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2.
Brain Nerve ; 71(10): 1039-1051, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588048

RESUMO

Dementia is a leading cause of death in many countries. Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, with approximately 35 million affected people. LOAD shows a high heritability (h2) of 58-79%. Clarifying the genetic architecture of LOAD could contribute to precision medicine. In recent years, large-scale genome-wide association studies (GWASs) and their meta-analyses with a large sample size have elucidated the disease-susceptible genes and disease-causing pathways. To date, meta-analyses of GWASs in the Caucasian population have successfully identified approximately 40 LOAD risk loci. The gene set and disease pathway analysis obtained from the results of GWASs suggested biological mechanisms involving brain immune function, lipid-related processes, tau binding proteins, and degradation of amyloid precursor proteins in the pathogenesis of LOAD. Furthermore, the exome sequencing analysis in Japanese individuals with LOAD also revealed a rare variant with a large effect of SHARPIN in LOAD susceptibility, and the variant protein possibly affects the immune response through aberrant cellular localization, which may result in attenuated NF-κB activity in the brain. These findings could provide biological and pharmaceutical approaches in precision medicine for LOAD.


Assuntos
Doença de Alzheimer/genética , Patrimônio Genético , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Humanos , NF-kappa B/metabolismo , Ubiquitinas/genética , Proteínas tau/metabolismo
3.
Brain Nerve ; 71(10): 1081-1088, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588052

RESUMO

During the past 20 years, genome studies for Alzheimer's disease (AD) have elucidated the pathogenesis of AD including the amyloid hypothesis. However, clinical trials of the disease modifying drugs for AD developed based on the amyloid hypothesis have been largely unsuccessful. New genes associated with AD have been identified through comprehensive genome analyses such as genome-wide association studies and whole genome/exome sequencing using next-generation sequencers. With these efforts, new therapeutic targets to AD have been explored. This review summarizes the genetic make-up of AD in terms of both risk and protective factors from the viewpoint of novel therapeutic targets to AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Testes Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Proteção , Fatores de Risco
4.
Brain Nerve ; 71(9): 953-959, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506397

RESUMO

Among the therapeutic agents for Parkinson's disease (PD), there are important drugs that precede drug repositioning. Amantadine, developed as a treatment for influenza A, has been long used as a treatment for PD. Zonisamide is an antiepileptic drug developed in Japan, where its therapeutic effects on PD were also discovered and developed. In recent years, dabrafenib, a therapeutic agent for malignant melanoma, has bean identified as a potential therapeutic agent for PD. Amantadine and zonisamide are drugs that have been serendipitously developed in clinical settings for patients with PD. Meanwhile, the potential for repurposing dabrafenib was discovered by utilizing the results of genome-wide association studies, drug databases, and protein-protein interaction databases.


Assuntos
Amantadina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Imidazóis/uso terapêutico , Oximas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Zonisamida/uso terapêutico , Reposicionamento de Medicamentos , Estudo de Associação Genômica Ampla , Humanos
5.
BMJ ; 366: l4410, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371314

RESUMO

OBJECTIVE: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. DESIGN: Mendelian randomisation study. SETTING: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). PARTICIPANTS: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. RESULTS: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. CONCLUSIONS: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.


Assuntos
Densidade Óssea/genética , Cálcio/sangue , Predisposição Genética para Doença , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/genética , Adenosina Trifosfatases/genética , Diacilglicerol Quinase/genética , Feminino , Fator de Transcrição GATA3/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Medição de Risco , Vitamina D3 24-Hidroxilase/genética , Vitamina K Epóxido Redutases/genética
6.
Gene ; 717: 144045, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31425741

RESUMO

The MADS-box gene family encodes transcription factors and plays an important role in plant growth and the development of flower and fruit. A perennial dioecious plant, the red bayberry genome has been published recently, providing the opportunity to analyze the MADS-box gene family and its role in fruit development and ripening. Here, we identified 54 MADS-box genes in the red bayberry genome, and classified them into two types based on phylogenetic analysis. Thirteen Type I MADS-box genes were subdivided into three subfamilies and 41 Type II MADS-box genes into 13 subfamilies. A total of 46 MADS-box genes were distributed across eight red bayberry chromosomes, and the other eight genes were located on the unmapped scaffolds. Transcriptome analysis suggested that the expression of most Type II genes was higher than Type I in five female tissues. Moreover, 26 MADS-box genes were expressed during red bayberry fruit development and ten of them showed high expression. qRT-PCR showed that the expression of MrMADS01 (SEP, MIKCC), with differences between the pale pink and red varieties, increased significantly at the final ripening stage, suggesting it may participate in ripening as positive regulator and related to anthocyanin biosynthesis. These results provide some clues for future study of MADS-box genes in red bayberry, especially in ripening process.


