scholarly journals Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits.

2021 ◽  
Author(s):  
Nancy Y.A Sey ◽  
Benxia Hu ◽  
Marina Iskhakova ◽  
Huaigu Sun ◽  
Neda Shokrian ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alcohol Use ◽  
Cigarette Smoking ◽  
Genetic Risk ◽  
Target Genes ◽  
Association Studies ◽  
Critical Role ◽  
Genetic Risk Factors ◽  
Genome Wide Association Studies ◽  
Risk Genes

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

The Association Between Genetic Risk Factors and the Size of Intracranial Aneurysms at Time of Rupture

Neurosurgery ◽  
2013 ◽  
Vol 73 (4) ◽  
pp. 705-708 ◽  
Author(s):  
Rachel Kleinloog ◽  
Femke N.G. van 't Hof ◽  
Franciscus J. Wolters ◽  
Ingeborg Rasing ◽  
Irene C. van der Schaaf ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Intracranial Aneurysms ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genetic Risk Factors ◽  
Genome Wide Association Studies ◽  
Aneurysm Size ◽  
Genome Wide

Abstract BACKGROUND: Genetic risk factors for intracranial aneurysms may influence the size of aneurysms. OBJECTIVE: To assess the association between genetic risk factors and the size of aneurysms at the time of rupture. METHODS: Genotypes of 7 independent single-nucleotide polymorphisms (SNPs) of the 6 genetic risk loci identified in genome-wide association studies of patients with intracranial aneurysms were obtained from 700 Dutch patients with an aneurysmal subarachnoid hemorrhage (1997-2007) previously genotyped in the genome-wide association studies; 255 additional Dutch patients with an aneurysmal subarachnoid hemorrhage (2007-2011) were genotyped for these SNPs. Aneurysms were measured on computerized tomography angiography or digital subtraction angiography. The mean aneurysm size (with standard error) was compared between patients with and without a genetic risk factor by the use of linear regression. The association between SNPs and size was assessed for single SNPs and for the combined effect of SNPs by using a weighted genetic risk score. RESULTS: Single SNPs showed no association with aneurysm size, nor did the genetic risk score. CONCLUSION: The 6 genetic risk loci have no major influence on the size of aneurysms at the time of rupture. Because these risk loci explain no more than 5% of the genetic risk, other genetic factors for intracranial aneurysms may influence aneurysm size and thereby proneness to rupture.

scholarly journals Chemotherapy-Related Cardiac Dysfunction

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Marijke Linschoten ◽  
Arco J. Teske ◽  
Maarten J. Cramer ◽  
Elsken van der Wall ◽  
Folkert W. Asselbergs
Keyword(s):  
Risk Factors ◽  
Risk Stratification ◽  
Genetic Variants ◽  
Cardiac Dysfunction ◽  
Genetic Risk ◽  
Drug Transport ◽  
Association Studies ◽  
Genetic Risk Factors ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies

Chemotherapy-related cardiac dysfunction is a significant side effect of anticancer treatment. Risk stratification is based on clinical- and treatment-related risk factors that do not adequately explain individual susceptibility. The addition of genetic variants may improve risk assessment. We conducted a systematic literature search in PubMed and Embase, to identify studies investigating genetic risk factors for chemotherapy-related cardiac dysfunction. Included were articles describing genetic variants in humans altering susceptibility to chemotherapy-related cardiac dysfunction. The validity of identified studies was assessed by 10 criteria, including assessment of population stratification, statistical methodology, and replication of findings. We identified 40 studies: 34 exploring genetic risk factors for anthracycline-induced cardiotoxicity (n=9678) and 6 studies related to trastuzumab-associated cardiotoxicity (n=642). The majority (35/40) of studies had a candidate gene approach, whereas 5 genome-wide association studies have been performed. We identified 25 genetic variants in 20 genes and 2 intergenic variants reported significant at least once. The overall validity of studies was limited, with small cohorts, failure to assess population ancestry and lack of replication. SNPs with the most robust evidence up to this point are CELF4 rs1786814 (sarcomere structure and function), RARG rs2229774 (topoisomerase-2β expression), SLC28A3 rs7853758 (drug transport), UGT1A6 rs17863783 (drug metabolism), and 1 intergenic variant (rs28714259). Existing evidence supports the hypothesis that genetic variation contributes to chemotherapy-related cardiac dysfunction. Although many variants identified by this systematic review show potential to improve risk stratification, future studies are necessary for validation and assessment of their value in a diagnostic and prognostic setting.

