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2.
Clin Epigenetics ; 13(1): 214, 2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863305

RESUMO

The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.


Assuntos
Estudo de Associação Genômica Ampla/tendências , Projetos de Pesquisa/normas , Estudo de Associação Genômica Ampla/métodos , Humanos , Projetos de Pesquisa/tendências
3.
Front Endocrinol (Lausanne) ; 12: 731217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34938269

RESUMO

The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits ("endophenotypes"), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Doenças Musculoesqueléticas/genética , Animais , Animais Geneticamente Modificados , Doenças Ósseas/genética , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/tendências , Humanos , Modelos Animais , Herança Multifatorial/genética , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Fenótipo , Locos de Características Quantitativas , Integração de Sistemas , Estudos de Validação como Assunto
4.
Cells ; 10(12)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34943774

RESUMO

Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers have suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients, even in those harboring limited risk factors. This suggests the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge for increasing the efficacy of therapies.


Assuntos
Inteligência Artificial/tendências , Terapia Baseada em Transplante de Células e Tecidos/tendências , Doença Arterial Periférica/terapia , Transcriptoma/genética , Estudo de Associação Genômica Ampla/tendências , Humanos , Doença Arterial Periférica/genética , Medicina de Precisão/tendências , Fatores de Risco , Sequenciamento Completo do Genoma/tendências
5.
PLoS Biol ; 19(5): e3001242, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939687

RESUMO

Genomic research led the way in open science, a tradition continued by genome-wide association studies (GWAS)-through the sharing of materials, results, and data. Coordinated quality control procedures also contributed to robust findings. However, recent years have seen declines in GWAS transparency. Here, we assess some shifts away from open science practices with the aim of stimulating a discussion of these issues.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/tendências , Disseminação de Informação/ética , Genoma/genética , Genômica/ética , Genômica/métodos , Genômica/tendências , Humanos , Disseminação de Informação/métodos , Controle de Qualidade
6.
Psychol Med ; 51(13): 2156-2167, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33879273

RESUMO

Bipolar disorder (BD) is a highly heritable mental disorder and is estimated to affect about 50 million people worldwide. Our understanding of the genetic etiology of BD has greatly increased in recent years with advances in technology and methodology as well as the adoption of international consortiums and large population-based biobanks. It is clear that BD is also highly heterogeneous and polygenic and shows substantial genetic overlap with other psychiatric disorders. Genetic studies of BD suggest that the number of associated loci is expected to substantially increase in larger future studies and with it, improved genetic prediction of the disorder. Still, a number of challenges remain to fully characterize the genetic architecture of BD. First among these is the need to incorporate ancestrally-diverse samples to move research away from a Eurocentric bias that has the potential to exacerbate health disparities already seen in BD. Furthermore, incorporation of population biobanks, registry data, and electronic health records will be required to increase the sample size necessary for continued genetic discovery, while increased deep phenotyping is necessary to elucidate subtypes within BD. Lastly, the role of rare variation in BD remains to be determined. Meeting these challenges will enable improved identification of causal variants for the disorder and also allow for equitable future clinical applications of both genetic risk prediction and therapeutic interventions.


Assuntos
Transtorno Bipolar , Estudo de Associação Genômica Ampla/tendências , Herança Multifatorial/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Comorbidade , Humanos , Farmacogenética/tendências , Transtornos Psicóticos/genética
7.
Psychol Med ; 51(13): 2168-2177, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33550997

RESUMO

Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.


Assuntos
Estudo de Associação Genômica Ampla/tendências , Grupos Raciais , Esquizofrenia/genética , Variações do Número de Cópias de DNA/genética , Loci Gênicos/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Polimorfismo de Nucleotídeo Único , Grupos Raciais/genética , Grupos Raciais/estatística & dados numéricos , Esquizofrenia/mortalidade
9.
Neuron ; 108(5): 801-821, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33096024

RESUMO

Alzheimer's disease (AD) is currently untreatable, and therapeutic strategies aimed to slow cognitive decline have not yet been successful. Many of these approaches have targeted the amyloid cascade, indicating that novel treatment strategies are required. Recent genome-wide association studies (GWASs) have identified a number of risk factors in genes expressed in microglia, underscoring their therapeutic potential in neurodegeneration. In this review, we discuss how the recently defined functions of these AD risk genes can be targeted therapeutically to modulate microglial cell state and slow the progression of AD. Antibody-mediated stimulation of the triggering receptor of myeloid cells 2 (TREM2) is on the forefront of these candidate therapeutic approaches based on a combination of compelling human genetics and emerging preclinical data. This and other approaches to modify microglial function are a topic of intensive study and provide an opportunity for innovative AD treatments, which may be applied alone or potentially in combination with classical anti-amyloid therapies.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Encéfalo/imunologia , Terapia Genética/tendências , Imunoterapia/tendências , Microglia/imunologia , Doença de Alzheimer/genética , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Encéfalo/efeitos dos fármacos , Estudo de Associação Genômica Ampla/tendências , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/uso terapêutico , Microglia/efeitos dos fármacos , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/uso terapêutico
10.
Cells ; 9(10)2020 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-33050425