Assuntos
Frutas/fisiologia , Proteínas de Domínio MADS/genética , Myricaceae/genética , Proteínas de Plantas/genética , Frutas/genética , Frutas/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Estudo de Associação Genômica Ampla , Família Multigênica , Filogenia
7.
BMC Plant Biol ; 19(1): 336, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370790

RESUMO

BACKGROUND: APETALA2-like genes encode plant-specific transcription factors, some of which possess one microRNA172 (miR172) binding site. The miR172 and its target euAP2 genes are involved in the process of phase transformation and flower organ development in many plants. However, the roles of miR172 and its target AP2 genes remain largely unknown in Brassica napus (B. napus). RESULTS: In this study, 19 euAP2 and four miR172 genes were identified in the B. napus genome. A sequence analysis suggested that 17 euAP2 genes were targeted by Bna-miR172 in the 3' coding region. EuAP2s were classified into five major groups in B.napus. This classification was consistent with the exon-intron structure and motif organization. An analysis of the nonsynonymous and synonymous substitution rates revealed that the euAP2 genes had gone through purifying selection. Whole genome duplication (WGD) or segmental duplication events played a major role in the expansion of the euAP2 gene family. A cis-regulatory element (CRE) analysis suggested that the euAP2s were involved in the response to light, hormones, stress, and developmental processes including circadian control, endosperm and meristem expression. Expression analysis of the miR172-targeted euAP2s in nine different tissues showed diverse spatiotemporal expression patterns. Most euAP2 genes were highly expressed in the floral organs, suggesting their specific functions in flower development. BnaAP2-1, BnaAP2-5 and BnaTOE1-2 had higher expression levels in late-flowering material than early-flowering material based on RNA-seq and qRT-PCR, indicating that they may act as floral suppressors. CONCLUSIONS: Overall, analyses of the evolution, structure, tissue specificity and expression of the euAP2 genes were peformed in B.napus. Based on the RNA-seq and experimental data, euAP2 may be involved in flower development. Three euAP2 genes (BnaAP2-1, BnaAP2-5 and BnaTOE1-2) might be regarded as floral suppressors. The results of this study provide insights for further functional characterization of the miR172 /euAP2 module in B.napus.


Assuntos
Brassica napus/genética , Flores/crescimento & desenvolvimento , Genes de Plantas/genética , MicroRNAs/genética , Brassica napus/crescimento & desenvolvimento , Mapeamento Cromossômico , Sequência Conservada/genética , Genes de Plantas/fisiologia , Estudo de Associação Genômica Ampla , MicroRNAs/fisiologia , Filogenia , Alinhamento de Sequência
8.
Science ; 365(6456): 869-870, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31467212
9.
Neuropsychopharmacol Hung ; 21(2): 69-84, 2019 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-31378724

RESUMO

IQ is a psychological indicator with exceptional psychometric properties and substantial real-life predictive power. Behavior genetic results have long suggested that IQ is strongly heritable, that is, inter-individual IQ differences are mostly due to genetic differences, and that the effects of the environment shared by siblings, such as the family's place of residence or socioeconomic status, is minimal. Recently these observations were confirmed by quantitative genetic studies of unprecedented sample sizes, SNP heritability studies combining quantitative and molecular genetic approaches, and genome-wide association studies identifying specific genetic variants underlying IQ. Genome-wide association studies enable the creation of polygenic scores which correlate with actual cognitive ability at approximately r=0.3. The increasing understanding of the genetic basis of IQ, especially the use of polygenic scores validates previous quantitative genetic paradigms and clears the path for several applications in psychology, but it may also be the source of bioethical dilemmas.


