RESUMO
Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
Assuntos
Asma/genética , Eczema/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/genética , Adolescente , Adulto , Idade de Início , Idoso , Asma/patologia , Criança , Eczema/patologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/patologiaRESUMO
BACKGROUND: Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression. METHODS: Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS). RESULTS: Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15-1.32, R2 = 1.47%). CONCLUSIONS: By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.
RESUMO
BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
Assuntos
Asma/genética , Eczema/genética , Genótipo , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Antígeno 2 Relacionado a Fos/genética , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interleucina-27/genética , Polimorfismo de Nucleotídeo Único , Risco , Equilíbrio Th1-Th2/genéticaRESUMO
The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.
Assuntos
Bancos de Espécimes Biológicos , Biomarcadores/análise , Doenças em Gêmeos/epidemiologia , Sistema de Registros/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Criança , Pré-Escolar , Bases de Dados Factuais , Doenças em Gêmeos/genética , Doenças em Gêmeos/psicologia , Família , Feminino , Seguimentos , Nível de Saúde , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Países Baixos/epidemiologia , Testes Neuropsicológicos , Linhagem , Fenótipo , Inquéritos e QuestionáriosRESUMO
For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of 253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568-1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.
Assuntos
Doenças em Gêmeos/genética , Neuroticismo/fisiologia , Gêmeos/genética , Família/psicologia , Feminino , Humanos , Masculino , Modelos Genéticos , Países Baixos/epidemiologia , Linhagem , Sistema de Registros , Meio Social , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genéticaRESUMO
The genetic contribution to the variation in human lifespan is â¼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Assuntos
Loci Gênicos/fisiologia , Longevidade/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 5 , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Masculino , Fenótipo , Estudos Prospectivos , População BrancaRESUMO
BACKGROUND: Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood. METHODS: We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo. RESULTS: A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10(-4)), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion. CONCLUSIONS: Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.
Assuntos
Artrite Reumatoide/genética , Autoanticorpos/análise , Adulto , Idoso , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metaloproteinase 3 da Matriz/biossíntese , Metaloproteinase 3 da Matriz/sangue , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Membrana Sinovial/metabolismoRESUMO
By treating the coronavirus disease 2019 (COVID-19) pandemic as a natural experiment, we examine the influence of substantial environmental change (i.e., lockdown measures) on individual differences in quality of life (QoL) in the Netherlands. We compare QoL scores before the pandemic (N = 25,772) to QoL scores during the pandemic (N = 17,222) in a sample of twins and their family members. On a 10-point scale, we find a significant decrease in mean QoL from 7.73 (SD = 1.06) before the pandemic to 7.02 (SD = 1.36) during the pandemic (Cohen's d = 0.49). Additionally, variance decomposition shows an increase in unique environmental variance during the pandemic (0.30-1.08), and a decrease in the heritability estimate from 30.9% to 15.5%. We hypothesize that the increased environmental variance is the result of lockdown measures not impacting everybody equally. Whether these effects persist over longer periods and how they impact health inequalities remain topics for future investigation.
Assuntos
COVID-19 , Pandemias , Humanos , Qualidade de Vida , Controle de Doenças Transmissíveis , FamíliaRESUMO
Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
In recent years, evidence has accumulated with regard to the ubiquity of pleiotropy across the genome, and shared genetic etiology is thought to play a large role in the widespread comorbidity among psychiatric disorders and risk factors. Recent methods investigate pleiotropy by estimating genetic correlation from genome-wide association summary statistics. More comprehensive estimates can be derived from the known relatedness between genetic relatives. Analysis of extended twin pedigree data allows for the estimation of genetic correlation for additive and non-additive genetic effects, as well as a shared household effect. Here we conduct a series of bivariate genetic analyses in extended twin pedigree data on lifetime major depressive disorder (MDD) and three indicators of lifestyle, namely smoking behavior, physical inactivity, and obesity, decomposing phenotypic variance and covariance into genetic and environmental components. We analyze lifetime MDD and lifestyle data in a large multigenerational dataset of 19,496 individuals by variance component analysis in the 'Mendel' software. We find genetic correlations for MDD and smoking behavior (rG = 0.249), physical inactivity (rG = 0.161), body-mass index (rG = 0.081), and obesity (rG = 0.155), which were primarily driven by additive genetic effects. These outcomes provide evidence in favor of a shared genetic etiology between MDD and the lifestyle factors.
Assuntos
Transtorno Depressivo Maior/genética , Estilo de Vida , Gêmeos Monozigóticos/genética , Adulto , Idoso , Transtorno Depressivo Maior/epidemiologia , Exercício Físico , Feminino , Pleiotropia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Linhagem , Fumar/epidemiologia , Gêmeos Monozigóticos/psicologiaRESUMO
BACKGROUND: Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting. METHODS: We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. RESULTS: We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality. CONCLUSION: Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.
Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/genética , Algoritmos , Saúde da Família , Feminino , Variação Genética , Humanos , Funções Verossimilhança , Modelos Estatísticos , Linhagem , FenótipoRESUMO
BACKGROUND: The apparent dominant model of colorectal cancer (CRC) inheritance in several large families, without mutations in known CRC susceptibility genes, suggests the presence of so far unidentified genes with strong or moderate effect on the development of CRC. Linkage analysis could lead to identification of susceptibility genes in such families. In comparison to classical linkage analysis with multi-allelic markers, single nucleotide polymorphism (SNP) arrays have increased information content and can be processed with higher throughput. Therefore, SNP arrays can be excellent tools for linkage analysis. However, the vast number of SNPs on the SNP arrays, combined with large informative pedigrees (e.g. >35-40 bits), presents us with a computational complexity that is challenging for existing statistical packages or even exceeds their capacity. We therefore setup a procedure for linkage analysis in large pedigrees and validated the method by genotyping using SNP arrays of a colorectal cancer family with a known MLH1 germ line mutation. METHODS: Quality control of the genotype data was performed in Alohomora, Mega2 and SimWalk2, with removal of uninformative SNPs, Mendelian inconsistencies and Mendelian consistent errors, respectively. Linkage disequilibrium was measured by SNPLINK and Merlin. Parametric linkage analysis using two flanking markers was performed using MENDEL. For multipoint parametric linkage analysis and haplotype analysis, SimWalk2 was used. RESULTS: On chromosome 3, in the MLH1-region, a LOD score of 1.9 was found by parametric linkage analysis using two flanking markers. On chromosome 11 a small region with LOD 1.1 was also detected. Upon linkage disequilibrium removal, multipoint linkage analysis yielded a LOD score of 2.1 in the MLH1 region, whereas the LOD score dropped to negative values in the region on chromosome 11. Subsequent haplotype analysis in the MLH1 region perfectly matched the mutation status of the family members. CONCLUSION: We developed a workflow for linkage analysis in large families using high-density SNP arrays and validated this workflow in a family with colorectal cancer. Linkage disequilibrium has to be removed when using SNP arrays, because it can falsely inflate the LOD score. Haplotype analysis is adequate and can predict the carrier status of the family members.
Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/genética , Genótipo , Mutação em Linhagem Germinativa , Humanos , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Controle de QualidadeRESUMO
BACKGROUND: In this paper, we propose a one degree of freedom test for association between a candidate gene and a binary trait. This method is a generalization of Terwilliger's likelihood ratio statistic and is especially powerful for the situation of one associated haplotype. As an alternative to the likelihood ratio statistic, we derive a score statistic, which has a tractable expression. For haplotype analysis, we assume that phase is known. RESULTS: By means of a simulation study, we compare the performance of the score statistic to Pearson's chi-square statistic and the likelihood ratio statistic proposed by Terwilliger. We illustrate the method on three candidate genes studied in the Leiden Thrombophilia Study. CONCLUSION: We conclude that the statistic follows a chi square distribution under the null hypothesis and that the score statistic is more powerful than Terwilliger's likelihood ratio statistic when the associated haplotype has frequency between 0.1 and 0.4 and has a small impact on the studied disorder. With regard to Pearson's chi-square statistic, the score statistic has more power when the associated haplotype has frequency above 0.2 and the number of variants is above five.
Assuntos
Locos de Características Quantitativas/genética , Distribuição de Qui-Quadrado , Simulação por Computador , Fibrinogênio/genética , Haplótipos , Humanos , Funções Verossimilhança , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.
Assuntos
Metilação de DNA , Interação Gene-Ambiente , Genoma Humano , Padrões de Herança , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Fatores Etários , Envelhecimento/genética , Pré-Escolar , Ilhas de CpG , Feminino , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Fumar/fisiopatologiaRESUMO
Over the past few years the presence of p53-like proteins in plants was frequently reported, by using the monoclonal antibody Pab240. By means of protein purification and screening a cDNA library, a Pab240 cross-reacting protein and a cDNA clone were isolated from barley. Peptide- and DNA-sequence analysis identified one and the same protein: 2-oxoglutarate dehydrogenase. Sequence analysis of 2-oxoglutarate dehydrogenase revealed that the protein contains a perfect Pab240 epitope. In barley, the 110 kDa oxoglutarate dehydrogenase was degraded during isolation to a 53 kDa Pab240 cross-reacting polypeptide, thereby mimicking curiously p53-like properties.
Assuntos
Hordeum/fisiologia , Complexo Cetoglutarato Desidrogenase/química , Proteínas de Plantas/química , Proteína Supressora de Tumor p53/química , Sequência de Aminoácidos , Sequência de Bases , Hordeum/enzimologia , Dados de Sequência Molecular , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Proteína Supressora de Tumor p53/metabolismoRESUMO
In this analysis, we investigate the contributions that linkage-based methods, such as identical-by-descent mapping, can make to association mapping to identify rare variants in next-generation sequencing data. First, we identify regions in which cases share more segments identical-by-descent around a putative causal variant than do controls. Second, we use a two-stage mixed-effect model approach to summarize the single-nucleotide polymorphism data within each region and include them as covariates in the model for the phenotype. We assess the impact of linkage disequilibrium in determining identical-by-descent states between individuals by using markers with and without linkage disequilibrium for the first part and the impact of imputation in testing for association by using imputed genome-wide association studies or raw sequence markers for the second part. We apply the method to next-generation sequencing longitudinal family data from Genetic Association Workshop 18 and identify a significant region at chromosome 3: 40249244-41025167 (p-value = 2.3 × 10(-3)).
RESUMO
We have extended our recently developed 2-step approach for gene-based analysis to the family design and to the analysis of rare variants. The goal of this approach is to study the joint effect of multiple single-nucleotide polymorphisms that belong to a gene. First, the information in a gene is summarized by 2 variables, namely the empirical Bayes estimate capturing common variation and the number of rare variants. By using random effects for the common variants, our approach acknowledges the within-gene correlations. In the second step, the 2 summaries were included as covariates in linear mixed models. To test the null hypothesis of no association, a multivariate Wald test was applied. We analyzed the simulated data sets to assess the performance of the method. Then we applied the method to the real data set and identified a significant association between FRMD4B and diastolic blood pressure (p-value = 8.3 × 10(-12)).
RESUMO
The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances ß-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
Assuntos
Quimotripsina/genética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Incretinas/metabolismo , Receptores de Glucagon/metabolismo , Adulto , Idoso , Diabetes Mellitus , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Feminino , Genótipo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/farmacocinética , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Glucagon/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.