scholarly journals The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2001 ◽  
Author(s):  
Wendy Yi-Ying Wu ◽  
Gunnar Johansson ◽  
Carl Wibom ◽  
Thomas Brännström ◽  
Annika Malmström ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Molecular Subtypes ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Molecular Alterations ◽  
Risk Variants ◽  
Genome Wide ◽  
Increased Risk ◽  
Genetic Risk Variants

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

scholarly journals Polygenic Susceptibility of Aortic Aneurysms Associates to the Diameter of the Aneurysm Sac: the Aneurysm-Express Biobank Cohort

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Constance J. H. C. M. van Laarhoven ◽  
Jessica van Setten ◽  
Joost A. van Herwaarden ◽  
Gerard Pasterkamp ◽  
Dominique P. V. de Kleijn ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Significant Risk ◽  
Aortic Aneurysms ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Best Fit ◽  
Genetic Risk Variants

AbstractRecent genome-wide association studies (GWAS) have discovered ten genetic risk variants for abdominal aortic aneurysms (AAA). To what extent these genetic variants contribute to the pathology of aneurysms is yet unknown. The present study aims to investigate whether genetic risk variants are associated with three clinical features: diameter of aneurysm sac, type of artery and aneurysm related-symptoms in aortic and peripheral aneurysm patients. Aneurysm tissue of 415 patients included in the Aneurysm-Express biobank was used. A best-fit polygenic risk score (PRS) based on previous GWAS effect estimates was modeled for each clinical phenotype. The best-fit PRS (including 272 variants at PT = 0.01015) showed a significant correlation with aneurysm diameter (R2 = 0.019, p = 0.001). No polygenic association was found with clinical symptoms or artery type. In addition, the ten genome-wide significant risk variants for AAA were tested individually, but no associations were observed with any of the clinical phenotypes. All models were corrected for confounders and data was normalized. In conclusion, a weighted PRS of AAA susceptibility explained 1.9% of the phenotypic variation (p = 0.001) in diameter in aneurysm patients. Given our limited sample size, future biobank collaborations need to confirm a potential causal role of susceptibility variants on aneurysmal disease initiation and progression.

scholarly journals The Genetic Basis of Hypertriglyceridemia

2021 ◽  
Vol 23 (8) ◽  
Author(s):  
Germán D. Carrasquilla ◽  
Malene Revsbech Christiansen ◽  
Tuomas O. Kilpeläinen
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Cumulative Effect ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
Severe Hypertriglyceridemia ◽  
Increased Risk ◽  
Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

scholarly journals The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology

2017 ◽  
Author(s):  
Isabell Brikell ◽  
Henrik Larsson ◽  
Yi Lu ◽  
Erik Pettersson ◽  
Qi Chen ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Risk Scores ◽  
General Factor ◽  
Genome Wide Association Studies ◽  
General Psychopathology ◽  
Oppositional Defiant ◽  
Risk Variants ◽  
Genetic Risk Variants

AbstractAttention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder, with common genetic risk variants implicated in the clinical diagnosis and symptoms of ADHD. However, given evidence of comorbidity and genetic overlap across neurodevelopmental and externalizing conditions, it remains unclear whether these genetic risk variants are ADHD-specific. The aim of this study was to evaluate the associations between ADHD genetic risks and related neurodevelopmental and externalizing conditions, and to quantify the extent to which any such associations can be attributed to a general genetic liability towards psychopathology. We derived ADHD polygenic risk scores (PRS) for 13,460 children aged 9 and 12 years from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. Associations between ADHD PRS, a latent general psychopathology factor, and six latent neurodevelopmental and externalizing factors were estimated using structural equation modelling. ADHD PRS were statistically significantly associated with elevated levels of inattention, hyperactivity/impulsivity, autistic traits, learning difficulties, oppositional-defiant, and conduct problems (standardized regression coefficients=0.07-0.12). Only the association with specific hyperactivity/impulsivity remained significant after accounting for a general psychopathology factor, on which all symptoms loaded positively (standardized mean loading=0.61, range=0.32-0.91). ADHD PRS simultaneously explained 1% (p-value<0.001) of the variance in the general psychopathology factor and 0.50% (p-value<0.001) in the specific hyperactivity/impulsivity factor. Our results suggest that common genetic risk variants associated with ADHD have largely general pleiotropic effects on neurodevelopmental and externalizing traits in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

scholarly journals Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome–wide interaction study

2013 ◽  
Vol 20 (6) ◽  
pp. 875-887 ◽  
Author(s):  
Anja Rudolph ◽  
Rebecca Hein ◽  
Sara Lindström ◽  
Lars Beckmann ◽  
Sabine Behrens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Association Studies ◽  
Meta Analysis ◽  
Case Control ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0×10−3 were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9×10−6), two SNPs in SLC25A21 (combined Pint≤4.8×10−5), and three SNPs in PLCG2 (combined Pint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7×10−5), one SNP in CD80 (combined Pint≤8.2×10−6), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10−6), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

scholarly journals The Role of 39 Psoriasis Risk Variants on Age of Psoriasis Onset

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Yingchang Lu ◽  
Sinae Kane ◽  
Haoyan Chen ◽  
Argentina Leon ◽  
Ethan Levin ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
False Discovery ◽  
Risk Variants ◽  
Genome Wide ◽  
Independent Cohort

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (). The imputed HLA-C*06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C*06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset.

scholarly journals Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jayaram Vijayakrishnan ◽  
Maoxiang Qian ◽  
James B. Studd ◽  
Wenjian Yang ◽  
Ben Kinnersley ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
B Cell ◽  
Lymphoblastic Leukaemia ◽  
Association Studies ◽  
Meta Analysis ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Specific Effects ◽  
Risk Variants ◽  
Genome Wide

AbstractThere is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10−8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10−8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10−8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10−8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

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