Assuntos
Estudo de Associação Genômica Ampla , Humanos , Testes de Inteligência , Herança Multifatorial , Polimorfismo de Nucleotídeo Único
10.
BMC Plant Biol ; 19(1): 351, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412785

RESUMO

BACKGROUND: Rubisco activase (RCA) regulates the activity of Rubisco and is a key enzyme of photosynthesis. RCA expression was widely reported to affect plant photosynthesis and crop yield, but the molecular basis of natural variation in RCA expression in a wide range of maize materials has not been fully elucidated. RESULTS: In this study, correlation analysis in approximately 200 maize inbred lines revealed a significantly positive correlation between the expression of maize RCA gene ZmRCAß and grain yield. A genome-wide association study revealed both cis-expression quantitative trait loci (cis-eQTLs) and trans-eQTLs underlying the expression of ZmRCAß, with the latter playing a more important role. Further allele mining and genetic transformation analysis showed that a 2-bp insertion and a 14-bp insertion in the promoter of ZmRCAß conferred increased gene expression. Because rice is reported to have higher RCA gene expression than does maize, we subsequently compared the genetic factors underlying RCA gene expression between maize and rice. The promoter activity of the rice RCA gene was shown to be stronger than that of the maize RCA gene, suggesting that replacing the maize RCA gene promoter with that of the rice RCA gene would improve the expression of RCA in maize. CONCLUSION: Our results revealed two DNA polymorphisms regulating maize RCA gene ZmRCAß expression, and the RCA gene promoter activity of rice was stronger than that of maize. This work increased understanding of the genetic mechanism that underlies RCA gene expression and identify new targets for both genetic engineering and selection for maize yield improvement.


Assuntos
Oryza/genética , Fotossíntese/genética , Proteínas de Plantas/genética , Zea mays/genética , Expressão Gênica , Regulação da Expressão Gênica de Plantas , Estudo de Associação Genômica Ampla , Oryza/metabolismo , Oryza/fisiologia , Folhas de Planta , Proteínas de Plantas/metabolismo , Proteínas de Plantas/fisiologia , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Ribulose-Bifosfato Carboxilase , Zea mays/metabolismo , Zea mays/fisiologia
11.
J Agric Food Chem ; 67(37): 10380-10391, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31464444

RESUMO

The timing of spring bud flush (TBF) is of economic importance for tea plant (Camellia sinensis) breeding. We employed a genome-wide association study (GWAS) to identify favorable single nucleotide polymorphism (SNP) allelic variations as well as candidate genes that control TBF of C. sinensis using specific-locus-amplified fragment sequencing (SLAF-seq) in a diversity panel comprising 151 tea plant germplasm resources. GWAS analysis revealed 26 SNPs associated with TBF in three years, and we eventually identified a final significant SNP for TBF. To identify candidate genes possibly related to TBF, we screened seven candidate genes within 100 kb regions surrounding the trait-related SNP loci. Furthermore, the favorable allelic variation, the "TT" genotype in the SNP loci, was discovered, and a derived cleaved amplified polymorphism (dCAPS) marker was designed that cosegregated with TBF, which could be used for marker-assisted selection (MAS) breeding in C. sinensis. The results obtained from this study can provide a theoretical and applied basis for the MAS of early breeding in tea plants in the future.


Assuntos
Camellia sinensis/genética , Polimorfismo de Nucleotídeo Único , Alelos , Cruzamento , Camellia sinensis/classificação , Camellia sinensis/crescimento & desenvolvimento , Mapeamento Cromossômico , Variação Genética , Genoma de Planta , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas
12.
Nervenarzt ; 90(9): 898-906, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31428829

RESUMO

Sporadic Alzheimer's disease is the most common neurodegenerative disorder and represents a very important public healthcare problem with a devastating economic burden for industrialized countries. Recent knowledge acquired from experimental, epidemiological, radiological and genome-wide association studies (GWAS) underline the role of the innate immune system in the pathophysiology of this disease. This article reviews and discusses the function of the cerebral innate immune system, the newly discovered genes associated with the disease development and the experimental evidence around the role of microglia in the onset and progression of Alzheimer's disease. The discovery of different microglia phenotypes associated with the pathology as well as new molecular players will enable the development of new preventive and therapeutic strategies by modulating neuroinflammation in neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Imunidade Inata , Inflamação , Microglia , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Progressão da Doença , Estudo de Associação Genômica Ampla , Humanos , Microglia/imunologia
13.
Gene ; 718: 144048, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421189

