scholarly journals The impact of schizophrenia and mood disorder risk alleles on emotional problems: investigating change from childhood to middle age

2017 ◽  
Vol 48 (13) ◽  
pp. 2153-2158 ◽  
Author(s):  
Lucy Riglin ◽  
Stephan Collishaw ◽  
Alexander Richards ◽  
Ajay K. Thapar ◽  
Frances Rice ◽  
...  
Keyword(s):  
Mood Disorder ◽  
Genetic Risk ◽  
Association Studies ◽  
Adult Life ◽  
Emotional Problems ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Different Ages ◽  
The Impact ◽  
Disorder Risk

AbstractBackgroundPrevious studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals.MethodsData were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years.ResultsSchizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228].ConclusionsOur prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development.

scholarly journals Pyk2 overexpression in postsynaptic neurons blocks amyloid β1–42-induced synaptotoxicity in microfluidic co-cultures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
The Impact

Abstract Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1–42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta—an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels—selectively in postsynaptic neurons is protective against amyloid β1–42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

scholarly journals Pyk2 Overexpression in Postsynaptic Neurons Blocks Aβ1-42-induced Synaptotoxicity in a Microfluidic Co-Culture Model

2019 ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Hippocampal Neurons ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
Tyrosine Kinase 2 ◽  
Model Of Alzheimer’S Disease ◽  
The Impact

AbstractRecent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this paper, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid-beta (Aβ) peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein (APP). Co-culture with cells overexpressing mutated APP exposed the synapses of primary hippocampal neurons to Aβ1-42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of Aβ suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta (Pyk2) –an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels–selectively in postsynaptic neurons is protective against Aβ1-42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically-relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

scholarly journals P825 The impact of a SNP-dose–response effect on course of inflammatory bowel disease: a numerical analysis of SNP distribution within the Swiss IBD Cohort Study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S640-S641
Author(s):  
L Biedermann ◽  
L Denoth ◽  
J B Rossel ◽  
M Butter ◽  
S Vavricka ◽  
...  
Keyword(s):  
Cohort Study ◽  
Risk Score ◽  
Association Studies ◽  
Large Population ◽  
Median Number ◽  
Clinical Disease ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Individual Snps ◽  
The Impact

Abstract Background Several large genome wide association studies have identified an increasing number of IBD risk loci with currently more than 240 established loci and generated robust data on disease association. However, knowledge remains limited on distinctive associations to specific clinical characteristics. The Swiss IBD Cohort Study (SIBDCS) represents a large prospective cohort study with clinically and phenotypically sound data collection since 2006 including genotyping. In this study, we aimed to determine individual associations of known risk loci with clinical features of patients in the SIBDCS, as well as their combined effect on clinical outcomes. Methods Based on 158 analysed SNPs, we investigated the numerical distribution of risk alleles and determined an individual SNP risk score (defined as percentage of risk alleles; i.e. number of risk alleles divided by twice the number of given SNPs multiplied with 100). We then performed linear regression modelling to investigate, whether relevant clinical disease characteristics associate with this SNP risk score. Further, for each given clinical outcome, a model was run with all SNPs as potential predictors, and the number of significant associations per SNP counted. Results In a total of 2304 genotyped patients, we observed a median number of risk alleles of 167, 168 and 167 for IBD overall, CD and UC/IC, respectively with a narrow inter quartile range [11 (q25 = 162, q75 = 173) for IBD and CD; 12 (q25 = 161, q75 = 173) for UC/IC]. A higher SNP risk score was significantly associated with any complications (defined as a composite of any or more of colorectal cancer, colon dysplasia, intestinal lymphoma, osteopenia/-porosis, anaemia, deep venous thrombosis, pulmonary embolism, nephro- or cholelithiasis, malabsorption syndrome, massive haemorrhage, perforation/peritonitis, pouchitis), stenosis in CD patients; pancolitis, conversion to CD, female sex in UC patients; higher clinical disease activity in both CD & UC. Regarding individual SNPs, we identified substantial differences in terms of the frequency of associations to disease-related outcomes with up to 11 for rs4899554 in CD and 7 for rs9557195 in UC, respectively. Conclusion In our large population of IBD patients there is high per patient frequency of hetero- and homozygous SNP risk alleles. The association of higher SNP risk score with several disease-related outcomes indicates a potential interplay of per patient given SNP risk alleles.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

scholarly journals Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

2021 ◽  
Author(s):  
Tiit Nikopensius ◽  
Priit Niibo ◽  
Toomas Haller ◽  
Triin Jagomägi ◽  
Ülle Voog-Oras ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Control Sample ◽  
Case Control ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sally K Hammad ◽  
Min Zi ◽  
Sukhpal Prehar ◽  
Robert Little ◽  
Ludwig Neyses ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Association Studies ◽  
Weight Ratio ◽  
Blood Pressure Regulation ◽  
Heart Weight ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
The Impact

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias

2021 ◽  
Author(s):  
Fernanda M Bosada ◽  
Mathilde R Rivaud ◽  
Jae-Sun Uhm ◽  
Sander Verheule ◽  
Karel van Duijvenboden ◽  
...  
Keyword(s):  
Sodium Current ◽  
Association Studies ◽  
Noncoding Region ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Atrial Cardiomyocytes ◽  
The Impact ◽  
Lineage Specific Gene

Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition. Methods and Results: The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.

scholarly journals Boosting GWAS using biological networks: A study on susceptibility to familial breast cancer

2021 ◽  
Vol 17 (3) ◽  
pp. e1008819
Author(s):  
Héctor Climente-González ◽  
Christine Lonjou ◽  
Fabienne Lesueur ◽  
Dominique Stoppa-Lyonnet ◽  
Nadine Andrieu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Biological Networks ◽  
Familial Breast Cancer ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Functional Relationships ◽  
Network Methods ◽  
The Impact

Genome-wide association studies (GWAS) explore the genetic causes of complex diseases. However, classical approaches ignore the biological context of the genetic variants and genes under study. To address this shortcoming, one can use biological networks, which model functional relationships, to search for functionally related susceptibility loci. Many such network methods exist, each arising from different mathematical frameworks, pre-processing steps, and assumptions about the network properties of the susceptibility mechanism. Unsurprisingly, this results in disparate solutions. To explore how to exploit these heterogeneous approaches, we selected six network methods and applied them to GENESIS, a nationwide French study on familial breast cancer. First, we verified that network methods recovered more interpretable results than a standard GWAS. We addressed the heterogeneity of their solutions by studying their overlap, computing what we called the consensus. The key gene in this consensus solution was COPS5, a gene related to multiple cancer hallmarks. Another issue we observed was that network methods were unstable, selecting very different genes on different subsamples of GENESIS. Therefore, we proposed a stable consensus solution formed by the 68 genes most consistently selected across multiple subsamples. This solution was also enriched in genes known to be associated with breast cancer susceptibility (BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30, and SLC4A7, P-value = 3 × 10−4). The most connected gene was CUL3, a regulator of several genes linked to cancer progression. Lastly, we evaluated the biases of each method and the impact of their parameters on the outcome. In general, network methods preferred highly connected genes, even after random rewirings that stripped the connections of any biological meaning. In conclusion, we present the advantages of network-guided GWAS, characterize their shortcomings, and provide strategies to address them. To compute the consensus networks, implementations of all six methods are available at https://github.com/hclimente/gwas-tools.

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