scholarly journals Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

2019 ◽  
Author(s):  
Sara R. Rashkin ◽  
Rebecca E. Graff ◽  
Linda Kachuri ◽  
Khanh K. Thai ◽  
Stacey E. Alexeeff ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Large Population ◽  
Regulatory Elements ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Pan Cancer ◽  
Shared Genetic

AbstractDeciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

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 Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

2020 ◽  
Author(s):  
Katherina C. Chua ◽  
Chenling Xiong ◽  
Carol Ho ◽  
Taisei Mushiroda ◽  
Chen Jiang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Elements ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Sensory Peripheral Neuropathy ◽  
Genome Wide ◽  
Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

scholarly journals Combined analysis of keratinocyte cancers identifies novel genome-wide loci

2019 ◽  
Vol 28 (18) ◽  
pp. 3148-3160 ◽  
Author(s):  
Upekha E Liyanage ◽  
Matthew H Law ◽  
Xikun Han ◽  
Jiyuan An ◽  
Jue-Sheng Ong ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Association Studies ◽  
Genetic Correlations ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multiple Trait ◽  
Total N ◽  
Risk Variants ◽  
Genome Wide ◽  
Meta Analyses

Abstract The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

scholarly journals Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Alejandra Vergara-Lope ◽  
M. Reza Jabalameli ◽  
Clare Horscroft ◽  
Sarah Ennis ◽  
Andrew Collins ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Genome Sequence ◽  
Sequence Data ◽  
Association Studies ◽  
Large Population ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Wide

Abstract Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3–4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.

scholarly journals Shared Genetic Architecture between Asthma and Allergic Diseases: A Genome-Wide Cross Trait Analysis of 112,000 Individuals from UK Biobank

2017 ◽  
Author(s):  
Zhaozhong Zhu ◽  
Phil H. Lee ◽  
Mark D. Chaffin ◽  
Wonil Chung ◽  
Po-Ru Loh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Allergic Diseases ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Trait Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Shared Genetic

AbstractClinical and epidemiological data suggest that asthma and allergic diseases are associated. And may share a common genetic etiology. We analyzed genome-wide single-nucleotide polymorphism (SNP) data for asthma and allergic diseases in 35,783 cases and 76,768 controls of European ancestry from the UK Biobank. Two publicly available independent genome wide association studies (GWAS) were used for replication. We have found a strong genome-wide genetic correlation between asthma and allergic diseases (rg = 0.75, P = 6.84×10−62). Cross trait analysis identified 38 genome-wide significant loci, including novel loci such as D2HGDH and GAL2ST2. Computational analysis showed that shared genetic loci are enriched in immune/inflammatory systems and tissues with epithelium cells. Our work identifies common genetic architectures shared between asthma and allergy and will help to advance our understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.

scholarly journals Genome wide association study identifies four loci for early onset schizophrenia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suqin Guo ◽  
Jiewei Liu ◽  
Wenqiang Li ◽  
Yongfeng Yang ◽  
Luxian Lv ◽  
...  
Keyword(s):  
Early Onset ◽  
Genetic Basis ◽  
Association Studies ◽  
Significant Risk ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Early Onset Schizophrenia ◽  
Risk Variants ◽  
Genome Wide ◽  
Discovery Stage

AbstractEarly onset schizophrenia (EOS, defined as first onset of schizophrenia before age 18) is a rare form of schizophrenia (SCZ). Though genome-wide association studies (GWASs) have identified multiple risk variants for SCZ, most of the cases included in these GWASs were not stratified according to their first age at onset. To date, the genetic architecture of EOS remains largely unknown. To identify the risk variants and to uncover the genetic basis of EOS, we conducted a two-stage GWAS of EOS in populations of Han Chinese ancestry in this study. We first performed a GWAS using 1,256 EOS cases and 2,661 healthy controls (referred as discovery stage). The genetic variants with a P < 1.0 × 10−04 in discovery stage were replicated in an independent sample (903 EOS cases and 3,900 controls). We identified four genome-wide significant risk loci for EOS in the combined samples (2,159 EOS cases and 6,561 controls), including 1p36.22 (rs1801133, Pmeta = 4.03 × 10−15), 1p31.1 (rs1281571, Pmeta = 4.14 × 10−08), 3p21.31 (rs7626288, Pmeta = 1.57 × 10−09), and 9q33.3 (rs592927, Pmeta = 4.01 × 10−11). Polygenic risk scoring (PRS) analysis revealed substantial genetic overlap between EOS and SCZ. These discoveries shed light on the genetic basis of EOS. Further functional characterization of the identified risk variants and genes will help provide potential targets for therapeutics and diagnostics.

