scholarly journals Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1964
Author(s):  
Anna Letko ◽  
Katie M. Minor ◽  
Elaine M. Norton ◽  
Voichita D. Marinescu ◽  
Michaela Drögemüller ◽  
...  
Keyword(s):  
Gene Locus ◽  
P Value ◽  
Chromosome 11 ◽  
Primary Bone Tumor ◽  
Genome Wide ◽  
Increased Risk ◽  
Canine Chromosome ◽  
Primary Bone ◽  
Coding Variants

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

scholarly journals Investigating Association of rs5918 Human Platelets Antigen 1 and rs1800790 Fibrinogen β Chain as Critical Players with Recurrent Pregnancy Loss

2018 ◽  
Vol 6 (4) ◽  
pp. 98 ◽  
Author(s):  
Fatemeh Karami ◽  
Maliheh Askari ◽  
Mohammad Modarressi
Keyword(s):  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Human Platelets ◽  
P Value ◽  
Increased Risk ◽  
History Of ◽  
Polymerase Chain ◽  
Β Chain ◽  
Larger Sample

Thrombophilia gene variants have been shown to be associated with higher risk of recurrent pregnancy loss (RPL). Due to the role of human platelets antigen 1 (HPA-1) and fibrinogen β chain (FGB) as critical players in the coagulation process, their most important variants including rs5918 T > C and rs1800790 G > A were selected to be studied in women affected by RPL. Three milliliters of peripheral blood were drawn from 110 women with history of at least two consecutive spontaneous abortion and 110 healthy women controls. rs5918 T > C and rs1800790 G > A of HPA-1 and FGB genes, respectively, were selected to be analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR_RFLP) following DNA isolation using QIAamp DNA Blood Mini Kit. Heterozygote genotype (TC) of HPA-1 gene rs5918 polymorphism was significantly associated with risk of RPL (p-value = 0.02). Although, rs1800790 G > A of FGB gene was not associated with RPL, its combination with rs5918 polymorphism was associated with increased risk of RPL. Owing to the critical roles of FGB and HPA-1 genes in coagulation, and thrombosis and several confinements on the meaningful association between the combination of those polymorphism with risk of RPL, including them in the thrombophilia panel may increase detection rate of hereditary thrombophilia patients. However, further studies with larger sample sizes are required to shed light on the exact role of the studied gene polymorphism, especially rs1800790 G > A of FGB gene variant in pathogenesis of RPL.

Abstract 14182: Genome Wide Association Study for High Sensitive Cardiac Troponin T Levels Identifies a Novel Gene in Europeans With Type 1 Diabetes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tarunveer S Ahluwalia ◽  
Frederik Persson ◽  
Tine W Hansen ◽  
Lise Tarnow ◽  
Hans-Henrik Parving ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Association Study ◽  
Gene Locus ◽  
Genome Wide Association Study ◽  
Troponin T ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide ◽  
Increased Risk

Introduction: Adults with diabetes have a two to four folds increased risk of dying with heart disease compared to those without diabetes. Higher cardiac troponins, especially Troponin T (TnT) is a specific biomarker for cardiac injury also guiding management of chest pain and associated with increased risk of heart failure. Hypothesis: There is limited knowledge on genes regulating cardiac TnT levels. We conducted a genome wide association study (GWAS) for circulating cardiac TnT levels among individuals with type 1 diabetes (T1D). Methods: The study included 849 T1D individuals recruited from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Serum high sensitive TnT (hsTnT) levels were measured and log transformed for normalization after check for outliers (mean ± 4 SD). Genotyping on 538,448 single nucleotide variants (SNVs) was done using Illumina Human Core Exome Chip. After quality control filters: hardy weinberg equilibrium (p >10 -6 ), European ancestry, genotype call rates >95%, common variants were examined in 740 individuals with hs TnT data. We ran linear regression based additive genetic models adjusting for age, sex, diabetes duration and population sub structure using Plink and R statistical programs. P <5 x 10 -8 was genome wide significant (GWS) while 5 x 10 -8 < p < 1 x 10 -6 was considered suggestive. Results: Participants had a mean (SD) age of 43.7 (11.1) years, 57.4% were men, with diabetes duration of 28.0 (9.5) years, HbA1c 8.9 (1.3) % and 50.5% with diabetic nephropathy. Median (IQR) hsTnT levels were 64.7 (29.2-175.6) pg/ml. We identified a GWS missense common variant in the CISD3 gene locus on chromosome 17 (p=1.7 x 10 -8 ) for cardiac hsTnT levels. This gene codes CDGSH Iron Sulfur Domain 3 protein also called Mitochondrial Inner NEET Protein. Two suggestive loci were PTPRD (Protein Tyrosine Phosphatase Receptor Type D; p=4.9 x 10 -7 ) and DCC (DCC Netrin 1 Receptor; 6.6 x 10 -7 ) on chromosomes 9 and 18. PTPRD is a known GWS locus for hsTnT that we reconfirm among T1D individuals. Conclusions: We identify a novel gene locus for circulating cardiac hsTnT levels among T1D individuals of European ancestry. CISD3 is expressed in heart tissue regulating mitochondrial functions. Further validation is suggested.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

scholarly journals Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: a 23-year Prospective Study

