμονωδών νόσων του εντέρου (ΙΦΝΕ), όπως η νόσος Crohn (NC) και η ελκώδης κολίτιδα (ΕΚ). Πρόσφατα, έχει δειχθεί ότι τα μεγάλα μη-κωδικά RNA μετάγραφα (large non-coding RNA transcripts, LncRNAs) διαδραματίζουν ρυθμιστικό ρόλο σε ποικίλα νοσήματα, μεταβάλλοντας το επίπεδο έκφρασης των γονιδίων προκαλώντας εναλλακτικό μάτισμα ή επιδρώντας στη δευτεροταγή δομή τους, συμπεριλαμβανομένων των ΙΦΝΕ. Ωστόσο, η παθογένεση των ΙΦΝΕ παραμένει έως σήμερα ασαφής και υπάρχουν περιορισμένα δεδομένα σχετικά με το ρόλο των lncRNAs σε αυτές τις παθήσεις. Επομένως, στόχος της παρούσας μελέτης είναι να εκτιμήσει τη συσχέτιση μεταξύ πολυμορφισμών σε lncRNA γονίδια και την εκδήλωση ΙΦΝΕ στον ελληνικό πληθυσμό και να συμβάλει στην αποσαφήνιση της παθοφυσιολογίας των ΙΦΝΕ. Πραγματοποιήθηκε μελέτη πληθυσμού ασθενώνμαρτύρων και γονοτύπηση των πολυμορφισμών μονού νουκλεοτιδίου (single nucleotide polymorphisms, SNPs) rs1476514, rs3757247 και rs597325 σε δείγμα ορού αίματος από 242 ασθενείς με NC, 185 ασθενείς με ΕΚ και 220 υγιείς μάρτυρες.Βρέθηκε ότι η συχνότητα του αλληλόμορφου Α του SNP rs1476514 επικρατή στον υγιή πληθυσμό. Επιπροσθέτως, σχετικά με τον SNP rs3757247, η συχνότητα του αλληλόμορφου G είναι υψηλότερη στους υγιείς μάρτυρες σε σύγκριση με του ασθενείς με ΕΚ ενώ σε όλα τα υπό μελέτη δείγματα διαπιστώθηκε ετεροζυγωτία για τον SNP rs597325. Συμπερασματικά, η κατανόηση των μηχανισμών που συμμετέχουν στην εκδήλωση των ΙΦΝΕ είναι επί του παρόντος περιορισμένη και η αιτιολογία τους παραμένει άγνωστη. Καθώς όμως συσσωρεύονται δεδομένα που υποδεικνύουν ότι υπάρχει συσχέτιση ορισμένων SNPs σε lncRNAs με τις ΙΦΝΕ, θα χρειαστούν μελέτες με μεγαλύτερο πληθυσμό ώστε να επιβεβαιωθούν τα αποτελέσματα και να αναζητηθεί ο ρόλος των απορρυθμισμένων lncRNAs στην παθογένεση των ΙΦΝΕ.

scholarly journals Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

2019 ◽  
Author(s):  
Konstantinos Hatzikotoulas ◽  
George AE Pickering ◽  
Matthew J Clark ◽  
Favour Felix-Ilemhenbhio ◽  
Klaudia Kocsy ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Association Studies ◽  
Human Mesenchymal Stem Cells ◽  
Genome Wide Association ◽  
Nodule Formation ◽  
Genome Wide Association Studies ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Functional Analyses ◽  
Long Non Coding Rna

ABSTRACTHeterotopic ossification (HO) is bone formation that occurs after trauma within tissues that do not normally have the property of ossification, resulting in pain and disability. The genetic architecture of HO remains unclear. In the first genome-wide association studies of this disease, we identify the human-only long non-coding RNA-encoding gene CASC20 as a robust, replicating susceptibility locus for HO and KIF26B as a potential severity locus. We find that both CASC20 and KIF26B are expressed in human bone. Both CASC20 and KIF26B expression is upregulated upon BMP2 induced osteogenic differentiation in primary human mesenchymal stem cells, followed by RUNX2 and OSTERIX upregulation and mineralised nodule formation. A CRISPR-Cas9 mediated knockout of Kif26b inhibits BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression in a murine myocyte model of osteogenic trans-differentiation, and prevents mineralised nodule formation. These studies provide the first insights into the heritable biology of common, complex HO.

scholarly journals A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nada A. Al-Tassan ◽  
Nicola Whiffin ◽  
Fay J. Hosking ◽  
Claire Palles ◽  
Susan M. Farrington ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Risk Variants ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Long Non Coding Rna