scholarly journals Type 2 diabetes genes – Present status and data from Norwegian studies

2013 ◽  
Vol 23 (1) ◽  
Author(s):  
Jens K. Hertel Hertel ◽  
Stefan Johansson ◽  
Kristian Midthjell ◽  
Ottar Nygård ◽  
Pål R. Njølstad ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Genetic Risk ◽  
Association Studies ◽  
Pancreatic Beta Cell ◽  
Genetic Risk Factors ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Complex Disorders

The worldwide rise in prevalence of type 2 diabetes has led to an intense search for the genetic risk factors of this disease. In type 2 diabetes and other complex disorders, multiple genetic and environmental factors, as well as the interaction between these factors, determine the phenotype. In this review, we summarize present knowledge, generated by more than two decades of efforts to dissect the genetic architecture of type 2 diabetes. Initial studies were either based on a candidate gene approach or attempted to fine-map signals generated from linkage analysis. Despite the detection of multiple genomic regions proposed to be linked to type 2 diabetes, subsequent positional fine-mapping of candidates were mostly inconclusive. However, the introduction of genome-wide association studies (GWAS), applied on thousands of patients and controls, completely changed the field. To date, more than 50 susceptibility loci for type 2 diabetes have been detected through the establishment of large research consortia, the application of GWAS on intermediary diabetes phenotypes and the use of study samples of different ethnicities. Still, the common variants identified in the GWAS era only explain some of the heritability seen for type 2 diabetes. Thus, focus is now shifting towards searching also for rare variants using new high-throughput sequencing technologies. For genes involved in the genetic predisposition to type 2 diabetes the emerging picture is that there are hundreds of different gene variants working in a complex interplay influencing pancreatic beta cell function/mass and, only to a lesser extent, insulin action. Several Norwegian studies have contributed to the field, extending our understanding of genetic risk factors in type 2 diabetes and in diabetes-related phenotypes like obesity and cardiovascular disease.

scholarly journals AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci

2020 ◽  
Author(s):  
Genevieve H.L. Roberts ◽  
Danny S. Park ◽  
Marie V. Coignet ◽  
Shannon R. McCurdy ◽  
Spencer C. Knight ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Large Scale ◽  
Association Studies ◽  
Genetic Risk Factors ◽  
Human Infection ◽  
Nasopharyngeal Swab ◽  
Genome Wide Association Studies ◽  
Health Crisis ◽  
Host Genetic

AbstractHuman infection with SARS-CoV-2, the causative agent of COVID-19, leads to a remarkably diverse spectrum of outcomes, ranging from asymptomatic to fatal. Recent reports suggest that both clinical and genetic risk factors may contribute to COVID-19 susceptibility and severity. To investigate genetic risk factors, we collected over 500,000 COVID-19 survey responses between April and May 2020 with accompanying genetic data from the AncestryDNA database. We conducted sex-stratified and meta-analyzed genome-wide association studies (GWAS) for COVID-19 susceptibility (positive nasopharyngeal swab test, ncases=2,407) and severity (hospitalization, ncases=250). The severity GWAS replicated associations with severe COVID-19 near ABO and SLC6A20 (P<0.05). Furthermore, we identified three novel loci with P<5×10−8. The strongest association was near IVNS1ABP, a gene involved in influenza virus replication1, and was associated only in males. The other two novel loci harbor genes with established roles in viral replication or immunity: SRRM1 and the immunoglobulin lambda locus. We thus present new evidence that host genetic variation likely contributes to COVID-19 outcomes and demonstrate the value of large-scale, self-reported data as a mechanism to rapidly address a health crisis.

Investigations of Genetic Risk Factors in MDS and AML Using High- Density 6.0 Affymetrix Arrays

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 638-638
Author(s):  
Bartlomiej P Przychodzen ◽  
Anna Malgorzata Jankowska ◽  
Sandra P Smieszek ◽  
Sanjay Ram Mohan ◽  
Ramon V. Tiu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Large Scale ◽  
Growth Regulation ◽  
Target Genes ◽  
Disease Risk ◽  
Association Studies ◽  
Snp Array ◽  
Genetic Risk Factors ◽  
Genetic Alterations