scholarly journals Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

2020 ◽  
Author(s):  
Hugo Peyre ◽  
Tabea Schoeler ◽  
Chaoyu Liu ◽  
Camille Michèle Williams ◽  
Nicolas Hoertel ◽  
...  
Keyword(s):  
Structural Equation ◽  
Association Studies ◽  
Autism Spectrum ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hyperactivity Disorder ◽  
Risk Variants ◽  
Genome Wide ◽  
Summary Data ◽  
Shared Genetic

ABSTRACTBackgroundSeveral lines of evidence point toward the presence of shared genetic factors underlying Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, Genome-Wide Association Studies (GWAS) have yet to identify risk variants (i.e. Single-Nucleotide Polymorphisms, SNPs) shared by ADHD and ASD.MethodsTwo complementary multivariate analyses – genomic structural equation modelling (SEM) and colocalization analysis – were exploited to identify the shared SNPs for ASD and ADHD, using summary data from two independent GWAS of ASD (N=46,350) and ADHD individuals (N=55,374).ResultsGenomic SEM identified 7 novel SNPs shared between ASD and ADHD (pgenome-wide<5e-8), including three SNPs that were not identified in any of the original univariate GWAS of ASD and ADHD (rs227378, rs2391769 and rs325506). We also mapped 4 novel genes (MANBA, DPYD, INSM1, and PAX1) to SNPs shared by ASD and ADHD, as well as 4 genes that had already been mapped to SNPs identified in either ASD or ADHD GWAS (SORCS3, XRN2, PTBP2 and NKX2-4). All the shared genes between ADHD and ASD were more prominently expressed in the brain than the genes mapped to SNPs specific to ASD or ADHD. Colocalization analyses revealed that 44% percent of the SNPs associated with ASD (p<1e-6) colocalized with ADHD SNPs and 26% of the SNPs associated with ADHD (p<1e-6) colocalized with ASD SNPs.ConclusionsUsing multivariate genomic analyses, the present study reveals the shared genetic pathways that underlie ASD and ADHD. Further investigation of these pathways may help identify new targets for treatment of these disorders.

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.

Genetics of Hypertension

2018 ◽  
Author(s):  
Matthew A. Sparks ◽  
Paul J Phelan
Keyword(s):  
Association Studies ◽  
Large Population ◽  
Antihypertensive Agents ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Monogenic Diseases ◽  
High Prevalence ◽  
Shared Risk

Despite the high prevalence of hypertension and its resulting morbidity and mortality, our knowledge of its pathogenesis remains limited. Strong evidence for a genetic role in blood pressure (BP) variability was first provided by familial segregation studies and the identification of mendelian disorders causing marked hypertension. These monogenic diseases, largely involving genes in sodium homeostatic pathways, have reinforced the Guytonian principle that BP is largely governed by renal sodium excretion. More recently, large population based genome wide association studies (GWAS) have attempted to fill in the missing heritability of the BP trait, with mixed results. Although many variants have been identified that are robustly associated with BP variability, they are mostly rare and together are responsible for a tiny percentage of total trait variability. Observations from GWAS include shared risk variants for cardiovascular and kidney disease, including polymorphisms in UMOD. Mutations in this gene are known to cause monogenic renal disease. GWAS data may be employed for pathway analysis to discover the etiology of hypertension as well providing the potential to interrogate drug responses to antihypertensive agents depending on genotype. The chapter concludes with describing future directions in BP genetics including evidence of the role of epigenetic mechanisms in BP pathogenesis. As we enter the era of whole genome sequencing, the possibility exists to discover the missing hereditability of BP variation although this technology will present its own challenges. This review contains 6 figures, 2 tables and 94 references Key words: adrenocorticotropic hormone, autosomal dominant,  autosomal recessive, cytosine-phosphate-guanine, epithelial sodium channel

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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