RESUMO

Main conclusion Among 247 RsAP2/ERF identified, the majority of the 21 representatives were preferably expressed under drought and heat while suppressed under heavy metals, indicating their potential roles in abiotic stress responses and tolerance. APETALA2/Ethylene-Responsive factor (AP2/ERF) transcription factor (TF) is one of the largest gene families in plants that play a fundamental role in growth and development as well as biotic and/or abiotic stresses responses. Although AP2/ERFs have been extensively characterized in many plant species, little is known about this family in radish, which is an important root vegetable with various medicinal properties. The available genome provides valuable opportunity to identify and characterize the global information on AP2/ERF TFs in radish. In this study, a total of 247 ERF family genes were identified from the radish genome, and sequence alignment and phylogenetic analyses classified the AP2/ERF superfamily into five groups (AP2, ERF, DREB, RAV and soloist). Motif analysis showed that other than AP2/ERF domains, other conserved regions were selectively distributed among different clades in the phylogenetic tree. Chromosome location analysis showed that tandem duplication may result in the expansion of RsAP2/ERF gene family. The RT-qPCR analysis confirmed that a proportion of AP2/ERF genes were preferably expressed under drought and heat stresses, whereas they were suppressed under the ABA and heavy metal stresses. These results provided valuable information for further evolutionary and functional characterization of RsAP2/ERF genes, and contributed to genetic improvement of stress tolerances in radish and other root vegetable crops.


Assuntos
Evolução Molecular , Proteínas de Homeodomínio , Metais Pesados/toxicidade , Família Multigênica , Proteínas Nucleares , Filogenia , Proteínas de Plantas , Raphanus , Estresse Fisiológico/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raphanus/genética , Raphanus/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Gene ; 718: 144018, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31454543

RESUMO

Cytosine DNA methylation (5mC) is an epigenetic mark that regulates gene expression in plant responses to environmental stresses. Zinc-finger protein (ZFP) is the largest family of DNA-binding transcription factors that also plays an essential role in eukaryote. In plant we have already identified and characterized different useful ZFP-genes. While, the main objective of this research was to observe and identify more targeted stress responsive genes of ZFPs epigenetically throughout genome in rice for the first time. A comprehensive correlation analysis was performed through methylated DNA immunoprecipitation (MeDIP)-chip hybridization in rice under salt and osmotic stresses. High salinity and drought are two major abiotic hazards that are destroying the crop world-wide. As a result, Through-out genome 14 unique stress responsive transcription factors of ZFP-genes with varying level of methylation and expression under two conditions (control vs. stress) were isolated. All the identified genes were confirmed from different databases for their specific structure, cis-regulatory elements, phylogenetic analysis, and synteny analysis. Moreover, the tissue-specific expression patterns, and expression under abiotic and phytohormones stresses were also investigated. Phylogenetically all the genes were divided into 6 distinct subgroups with Arabidopsis and orthologous proteins were find-out through synteny analysis. Available RNA-seq data in response to various phytohormones provided hormone inducible gene expression profile. Through Reverse Transcriptase qPCR (RT-qPCR) analysis tissue-specific expression in shoot and root over various time points against salt and osmotic stresses exhibited the diverse expression patterns of identified genes. Overall, the present study providing a foundation for in-depth characterization of identified genes and to further understand the epigenetic role of DNA methylation for genes expression and environmental stresses regulation in higher plant.


Assuntos
Metilação de DNA/fisiologia , DNA de Plantas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/fisiologia , Oryza , Proteínas de Plantas , Estresse Fisiológico/fisiologia , Fatores de Transcrição , DNA de Plantas/genética , DNA de Plantas/metabolismo , Estudo de Associação Genômica Ampla , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/classificação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Yi Chuan ; 41(8): 677-685, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447419

RESUMO

MicroRNAs (miRNAs) compose a class of non-coding transcripts with a mean length of 22 nucleotides, and play critical roles in regulating gene expression in the process of development, proliferation and differentiation of neurons. Recent genome-wide association studies (GWAS) find most of schizophrenia-associated single nucleotide polymorphisms (SNPs) locating in the non-coding regions, providing functional implications of miRNAs in the development of schizophrenia. In this review, we highlight the interplays between GWAS-SNPs and miRNAs in four perspectives: SNP in miRNA gene; miRNA located in the host gene; SNP located in the miRNA's seed sequence; SNP located in the miRNA's binding site. We also speculate on the future research on the role of miRNA in the development of schizophrenia.