Abstract Genetic predisposition to MDS and AML is likely polygenic and may involve several low penetrance alleles which in concert with exogenous factors result in highly variable presentation, not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies utilizing various SNP array (SNP-A) platforms, large scale investigations in various disorders have been conducted. In hematological malignancies to date no systematic disease-association studies using SNP-A have been reported, likely due to lower prevalence of these conditions and a highly variable phenotype. We have applied SNP-A to conduct the first GWS in MDS and MDS-derived AML with the goal to identify possible low prevalence genetic variants that contribute to the pathogenesis of these conditions and explain individual disease risk. We have studied 189 patients with MDS and secondary AML as well 119 internal controls using SNP-A. Affymetrix GeneChip 6.0 (924644 SNP probes covering most of the known LD blocks) is designed to capture 67%-89% of SNP variation among Caucasians. Following exclusion of SNP’s with a call rate of &lt;95%, and those with serious violation of Hardy Weinberg equilibrium, single allele X2 statistics for all autosomal markers was performed. For the purpose of this study, SNP’s with minor allele frequency (MAF) &lt;10% and p&lt;0.001 after false discovery rate correction, were selected. Top 11 polymorphisms were chosen pointing directly to 4 genes or indirectly to informative loci through LD, informative genes include e.g., LAMC2, SGCE, FRAP1 and PTPRT. Remarkably, several informative LD blocks were also identified represented by multiple markers pointing to the presence of an informative polymorphisms in the corresponding regions. For example, 5/30 markers (all p&lt;8×10−4) including, rs2477436, rs503243, rs3768593, rs4651151 and rs549191 are part of an LD block spanning NMAT2 and LAMC2 loci. The corresponding minor variant frequencies were 6.6% and 37.6% in homozygous and heterozygous constellation, respectively (controls: 0% and 21.6%). Second potential locus identified in our study consisted of 4 markers, all of them located on SGCE gene (rs1357318, rs2037496, rs4330611, rs13225971; p&lt;1.9×10−4) with frequencies of homozygous variant in patients at 0.8% and 28.9% with heterozygous variant (controls 0% and 15.2%), respectively. FRAP1 (MTOR) gene was represented by singular rs3730380 marker (p=2.7×10−6), occurring at the heterozygous frequency of 17.8% vs. allelic frequency of 0% in controls. FRAP1 is a critical downstream effector of Akt involved in cell cycle regulation and angiogenesis being central regulator in PI3K/Akt/mTOR pathway. Genetic alterations of the pathway are frequent events in preneoplastic lesions and advanced cancers. Similarly, increased frequency of minor alleles of rs6030469 in PTPRT locus was found in homozygous and heterozygous constellation at 1.4% vs. 0% and 27.3% vs. 8.5% (p=4.80 × 10-5) in patients and controls, respectively. PTPRT gene was also found to be frequently mutated in cancer and is involved in growth regulation. For example, overexpression of PTPRT may lead to reduced expression of STAT3 target genes. In sum, our study constituting the first systematic approach of WGS to identify genetic risk factors in AMS and AML, suggests that several informative loci can be selected for delineation of the causative polymorphisms.

scholarly journals Is Schizophrenia a Risk Factor for Breast Cancer?—Evidence From Genetic Data

2018 ◽  
Vol 45 (6) ◽  
pp. 1251-1256 ◽  
Author(s):  
Enda M Byrne ◽  
Manuel A R Ferreira ◽  
Angli Xue ◽  
Sara Lindström ◽  
Xia Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Causal Effect ◽  
Association Studies ◽  
Genetic Risk Factors ◽  
Epidemiological Studies ◽  
Genome Wide Association Studies ◽  
Shared Genetic

Abstract Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10–8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10–4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = −0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

scholarly journals Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

2018 ◽  
Author(s):  
Milton Pividori ◽  
Nathan Schoettler ◽  
Dan L. Nicolae ◽  
Carole Ober ◽  
Hae Kyung Im
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Age Of Onset ◽  
Association Studies ◽  
Genetic Risk Factors ◽  
Genome Wide Association Studies ◽  
Adult Onset ◽  
Childhood Onset ◽  
Large Samples ◽  
Genome Wide