2019 ◽  
Author(s):  
Oana A. Zeleznik ◽  
Clary B. Clish ◽  
Peter Kraft ◽  
Julian Avila-Pancheco ◽  
A. Heather Eliassen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Postmenopausal Women ◽  
Clear Cell ◽  
Statistical Significance ◽  
Experimental Studies ◽  
P Value ◽  
Ovarian Cancer Risk ◽  
Increased Risk

AbstractBackgroundExperimental evidence supports a role of lipid dysregulation in ovarian cancer progression and metastasis. We estimated associations with ovarian cancer risk for circulating levels of four lipid groups measured 3-23 years before diagnosis.MethodsAnalyses were conducted among cases (N = 252) and matched controls (N = 252) from the Nurses’ Health Studies. We used logistic regression adjusting for risk factors to investigate associations of lysophosphatidylcholines (LPC), phosphatidylcholines (PC), ceramides (CER), and sphingomyelins (SM) with ovarian cancer risk overall and by histotype. A Bonferroni adjusted p-value threshold of 0.0125 (0.05/4; 4 measured lipid groups) was used to evaluate statistical significance. Odds ratios (OR; 10thto the 90thpercentile) and 95% confidence intervals of ovarian cancer risk were estimated.ResultsC16:0 SM, C18:0 SM, C16:0 CER and SM sum were significantly positively associated with ovarian cancer risk, with ORs ranging from 1.95-2.10, with stronger ORs for postmenopausal women (2.02-3.22). ORs were generally similar for serous/poorly differentiated and endometrioid/clear cell tumors, although most did not meet the Bonferroni-adjusted p-value for significance. C18:1 LPC and the ratio of LPC to PC were significantly inversely, while C18:0 SM was significantly positively, associated with risk of endometrioid/clear cell tumors.ConclusionElevated levels of circulating SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women. Prospective and experimental studies are required to validate our findings and understand the role of lipid dysregulation, SMs in particular, in ovarian carcinogenesis.

scholarly journals Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain

2018 ◽  
Author(s):  
Guillermo Carbajosa ◽  
Karim Malki ◽  
Nathan Lawless ◽  
Hong Wang ◽  
John W. Ryder ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Late Onset ◽  
Brain Cell ◽  
Rna Seq ◽  
Cell Type ◽  
Neuronal Identity ◽  
Increased Risk ◽  
Coding Variants ◽  
App Gene

AbstractRare heterozygous coding variants in the Triggering Receptor Expressed in Myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial-gene enriched subnetwork at 4 months, including a shift towards a more central role for the Amyloid Precursor Protein (App) gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signalling hub, suggesting an underlying link between immune response and vascular disease in dementia.

scholarly journals Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Transthyretin Val122Ile Mutation Is Modulated by Non-Coding Variants

2019 ◽  
Vol 8 (2) ◽  
pp. 269 ◽  
Author(s):  
Renato Polimanti ◽  
Yaira Nuñez ◽  
Joel Gelernter
Keyword(s):  
African American ◽  
Medical History ◽  
Fold Increase ◽  
Upstream Region ◽  
Negative Consequences ◽  
Hepatic Expression ◽  
Increased Risk ◽  
History Of ◽  
Coding Variants

Background: African-Americans (AAs) have a 3.5% carrier prevalence of Transthyretin (TTR) Val122Ile mutation (rs76992529), which is the genetic cause of a hereditary form of amyloidosis. Methods: We investigated the medical history of Val122Ile carriers and assessed the role of a non-coding variation in 4361 unrelated AAs. Results: We observed that the Ile122 allele was associated with a 6.8-fold increase in the odds of having 10 or more outpatient surgeries (p = 7.81 × 10−5). Stratifying the analysis by sex, the Ile122 allele was associated with a 15.2-fold increase in the odds of having 10 or more outpatient surgeries in men (p = 6.49 × 10−7). A similar sex difference was observed with respect to the association of Val122Ile with musculoskeletal and connective-tissue disorders in an independent cohort of British subjects (n = 361,194, p = 2.47 × 10−13; nmale = 167,020, pmale = 4.02 × 10−24). In Val122Ile African-American carriers, we observed that haplotypes in the upstream region regulating TTR hepatic expression are associated with having 10 or more outpatient surgeries (p = 2.56 × 10−9). Conclusions: TTR Val122Ile showed a large effect with respect to an extreme phenotype identified in medical history that may be related to osteoarthritis, an early sign of the disease. Additionally, the non-coding variation appears to accelerate the negative consequences associated with Val122Ile mutation via TTR expression regulation.