RESUMO

Over the last 15 years, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic landscape of complex phenotypes. Nevertheless, causal interpretations of GWAS data are challenging but crucial to understand underlying mechanisms and pathologies. In this review, we explore to what extend the research community follows up on GWAS data. We have traced the scientific activities responding to the two largest GWAS conducted on age-related macular degeneration (AMD) so far. Altogether 703 articles were manually categorized according to their study type. This demonstrates that follow-up studies mainly involve "Review articles" (33%) or "Genetic association studies" (33%), while 19% of publications report on findings from experimental work. It is striking to note that only three of 16 AMD-associated loci described de novo in 2016 were examined in the four-year follow-up period after publication. A comparative analysis of five studies on gene expression regulation in AMD-associated loci revealed consistent gene candidates for 15 of these loci. Our random survey highlights the fact that functional follow-up studies on GWAS results are still in its early stages hampering a significant refinement of the vast association data and thus a more accurate insight into mechanisms and pathways.


Assuntos
Estudo de Associação Genômica Ampla/tendências , Degeneração Macular/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética
11.
Eur Neuropsychopharmacol ; 39: 1-18, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896454

RESUMO

Depression is the world's leading cause of disability. Greater understanding of the neurobiological basis of depression is necessary for developing novel treatments with improved efficacy and acceptance. Recently, major advances have been made in the search for genetic variants associated with depression which may help to elucidate etiological mechanisms. The present review has two major objectives. First, we offer a brief review of two major biological systems with strong evidence for involvement in depression pathology: neurotransmitter systems and the stress response. Secondly, we provide a synthesis of the functions of the 269 genes implicated by the most recent genome-wide meta-analysis, supporting the importance of these systems in depression and providing insights into other possible mechanisms involving neurodevelopment, neurogenesis, and neurodegeneration. Our goal is to undertake a broad, preliminary stock-taking of the most recent hypothesis-free findings and examine the weight of the evidence supporting these existing theories and highlighting novel directions. This qualitative review and accompanying gene function table provides a valuable resource and guide for basic and translational researchers, with suggestions for future mechanistic research, leveraging genetics to prioritize studies on the neurobiological processes involved in depression etiology and treatment.


Assuntos
Depressão/genética , Depressão/psicologia , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Neurotransmissores/genética , Depressão/metabolismo , Estudos de Associação Genética/tendências , Estudo de Associação Genômica Ampla/tendências , Humanos , Neurotransmissores/metabolismo
12.
Nat Rev Neurol ; 16(10): 529-546, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32796930

RESUMO

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.


Assuntos
Estudo de Associação Genômica Ampla/tendências , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/terapia , Mutação/genética , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Ensaios Clínicos como Assunto/métodos , Reparo do DNA/genética , Terapia Genética/métodos , Terapia Genética/tendências , Estudo de Associação Genômica Ampla/métodos , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/metabolismo
13.
Neuropharmacology ; 177: 108234, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738310

RESUMO

Over the last decade, robust human genetic findings have been instrumental in elucidating the heritable basis of nicotine addiction (NA). They highlight coding and synonymous polymorphisms in a cluster on chromosome 15, encompassing the CHRNA5, CHRNA3 and CHRNB4 genes, coding for three subunits of the nicotinic acetylcholine receptor (nAChR). They have inspired an important number of preclinical studies, and will hopefully lead to the definition of novel drug targets for treating NA. Here, we review these candidate gene and genome-wide association studies (GWAS) and their direct implication in human brain function and NA-related phenotypes. We continue with a description of preclinical work in transgenic rodents that has led to a mechanistic understanding of several of the genetic hits. We also highlight important issues with regards to CHRNA3 and CHRNB4 where we are still lacking a dissection of their role in NA, including even in preclinical models. We further emphasize the use of human induced pluripotent stem cell-derived models for the analysis of synonymous and intronic variants on a human genomic background. Finally, we indicate potential avenues to further our understanding of the role of this human genetic variation. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.