BackgroundChildhood and adult onset asthma differ with respect to severity and co-morbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood and adult onset asthma, and the genes that may mediate the effects of associated variation.MethodsWe used data from UK Biobank to conduct genome-wide association studies (GWASs) in 37,846 subjects with asthma, including 9,433 childhood onset cases (onset before age 12) and 21,564 adult onset cases (onset between ages 26 and 65), and 318,237 subjects without asthma (controls; older than age 38). We conducted GWASs for childhood onset asthma and adult onset asthma each compared to shared controls, and for age of asthma onset in all 37,846 asthma cases. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.FindingsWe detected 61 independent asthma loci: 23 were childhood onset specific, one was adult onset specific, and 37 were shared. Nineteen loci were associated with age of asthma onset. Genes at the childhood onset loci were most highly expressed in skin, blood and small intestine; genes at the adult onset loci were most highly expressed in lung, blood, small intestine and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci.InterpretationGenetic risk factors for adult onset asthma are largely a subset of the genetic risk for childhood onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult onset asthma. In contrast, the onset of disease in childhood is associated with additional genes with relatively large effect sizes, and SNP-based heritability estimates that are over 3-times larger than for adult onset disease. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes whereas the etiology of adult onset asthma is more lung-centered and environmentally determined, but with immune mediated mechanisms driving disease progression in both children and adults.FundingThis work was supported by the National Institutes of Health grants R01 MH107666 and P30 DK20595 to HKI, R01 HL129735, R01 HL122712, P01 HL070831, and UG3 OD023282 to CO; NS was supported by T32 HL007605.Research in ContextEvidence before this studyGenome-wide association studies in large samples that include both childhood onset and adult onset asthma have identified many loci associated with asthma risk. However, little was known about the shared or distinct effects of those or other loci on age of asthma onset, or about the genes that may mediate the effects of loci associated with childhoon and/or adult onset asthma.Added value of this studyLeveraging the resources of UK Biobank, we identified loci with both age of onset specific effects and shared effects. We further showed a significantly greater contribution of genetic variation to childhood onset asthma, implying a greater role for environmental risk factors in adult onset asthma, and different biological pathways and tissue enrichments for genes at loci associated with childhood vs adult onset asthma.Implications of all the available evidenceOur results suggest that childhood onset specific loci and those associated with age of onset play a role in disease initiation, whereas the other associated loci reflect shared mechanisms of disease progression. The childhood onset specific loci highlight skin as a primiary target tissue for early onset disease and support the idea that asthma in childhood is due to impaired barrier function in the skin and other epithelial surfaces.

Evaluation of genes associated with undescended testes as predictors of TGCT susceptibility.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1539-1539
Author(s):  
Ariela Marshall ◽  
Stephanie L. Ciosek ◽  
Saran Vardhanabhuti ◽  
Nandita Mitra ◽  
David J. Vaughn ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Association Studies ◽  
Snp Array ◽  
Genetic Risk Factors ◽  
Genome Wide Association Studies ◽  
Undescended Testes ◽  
Genome Wide ◽  
Increased Risk ◽  
Genotype Information

1539 Background: Testicular germ cell tumors (TGCTs) are highly heritable. Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT, with increased risk to both the ipsilateral and contralateral testes. However, recent genome-wide association studies (GWAS) identifying genetic variants associated with TGCT susceptibility have not found differences in genotype carriage between TGCT patients with and without UDT. We investigated the role of potential risk variants for UDT as risk factors for TGCT. Methods: 1300 SNPs in and around 25 gene regions with published associations with UDT were evaluated in 474 TGCT cases (45 with UDT) and 919 controls. Genotype information was available from the Affymetrix Genome-Wide Human SNP Array 6.0. Statistical analysis was performed using PLINK, and statistical significance was assessed by Fisher's Exact test. Results: Comparing TGCT cases with and without UDT, variants in the region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively associated with UDT. When TGCT cases with UDT were compared with unaffected controls, the associations all met the required level of significance (p < 4 x 10-5). Only variation at ESR1 approached significance (P=0.0004) when TGCT cases and unaffected controls were compared. Conclusions: We identified variants at three genetic loci - SEMA3C, TGFBR3 and EPHB2 - that were significantly associated with UDT, but not with TGCT. The association of variation in EPHB2 and SEMA3C with UDT are novel findings. While associated with UDT, variation at ESR1 is also potentially associated with TGCT risk. These data continue to suggest that genetic risk factors for UDT are largely independent of those for TGCT. Thus, screening for TGCT could be targeted in a UDT population to those with genetic risk factors. Further studies should be done to investigate the genetic link between UDT and TGCT.

Sign in / Sign up

Export Citation Format

Share Document