Genome-wide association study of tanning phenotype in a population of European ancestry.
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ABSTRACT:
SUBMITTER: Nan H
PROVIDER: S-EPMC2758927 | biostudies-literature | 2009 Sep
REPOSITORIES: biostudies-literature
Publications
Genome-wide association study of tanning phenotype in a population of European ancestry.
Nan Hongmei H Kraft Peter P Qureshi Abrar A AA Guo Qun Q Chen Constance C Hankinson Susan E SE Hu Frank B FB Thomas Gilles G Hoover Robert N RN Chanock Stephen S Hunter David J DJ Han Jiali J
The Journal of investigative dermatology 20090402 9
We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case-control study with joint P-val ...[more]
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Project description:BackgroundDifferences in fast beta (20-28Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2).MethodIn a sample of 1564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings.ResultsThree intronic variants located within DSE (dermatan sulfate epimerase) on 6q22 were associated with fast beta EEG at a genome wide significant level (p<5×10-8). The most significant SNP was rs2252790 (p<2.6×10-8; MAF=0.36; β=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10-6) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10-4; β=0.29). Previous studies have indicated that DSE is involved in a network of genes integral to membrane organization; gene-based tests indicated that several variants within this network (i.e., DSE, ZEB2, RND3, MCTP1, and CTBP2) were also associated with beta EEG (empirical p<0.05), and of these genes, ZEB2 and CTBP2 were associated with DSM-V Alcohol Use Disorder (AUD; empirical p<0.05).'DiscussionIn this sample of EA families enriched for AUDs, fast beta EEG is associated with variants within DSE on 6q22; the most significant SNP influences the mRNA expression of DSE and ROS1 in hippocampus and temporal cortex, brain regions important for beta EEG activity. Gene-based tests suggest evidence of association with related genes, ZEB2, RND3, MCTP1, CTBP2, and beta EEG. Converging data from GWAS, gene expression, and gene-networks presented in this study provide support for the role of genetic variants within DSE and related genes in neural hyperexcitability, and has highlighted two potential candidate genes for AUD and/or related neurological conditions: ZEB2 and CTBP2. However, results must be replicated in large, independent samples.
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Project description:BackgroundFew genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.MethodsIn this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.FindingsWe included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).InterpretationWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.FundingAsthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.MethodsWe did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.FindingsWe identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18?×?10-8) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69?×?10-5).InterpretationA common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.FundingInstituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
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