Assuntos
Predisposição Genética para Doença/genética , Família Multigênica/genética , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Tabagismo/genética , Animais , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/tendências , Humanos , Tabagismo/diagnóstico
14.
Alcohol Alcohol ; 55(6): 681-689, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32666120

RESUMO

AIMS: We aim to describe alcohol consumption and related problems from a nationwide survey in 2010 in Samoa in association with sociodemographic variables as part of an intervention development. METHODS: The sample consisted of 3463 adults, 25-65 years of age. Participants self-reported alcohol consumption in the previous 12 months, patterns of drinking and alcohol-related psychosocial problems. Data about age, census region of residence, highest attained education level, employment, marital status, household assets score and current smoking status were gathered. RESULTS: More than one-third of men, 36.1%, and 4.1% of women consumed alcohol in the past year. There were greater proportions of alcohol users among younger adults, <45 years, in both men and women. Among men, being unemployed and residing outside of rural Savai'i and smoking cigarettes were associated with current alcohol use. Among women, tertiary education and cigarette smoking were strongly associated with alcohol use. Among alcohol consumers, almost 75% of both men and women reported being drunk more than once in the prior month, and 58% of men and 81% of women drank heavily, consuming >4 drinks for women and >5 drinks for men at least once per episode in the prior week. More men than women, 51% versus 26%, felt that alcohol consumption had interfered with their daily life. CONCLUSION: Our analyses identified correlates of alcohol consumption and associated problems that can help guide the development of targeted interventions for different sex and age groups to mitigate the social and physiological harms of alcohol misuse.


Assuntos
Consumo de Bebidas Alcoólicas/etnologia , Consumo de Bebidas Alcoólicas/tendências , Estudo de Associação Genômica Ampla/tendências , Inquéritos Epidemiológicos/tendências , Adulto , Consumo de Bebidas Alcoólicas/economia , Consumo de Bebidas Alcoólicas/psicologia , Estudos Transversais , Emprego/economia , Emprego/psicologia , Emprego/tendências , Feminino , Estudo de Associação Genômica Ampla/métodos , Inquéritos Epidemiológicos/métodos , Humanos , Masculino , Estado Civil/etnologia , Pessoa de Meia-Idade , Samoa/etnologia , Fatores Socioeconômicos
15.
Nat Rev Neurol ; 16(9): 465-480, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641861

RESUMO

Neurodegenerative, neurodevelopmental and neuropsychiatric disorders are among the greatest public health challenges, as many lack disease-modifying treatments. A major reason for the absence of effective therapies is our limited understanding of the causative molecular and cellular mechanisms. Genome-wide association studies are providing a growing catalogue of disease-associated genetic variants, and the next challenge is to elucidate how these variants cause disease and to translate this understanding into therapies. This Review describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases. The bacterial CRISPR system can be used in experimental disease models to edit genomes and to control gene expression levels through CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). These genetic perturbations can be implemented in massively parallel genetic screens to evaluate the functional consequences for human cells. CRISPR screens are particularly powerful in combination with induced pluripotent stem cell technology, which enables the derivation of differentiated cell types, such as neurons and glia, and brain organoids from cells obtained from patients. Modelling of disease-associated changes in gene expression via CRISPRi and CRISPRa can pinpoint causal changes. In addition, genetic modifier screens can be used to elucidate disease mechanisms and causal determinants of cell type-selective vulnerability and to identify therapeutic targets.


Assuntos
Sistemas CRISPR-Cas/genética , Estudo de Associação Genômica Ampla/tendências , Genômica/tendências , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Animais , Edição de Genes/métodos , Edição de Genes/tendências , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia
16.
Nat Rev Neurol ; 16(7): 366-379, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32528109

RESUMO

Schizophrenia is a severe psychiatric disorder with considerable morbidity and mortality. Although the past two decades have seen limited improvement in the treatment of schizophrenia, research into the genetic causes of this condition has made important advances that offer new insights into the aetiology of schizophrenia. This Review summarizes the evidence for a polygenic architecture of schizophrenia that involves a large number of risk alleles across the whole range of population frequencies. These genetic risk loci implicate biological processes related to neurodevelopment, neuronal excitability, synaptic function and the immune system in the pathogenesis of schizophrenia. Mathematical models also suggest a substantial overlap between schizophrenia and psychiatric, behavioural and cognitive traits, a situation that has implications for understanding its clinical epidemiology, psychiatric nosology and pathobiology. Looking ahead, further genetic discoveries are expected to lead to clinically relevant predictive approaches for identifying high-risk individuals, improved diagnostic accuracy, increased yield from drug development programmes and improved stratification strategies to address the heterogeneous disease course and treatment responses observed among affected patients.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Esquizofrenia/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/tendências , Humanos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico
17.
Pharmacogenomics ; 21(7): 487-503, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32343194

RESUMO

The majority of prostate cancer (PCa) is indolent, however, a percentage of patients are initially diagnosed with metastatic disease, for which there is a worse prognosis. There is a lack of biomarkers to identify men at greater risk for developing aggressive PCa. Genome-wide association studies (GWAS) scan the genome to search associations of SNPs with specific traits, like cancer. To date, eight GWAS have resulted in the reporting of 16 SNPs associated with aggressive PCa (p < 5.00 × 10-2). Still, validation studies need to be conducted to confirm the obtained results as GWAS can generate false-positive results. Furthermore, post-GWAS studies provide a better understanding of the functional consequences.