Assuntos
MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Sítios de Ligação , Estudo de Associação Genômica Ampla , Humanos
16.
Adv Exp Med Biol ; 1193: 135-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368102

RESUMO

Obesity is multifactorial and complex. Remarkable progress has been made recently in search for polygenic obesity through genome-wide association study (GWAS), but biology of polygenic effects on obesity is largely poor. This review summarizes the available evidence and provides an overview of the links between ALDH2 variants and adiposity, which were firstly and mainly derived from studies of polygenic obesity and also indirectly investigated by using cell lines and mice. The genetic association studies have observed consistent associations of ALDH2 variants with obesity-related traits including BMI, waist circumference (WC), waist-to-hip ratio (WHR), and visceral fat accumulation. In consideration of ALDH2 variants with enzyme activity and alcohol consumption behavior in physiological mechanism studies, we proposed a model by which the physiological and behavioral consequences of alcohol consumption serve as an intermediary process between polymorphisms in ALDH2 and obesity.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Obesidade/genética , Adiposidade/genética , Animais , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Circunferência da Cintura , Relação Cintura-Quadril
17.
Adv Exp Med Biol ; 1193: 237-253, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368109

RESUMO

Aging is a complex irreversible biological process associated with increased prevalence of chronic disease and high healthcare burden. Several theories have been proposed for the biology of aging including free radical accumulation, DNA damage, apoptosis, telomere shortening, autophagy failure, and disturbed autonomic response. Aging is also closely associated with progressive deterioration of cardiovascular and neurological functions. Linkage, genome-wide association (GWAS), and next-generation sequencing analysis have confirmed a number of susceptibility loci for aging, in particular, Alzheimer's disease. Recent evidence from our group and others also revealed a tie between genetic mutation of mitochondrial aldehyde dehydrogenase (ALDH2) and life span as well as cardiovascular aging. ALDH2 represents the single most gene with the greatest number of human genetic polymorphism and is deemed an important enzyme for detoxification of reactive aldehydes. Here, we will briefly review the tie between ALDH2 and cardiovascular aging process. While recent work on ALDH2 research has broadened the pathogenic mechanisms of ALDH2 mutation or deficiency, therapeutic potential targeting ALDH2 in the elderly still remains debatable.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Sistema Cardiovascular , Longevidade/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo Genético
18.
Medicine (Baltimore) ; 98(32): e16825, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393416

RESUMO

Observational studies have reported that childhood obesity is positively associated with risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in adults; however, whether this association is causal is still unclear. In the present study, we conducted the 2-sample Mendelian randomization (MR) studies to investigate whether childhood obesity is causally associated with T2D and CAD in adults.Seven single-nucleotide polymorphisms (SNPs) that significantly associated with childhood obesity were used as instrumental variables. The 2-sample MR analyses were performed with the summary-level data of large-sample genome-wide association studies to evaluate the causal effects of childhood obesity on adult T2D and CAD and the levels of cardiometabolic traits.The 2-sample MR analyses suggested that each 1-unit increase in the log-odds of having childhood obesity was causally associated with an increased risk of adult T2D (odds ratio [OR] = 1.16, 95% confidential interval [CI] = 1.06-1.28; P = 1.0 × 10) and CAD (OR = 1.07, 95% CI = 1.02-1.12; P = 4.0 × 10) based on the inverse-variance weighted method. The MR analyses also suggested that childhood obesity was positively associated with the levels of adult body mass index, waist circumference, hip circumference, waist and hip ratio, log-transformed fasting glucose, log-transformed homeostatic model assessment (HOMA) of insulin resistance (%), and triglycerides. The childhood obesity was negatively associated with the adult high-density lipoprotein cholesterol level; however, there was no evidence of a causal association between childhood obesity and the levels of fasting glucose, 2-hour glucose, HbA1c (%), log-transformed HOMA of ß-cell function (%), low-density lipoprotein cholesterol, or total cholesterol in adults.In conclusion, a genetic predisposition to childhood obesity was associated with an increased risk of adult T2D and CAD, providing causal relations between childhood obesity and the risks of T2D and CAD in adults; however, the results need to be validated with larger-scale intervention studies.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/genética , Glicemia , Índice de Massa Corporal , Pesos e Medidas Corporais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Genet Sel Evol ; 51(1): 37, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269896