scholarly journals Genome-Wide Association Analyses Identify Variants in IRF4 Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility

2021 ◽  
Vol 12 ◽  
Author(s):  
Junke Wang ◽  
Alyssa I. Clay-Gilmour ◽  
Ezgi Karaesmen ◽  
Abbas Rizvi ◽  
Qianqian Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Genetic Variation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Increased Risk ◽  
Acute Myeloid

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2,309 cases and 2,814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 × 10–12) in patients carrying the T allele at s12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR = 3.90, 95% CI, 2.36-6.44, Pmeta = 1.0 × 10–7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

scholarly journals Scarless genome editing reveals risk SNP rs6983267-G and lncRNA CCAT2 dictate targetable PI3K signaling dependence in WNT-dysregulated CRC

2021 ◽  
Author(s):  
Nicole B. Coggins ◽  
Henriette O’Geen ◽  
Paul C. Lott ◽  
David J. Segal ◽  
Luis Carvajal Carmona
Keyword(s):  
Risk Allele ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Growth Factor Signaling ◽  
Cellular Models ◽  
Genome Wide ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Hct 116

Abstract Genome-wide association studies have identified numerous loci associated with increased risk for colorectal cancer (CRC), including 8q24.21 which contains a known enhancer of proto-oncogene MYC . However, the role of candidate functional SNP rs6983267 within this locus remains unclear. Here, we generate isogenic cellular models of risk SNP rs6983267 in human CRC line, HCT-116. Comprehensive molecular characterization reveals risk allele-G drives enhancer DNA contacts with downstream regions that include MYC . Absence of risk allele leads to activation of lncRNA CCAT2 . Rather than changes in MYC expression, we observe activation of alternative growth factor signaling pathways with loss of both risk allele and CCAT2 expression. Analysis of TCGA CRC cases demonstrates low CCAT2 expression combined with non-risk rs6983267 genotype correlate with higher frequency of PI3K mutations in CRC patients displaying WNT dysregulation. Together, these provide a potential biomarker for therapeutically targetable PI3K dysregulation in CRC and application in cancer precision medicine.

scholarly journals Novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide

2018 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Amy Ferguson ◽  
Nicholas Graham ◽  
Richard J Shaw ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Risk Scores ◽  
Worth Living ◽  
Uk Biobank ◽  
Chromosome 11 ◽  
Polygenic Risk ◽  
Completed Suicide ◽  
Genome Wide ◽  
Increased Risk ◽  
Self Harm

Abstract:Background: Suicide is a major issue for global public health. ‘Suicidality’ describes a broad clinical spectrum of thoughts and behaviours, some of which are common in the general population.Methods: UK Biobank recruited ∼0·5 million middle age individuals from the UK, of whom 157,000 completed an assessment of suicidality. Mutually exclusive groups were assessed in an ordinal genome-wide association study of suicidality: ‘no suicidality’ controls (N=83,557); ‘thoughts that life was not worth living’ (N=21,063); ‘ever contemplated self-harm’ (N=13,038); ‘an act of deliberate self-harm in the past’ (N=2,498); and ‘a previous suicide attempt’ (N=2,666). Linkage of UK Biobank to death certification records identified a small sub-group of ‘completed suicide’ (N=137).Outcomes: We identified three novel genome-wide significant loci for suicidality (on Chromosomes 9, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81). Higher polygenic risk scores for suicidality were associated with increased risk of completed suicide relative to controls in an independent sub-group (N=137 vs N=5,330, OR 1·23, 95%CI 1·06 to 1·41, p=0.03). Rs598046-G (chromosome 11) demonstrated a similar effect size and direction (p=0·05) within a Danish suicidality study.Interpretation: These findings have significant implications for our understanding of genetic vulnerability to suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level.Funding: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217).

scholarly journals Genome-wide association analyses identify variants in IRF4 associated with acute myeloid leukemia and myelodysplastic syndrome susceptibility

2019 ◽  
Author(s):  
Junke Wang ◽  
Alyssa I. Clay-Gilmour ◽  
Ezgi Karaesmen ◽  
Abbas Rizvi ◽  
Qianqian Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Genetic Variation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Increased Risk ◽  
Acute Myeloid

ABSTRACTThe role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR=1.38, 95% CI, 1.26-1.51, Pmeta=2.8×10-12) in patients carrying the T allele at rs12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR=3.90, 95% CI, 2.36-6.44, Pmeta =1.0×10-7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

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