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1.
Nature ; 610(7933): 704-712, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36224396

RESUMO

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.


Assuntos
Estatura , Mapeamento Cromossômico , Polimorfismo de Nucleotídeo Único , Humanos , Estatura/genética , Frequência do Gene/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Europa (Continente)/etnologia , Tamanho da Amostra , Fenótipo
2.
J Intern Med ; 292(3): 390-408, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35404524

RESUMO

DNA methylation is an epigenetic modification that has consistently been shown to be linked with a variety of human traits and diseases. Because DNA methylation is dynamic and potentially reversible in nature and can reflect environmental exposures and predict the onset of diseases, it has piqued interest as a potential disease biomarker. DNA methylation patterns are more stable than transcriptomic or proteomic patterns, and they are relatively easy to measure to track exposure to different environments and risk factors. Importantly, technologies for DNA methylation quantification have become increasingly cost effective-accelerating new research in the field-and have enabled the development of novel DNA methylation biomarkers. Quite a few DNA methylation-based predictors for a number of traits and diseases already exist. Such predictors show potential for being more accurate than self-reported or measured phenotypes (such as smoking behavior and body mass index) and may even hold potential for applications in clinics. In this review, we will first discuss the advantages and challenges of DNA methylation biomarkers in general. We will then review the current state and future potential of DNA methylation biomarkers in two human traits that show rather consistent alterations in methylome-obesity and smoking. Lastly, we will briefly speculate about the future prospects of DNA methylation biomarkers, and possible ways to achieve them.


Assuntos
Metilação de DNA , Proteômica , Epigênese Genética , Marcadores Genéticos , Humanos , Obesidade/genética , Fumar/efeitos adversos
3.
Alcohol Clin Exp Res ; 45(2): 318-328, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33277923

RESUMO

BACKGROUND: DNA methylation may play a role in the progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. We examined the association between alcohol consumption and DNA methylation patterns using 3 approaches: a conventional epigenome-wide association study (EWAS); a co-twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption. METHODS: Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1,004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome-wide DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. RESULTS: In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co-twin comparisons replicated 4 CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker vs. light drinker/abstainer or moderate drinker vs. abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co-twins. CONCLUSIONS: Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood.


Assuntos
Envelhecimento/genética , Consumo de Bebidas Alcoólicas/genética , Metilação de DNA/fisiologia , Epigenoma/fisiologia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Envelhecimento/sangue , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Coortes , Estudos Transversais , Epigênese Genética/fisiologia , Feminino , Finlândia/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Humanos , Estudos Longitudinais , Masculino , Adulto Jovem
4.
Twin Res Hum Genet ; 22(4): 240-254, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31462340

RESUMO

The older Finnish Twin Cohort (FTC) was established in 1974. The baseline survey was in 1975, with two follow-up health surveys in 1981 and 1990. The fourth wave of assessments was done in three parts, with a questionnaire study of twins born during 1945-1957 in 2011-2012, while older twins were interviewed and screened for dementia in two time periods, between 1999 and 2007 for twins born before 1938 and between 2013 and 2017 for twins born in 1938-1944. The content of these wave 4 assessments is described and some initial results are described. In addition, we have invited twin-pairs, based on response to the cohortwide surveys, to participate in detailed in-person studies; these are described briefly together with key results. We also review other projects based on the older FTC and provide information on the biobanking of biosamples and related phenotypes.


Assuntos
Bancos de Espécimes Biológicos , Doenças em Gêmeos/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Estudos de Coortes , Doenças em Gêmeos/epidemiologia , Feminino , Finlândia/epidemiologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/epidemiologia , Fumar/genética , Inquéritos e Questionários
5.
Genome Biol ; 22(1): 242, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425859

RESUMO

To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that modulate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.


Assuntos
COVID-19/genética , Proteínas de Membrana Transportadoras/genética , Locos de Características Quantitativas , Receptores CXCR6/genética , Cromossomos Humanos Par 3/genética , Humanos , Fenótipo
6.
Med Sci Sports Exerc ; 53(3): 487-495, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32868581

RESUMO

PURPOSE: Greater leisure-time physical activity (LTPA) associates with healthier lives, but knowledge regarding occupational physical activity (OPA) is more inconsistent. DNA methylation (DNAm) patterns capture age-related changes in different tissues. We aimed to assess how LTPA and OPA are associated with three DNAm-based epigenetic age estimates, namely, DNAm age, PhenoAge, and GrimAge. METHODS: The participants were young adult (21-25 yr, n = 285) and older (55-74 yr, n = 235) twin pairs, including 16 pairs with documented long-term LTPA discordance. Genome-wide DNAm from blood samples was used to compute DNAm age, PhenoAge, and GrimAge Age acceleration (Acc), which describes the difference between chronological and epigenetic ages. Physical activity was assessed with sport, leisure-time, and work indices based on the Baecke Questionnaire. Genetic and environmental variance components of epigenetic age Acc were estimated by quantitative genetic modeling. RESULTS: Epigenetic age Acc was highly heritable in young adult and older twin pairs (~60%). Sport index was associated with slower and OPA with faster DNAm GrimAge Acc after adjusting the model for sex. Genetic factors and nonshared environmental factors in common with sport index explained 1.5%-2.7% and 1.9%-3.5%, respectively, of the variation in GrimAge Acc. The corresponding proportions considering OPA were 0.4%-1.8% and 0.7%-1.8%, respectively. However, these proportions were minor (<0.5%) after adjusting the model for smoking status. CONCLUSIONS: LTPA associates with slower and OPA with faster epigenetic aging. However, adjusting the models for smoking status, which may reflect the accumulation of unhealthy lifestyle habits, attenuated the associations.


Assuntos
Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Epigênese Genética/fisiologia , Exercício Físico/fisiologia , Atividades de Lazer , Saúde Ocupacional , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fatores Sexuais , Fumar/efeitos adversos , Fumar/genética , Fumar/fisiopatologia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto Jovem
7.
Nat Genet ; 53(9): 1311-1321, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34493871

RESUMO

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.


Assuntos
Metilação de DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Transcriptoma/genética
8.
R Soc Open Sci ; 7(10): 200872, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33204460

RESUMO

We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m-2). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.

9.
Epigenomics ; 11(13): 1469-1486, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31466478

RESUMO

Aim: Smoking strongly influences DNA methylation, with current and never smokers exhibiting different methylation profiles. Methods: To advance the practical applicability of the smoking-associated methylation signals, we used machine learning methodology to train a classifier for smoking status prediction. Results: We show the prediction performance of our classifier on three independent whole-blood datasets demonstrating its robustness and global applicability. Furthermore, we examine the reasons for biologically meaningful misclassifications through comprehensive phenotypic evaluation. Conclusion: The major contribution of our classifier is its global applicability without a need for users to determine a threshold value for each dataset to predict the smoking status. We provide an R package, EpiSmokEr (Epigenetic Smoking status Estimator), facilitating the use of our classifier to predict smoking status in future studies.


Assuntos
Metilação de DNA , Epigenômica/métodos , Fumar Tabaco/genética , Adulto , Idoso , Biologia Computacional/métodos , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Software
10.
Clin Epigenetics ; 10(1): 126, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-30342560

RESUMO

BACKGROUND: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. METHODS: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. RESULTS: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. CONCLUSIONS: Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.


Assuntos
Tecido Adiposo/química , Metilação de DNA , Perfilação da Expressão Gênica/métodos , Fumar/genética , Gêmeos/genética , Regulação para Cima , Adulto , Idoso , Proteínas Sanguíneas/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocinas/genética , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Notch1/genética , Receptores de Trombina
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