RESUMO

BACKGROUND: This study aimed at identifying genomic regions that underlie genetic variation of worm egg count, as an indicator trait for parasite resistance in a large population of Australian sheep, which was genotyped with the high-density 600 K Ovine single nucleotide polymorphism array. This study included 7539 sheep from different locations across Australia that underwent a field challenge with mixed gastrointestinal parasite species. Faecal samples were collected and worm egg counts for three strongyle species, i.e. Teladorsagia circumcincta, Haemonchus contortus and Trichostrongylus colubriformis were determined. Data were analysed using genome-wide association studies (GWAS) and regional heritability mapping (RHM). RESULTS: Both RHM and GWAS detected a region on Ovis aries (OAR) chromosome 2 that was highly significantly associated with parasite resistance at a genome-wise false discovery rate of 5%. RHM revealed additional significant regions on OAR6, 18, and 24. Pathway analysis revealed 13 genes within these significant regions (SH3RF1, HERC2, MAP3K, CYFIP1, PTPN1, BIN1, HERC3, HERC5, HERC6, IBSP, SPP1, ISG20, and DET1), which have various roles in innate and acquired immune response mechanisms, as well as cytokine signalling. Other genes involved in haemostasis regulation and mucosal defence were also detected, which are important for protection of sheep against invading parasites. CONCLUSIONS: This study identified significant genomic regions on OAR2, 6, 18, and 24 that are associated with parasite resistance in sheep. RHM was more powerful in detecting regions that affect parasite resistance than GWAS. Our results support the hypothesis that parasite resistance is a complex trait and is determined by a large number of genes with small effects, rather than by a few major genes with large effects.


Assuntos
Enteropatias Parasitárias/veterinária , Doenças dos Ovinos/genética , Doenças dos Ovinos/parasitologia , Animais , Austrália , Mapeamento Cromossômico/veterinária , Resistência à Doença/genética , Fezes/parasitologia , Estudo de Associação Genômica Ampla/veterinária , Hereditariedade , Enteropatias Parasitárias/genética , Ovinos/genética
20.
Genet Sel Evol ; 51(1): 34, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262251

RESUMO

BACKGROUND: Milk quality in dairy cattle is routinely assessed via analysis of mid-infrared (MIR) spectra; this approach can also be used to predict the milk's cheese-making properties (CMP) and composition. When this method of high-throughput phenotyping is combined with efficient imputations of whole-genome sequence data from cows' genotyping data, it provides a unique and powerful framework with which to carry out genomic analyses. The goal of this study was to use this approach to identify genes and gene networks associated with milk CMP and composition in the Montbéliarde breed. RESULTS: Milk cheese yields, coagulation traits, milk pH and contents of proteins, fatty acids, minerals, citrate, and lactose were predicted from MIR spectra. Thirty-six phenotypes from primiparous Montbéliarde cows (1,442,371 test-day records from 189,817 cows) were adjusted for non-genetic effects and averaged per cow. 50 K genotypes, which were available for a subset of 19,586 cows, were imputed at the sequence level using Run6 of the 1000 Bull Genomes Project (comprising 2333 animals). The individual effects of 8.5 million variants were evaluated in a genome-wide association study (GWAS) which led to the detection of 59 QTL regions, most of which had highly significant effects on CMP and milk composition. The results of the GWAS were further subjected to an association weight matrix and the partial correlation and information theory approach and we identified a set of 736 co-associated genes. Among these, the well-known caseins, PAEP and DGAT1, together with dozens of other genes such as SLC37A1, ALPL, MGST1, SEL1L3, GPT, BRI3BP, SCD, GPAT4, FASN, and ANKH, explained from 12 to 30% of the phenotypic variance of CMP traits. We were further able to identify metabolic pathways (e.g., phosphate and phospholipid metabolism and inorganic anion transport) and key regulator genes, such as PPARA, ASXL3, and bta-mir-200c that are functionally linked to milk composition. CONCLUSIONS: By using an approach that integrated GWAS with network and pathway analyses at the whole-genome sequence level, we propose candidate variants that explain a substantial proportion of the phenotypic variance of CMP traits and could thus be included in genomic evaluation models to improve milk CMP in Montbéliarde cows.


Assuntos
Bovinos/genética , Queijo , Estudo de Associação Genômica Ampla/veterinária , Leite/química , Animais , Simulação por Computador , Conjuntos de Dados como Assunto , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Locos de Características Quantitativas , Sequenciamento Completo do Genoma/veterinária
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