Abstract Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10−8, odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10−8; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10-8; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

scholarly journals Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8600 ◽  
Author(s):  
Yangyu Zhang ◽  
Yanhua Wu ◽  
Zhifang Jia ◽  
Donghui Cao ◽  
Na Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chinese Population ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chinese Populations ◽  
Risk Of Death ◽  
Non Coding Rna ◽  
Increased Risk ◽  
Long Non Coding Rna

Background Gastric cancer (GC) remains the third leading cause of cancer death in China. Although genome-wide association studies have identified the association between several single nucleotide polymorphisms (SNPs) on 8q24 and the risk of GC, the role of these SNPs in the prognosis of GC in Chinese populations has not yet been fully evaluated. Therefore, this study was conducted to explore the association between long non-coding RNA (lncRNA) polymorphisms on 8q24 and the prognosis of GC. Methods We genotyped 726 surgically resected GC patients to explore the association between eight SNPs in the lncRNAs CCAT1 (rs10087719, rs7816475), PCAT1 (rs1026411), PRNCR1 (rs12682421, rs13252298), and CASC8 (rs1562430, rs4871789, rs6983267) transcribed from the 8q24 locus and the prognosis of GC in a Chinese population. Results We found that the patients carrying rs12682421 AA genotypes survived for a shorter time than those with the GG/GA genotype (HR = 1.39, 95% confidence interval (CI) [1.09–1.78]). Compared with the CC/CT genotype, the TT genotype of rs1562430 was associated with an increased risk of death (HR = 1.38, 95% CI [1.06–1.80]). Furthermore, the results also identified the rs1026411 SNP as an independent prognostic factor for poor survival in GC patients. Patients carrying AA/AG variant genotypes had a 36% increased risk of death compared to those carrying the GG genotype (HR = 1.36, 95% CI [1.06–1.74]). These findings suggested that the rs12682421, rs1026411 and rs1562430 SNPs may contribute to the survival of GC and be prognostic markers for GC.

scholarly journals Genetic Predictors of Lithium Response

2019 ◽  
pp. 26-27
Author(s):  
U. Heilbronner
Keyword(s):  
Statistical Power ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Response Scale ◽  
Single Nucleotide ◽  
Genetic Predictors ◽  
Genome Wide ◽  
Lithium Response ◽  
Initial Genome

Lithium remains a first-line pharmacological treatment of bipolar disorder (BD). However, treatment response is heterogeneous, with several lines of evidence implicating genetic factors. Unfortunately, neither hypothesis-driven approaches nor initial genome-wide association studies (GWAS) were successful in identifying genetic drivers of response heterogeneity, probably due to low statistical power and different phenotype measurements. Recently, a GWAS of the Consortium of Lithium Genetics (ConLiGen) has identified four single nucleotide polymorphisms (SNPs) mediating response to lithium, located in genes for two long non-coding RNAs. This success was only possible by international collaboration and the use of an established lithium response scale. The findings await further replication.

scholarly journals GWAS Links New Variant in Long Non-Coding RNA LINC02006 with Colorectal Cancer Susceptibility

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 465
Author(s):  
Ewa E. Hennig ◽  
Anna Kluska ◽  
Magdalena Piątkowska ◽  
Maria Kulecka ◽  
Aneta Bałabas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Bioinformatic Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Tumor Invasiveness ◽  
Non Coding Rna ◽  
New Variant ◽  
Long Non Coding Rna

Despite great efforts, most of the genetic factors contributing to the risk of colorectal cancer (CRC) remain undetermined. Including small but homogenous populations in genome-wide association studies (GWAS) can help us discover new common risk variants specific to the studied population. In this study, including 465 CRC patients and 1548 controls, a pooled DNA samples-based GWAS was conducted in search of genetic variants associated with CRC in a Polish population. Combined with a new method of selecting single-nucleotide polymorphisms (SNPs) for verification in individual DNA samples, this approach allowed the detection of five new susceptibility loci not previously reported for CRC. The discovered loci were found to explain 10% of the overall risk of developing CRC. The strongest association was observed for rs10935945 in long non-coding RNA LINC02006 (3q25.2). Three other SNPs were also located within genes (rs17575184 in NEGR1, rs11060839 in PIWIL1, rs12935896 in BCAS3), while one was intergenic (rs9927668 at 16p13.2). An expression quantitative trait locus (eQTL) bioinformatic analysis suggested that these polymorphisms may affect transcription factor binding sites. In conclusion, four of the identified variants were located within genes likely involved in tumor invasiveness and metastasis. Therefore, they could possibly be markers of poor prognosis in CRC patients.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

scholarly journals Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

2021 ◽  
Author(s):  
Robin N Beaumont ◽  
Isabelle K Mayne ◽  
Rachel M Freathy ◽  
Caroline F Wright
Keyword(s):  
Birth Weight ◽  
Statistical Power ◽  
Developmental Disorders ◽  
Association Studies ◽  
Later Life ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Causal Genes

Abstract Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

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