Assuntos
Progressão da Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla/tendências , Fenótipo , Neoplasias da Próstata/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Fatores de Risco
18.
Brain Res Bull ; 158: 84-89, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32119964

RESUMO

AIMS: Insomnia, intelligence and neuroticism are three typical traits and dysfunctions mainly regulated by human brain. Our research aimed to explore the potential genetic relationships between brain function related traits and more than 3000 human plasma proteins. MATERIALS AND METHODS: We conducted a large-scale genetic correlation scan of human plasma proteins and three brain function related traits, including insomnia, intelligence and neuroticism. Linkage disequilibrium score regression (LDSC) analysis was performed to estimate the genetic correlations between each of the blood proteins and insomnia, intelligence and neuroticism via utilizing the genome-wide association study summary statistics of plasma proteins and those three traits. RESULTS: LDSC analysis identified 18 specific plasma proteins shown suggestive genetic correlations with insomnia such as Periostin (coefficient=-0.3910, P value = 0.0070). Twenty-one plasma proteins exhibited genetic correlations with intelligence such as Ecto-ADP-ribosyltransferase 3 (coefficient = 0.3066, P value = 0.0013). Six specific plasma proteins shown suggestive genetic correlations with neuroticism, such as CD70 antigen (coefficient = 0.2979, P value = 0.0134). After further comparing the suggestive proteins between insomnia, intelligence and neuroticism, we detected 3 common plasma proteins shared by insomnia and intelligence such as Periostin (coefficient insomnia =-0.3910, Pinsomnia value = 0.0070; coefficient intelligence =0.2673, Pintelligence value = 0.0159) and Neurexin-1 (coefficient insomnia =-0.2913, Pinsomnia value = 0.0197; coefficient intelligence = 0.2399, Pintelligence value = 0.0035). We also detected 2 common plasma proteins shared by intelligence and neuroticism, including CD70 antigen (coefficient intelligence =-0.2092, Pintelligence value = 0.0337; coefficient neuroticism = 0.2979, Pneuroticism value = 0.0134). CONCLUSION: Our results provide novel clues for unveiling the functional relevance of plasma proteins and brain function related traits.


Assuntos
Proteínas Sanguíneas/genética , Estudo de Associação Genômica Ampla/métodos , Inteligência/genética , Neuroticismo/fisiologia , Característica Quantitativa Herdável , Distúrbios do Início e da Manutenção do Sono/genética , Encéfalo/fisiologia , Estudos de Coortes , Bases de Dados Genéticas/tendências , Estudo de Associação Genômica Ampla/tendências , Humanos , Distúrbios do Início e da Manutenção do Sono/diagnóstico
19.
Med Sci (Paris) ; 36(2): 181-184, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32129759

RESUMO

Evidence for a "homosexuality gene" was claimed in the early 1990's on the basis of linkage studies that, by current criteria, were woefully underpowered. Indeed, follow up studies gave contradictory results. Genome-wide association studies, and very large databases with detailed genetic and phenotypic data, have made possible a re-examination of this issue. While modest heritability (ca. 0.3) for homosexuality is confirmed, no major locus is found and the genetic influence appears extremely polygenic. Thus, there is no single gene, or even small set of genes, that have a strong influence on homosexuality.


Assuntos
Marcadores Genéticos , Homossexualidade/fisiologia , Padrões de Herança/genética , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla/história , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estudo de Associação Genômica Ampla/tendências , História do Século XX , História do Século XXI , Homossexualidade/estatística & dados numéricos , Humanos , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Prevalência
20.
Cereb Cortex ; 30(4): 2307-2320, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32109272

RESUMO

We analyzed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and single nucleotide polymorphism (SNP) data from >26 000 individuals from the UK Biobank project and 5 other projects that had previously participated in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our results confirm the polygenic architecture of neuroanatomical diversity, with SNPs capturing from 40% to 54% of regional brain volume variance. Chromosomal length correlated with the amount of phenotypic variance captured, r ~ 0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a local scale, SNPs within genes (~51%) captured ~1.5 times more genetic variance than the rest, and SNPs with low minor allele frequency (MAF) captured less variance than the rest: the 40% of SNPs with MAF <5% captured

Assuntos
Encéfalo/diagnóstico por imagem , Interação Gene-Ambiente , Variação Genética/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Coortes , Estudo de Associação Genômica Ampla/tendências , Humanos , Imageamento por Ressonância Magnética/tendências
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