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2.
Nat Genet ; 51(8): 1295, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31239548

RESUMO

In the version of the paper initially published, no competing interests were declared. The 'Competing interests' statement should have stated that B.M.N. is on the Scientific Advisory Board of Deep Genomics. The error has been corrected in the HTML and PDF versions of the article.

3.
Nat Genet ; 50(2): 229-237, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29292387

RESUMO

We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (N eff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.

4.
Nat Hum Behav ; 2(12): 948-954, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30988446

RESUMO

Preference for mates with similar phenotypes; that is, assortative mating, is widely observed in humans1-5 and has evolutionary consequences6-8. Under Fisher's classical theory6, assortative mating is predicted to induce a signature in the genome at trait-associated loci that can be detected and quantified. Here, we develop and apply a method to quantify assortative mating on a specific trait by estimating the correlation (θ) between genetic predictors of the trait from single nucleotide polymorphisms on odd- versus even-numbered chromosomes. We show by theory and simulation that the effect of assortative mating can be quantified in the presence of population stratification. We applied this approach to 32 complex traits and diseases using single nucleotide polymorphism data from ~400,000 unrelated individuals of European ancestry. We found significant evidence of assortative mating for height (θ = 3.2%) and educational attainment (θ = 2.7%), both of which were consistent with theoretical predictions. Overall, our results imply that assortative mating involves multiple traits and affects the genomic architecture of loci that are associated with these traits, and that the consequence of mate choice can be detected from a random sample of genomes.


Assuntos
Genoma Humano , Casamento , Alelos , Estatura/genética , Escolaridade , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genoma Humano/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável
7.
Nat Genet ; 49(8): 1174-1181, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28692066

RESUMO

Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10-18), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 × 10-5 and LRT = 30.80, P = 1.42 × 10-8), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.


Assuntos
Índice de Massa Corporal , Obesidade/genética , Adolescente , Adulto , Idoso , Envelhecimento/genética , Teorema de Bayes , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Gêmeos/genética , Adulto Jovem
8.
Nat Genet ; 49(7): 1107-1112, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530673

RESUMO

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.


Assuntos
Estudo de Associação Genômica Ampla , Inteligência/genética , Adolescente , Adulto , Idoso , Encéfalo/metabolismo , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
9.
Nat Neurosci ; 19(12): 1538-1539, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27898085
10.
Twin Res Hum Genet ; 19(5): 407-17, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27546527

RESUMO

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.


Assuntos
Afeto , Herança Multifatorial , Satisfação Pessoal , Desenvolvimento da Personalidade , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Reino Unido
11.
Curr Dir Psychol Sci ; 24(4): 304-312, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26556960

RESUMO

Behavior genetics is the study of the relationship between genetic variation and psychological traits. Turkheimer (2000) proposed "Three Laws of Behavior Genetics" based on empirical regularities observed in studies of twins and other kinships. On the basis of molecular studies that have measured DNA variation directly, we propose a Fourth Law of Behavior Genetics: "A typical human behavioral trait is associated with very many genetic variants, each of which accounts for a very small percentage of the behavioral variability." This law explains several consistent patterns in the results of gene discovery studies, including the failure of candidate gene studies to robustly replicate, the need for genome-wide association studies (and why such studies have a much stronger replication record), and the crucial importance of extremely large samples in these endeavors. We review the evidence in favor of the Fourth Law and discuss its implications for the design and interpretation of gene-behavior research.

12.
Big Data ; 3(3): 198-202, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26487990

RESUMO

Despite clear links between genes and smoking, effective public policy requires far richer measurement of the feedback between biological, behavioral, and environmental factors. The Kavli HUMAN Project (KHP) plans to exploit the plummeting costs of data gathering and to make creative use of new technologies to construct a longitudinal panel data set that would compare favorably to existing longitudinal surveys, both in terms of the richness of the behavioral measures and the cost-effectiveness of the data collection. By developing a more comprehensive approach to characterizing behavior than traditional methods, KHP will allow researchers to paint a much richer picture of an individual's life-cycle trajectory of smoking, alcohol, and drug use, and interactions with other choices and environmental factors. The longitudinal nature of KHP will be particularly valuable in light of the increasing evidence for how smoking behavior affects physiology and health. The KHP could have a transformative impact on the understanding of the biology of addictive behaviors such as smoking, and of a rich range of prevention and amelioration policies.

13.
Nat Neurosci ; 18(7): 953-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26053403

RESUMO

We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.


Assuntos
Transtorno Bipolar/genética , Criatividade , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Transtornos Psicóticos/genética , Sistema de Registros , Esquizofrenia/genética , Estudos de Coortes , Feminino , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Risco , Suécia/epidemiologia
14.
Science ; 347(6217): 81-3, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25477213

RESUMO

Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared with females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.8 to 6.7; Uppsala Longitudinal Study of Adult Men: OR = 2.4, 95% CI = 1.6 to 3.6; and Prospective Investigation of the Vasculature in Uppsala Seniors: OR = 3.5, 95% CI = 1.4 to 8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.


Assuntos
Cromossomos Humanos Y/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Fumar , Idoso , Idoso de 80 Anos ou mais , Células Sanguíneas/metabolismo , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutagênese , Fatores de Risco , Fatores Sexuais , Suécia
15.
Sociol Sci ; 2(6): 82-105, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-29051911

RESUMO

Parental education is the strongest measured predictor of offspring education, and thus many scholars see the parent-child correlation in educational attainment as an important measure of social mobility. But if social changes or policy interventions are going to have dynastic effects, we need to know what accounts for this intergenerational association, that is, whether it is primarily environmental or genetic in origin. Thus, to understand whether the estimated social influence of parental education on offspring education is biased owing to genetic inheritance (or moderated by it), we exploit the findings from a recent large genome-wide association study of educational attainment to construct a genetic score designed to predict educational attainment. Using data from two independent samples, we find that our genetic score significantly predicts years of schooling in both between-family and within-family analyses. We report three findings that should be of interest to scholars in the stratification and education fields. First, raw parent-child correlations in education may reflect one-sixth genetic transmission and five-sixths social inheritance. Second, conditional on a child's genetic score, a parental genetic score has no statistically significant relationship to the child's educational attainment. Third, the effects of offspring genotype do not seem to be moderated by measured sociodemographic variables at the parental level (but parent-child genetic interaction effects are significant). These results are consistent with the existence of two separate systems of ascription: genetic inheritance (a random lottery within families) and social inheritance (across-family ascription). We caution, however, that at the presently attainable levels of explanatory power, these results are preliminary and may change when better-powered genetic risk scores are developed.

16.
Psychol Sci ; 25(11): 1975-86, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25287667

RESUMO

A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.


Assuntos
Logro , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Escolaridade , Genótipo , Humanos , Massachusetts , Análise de Componente Principal , Queensland , Sistema de Registros , Reprodutibilidade dos Testes
17.
PLoS One ; 9(7): e100248, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25032841

RESUMO

Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10(-10)) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10(-04) and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.


Assuntos
Testes de Inteligência , Inteligência/genética , Aprendizagem , Adolescente , Adulto , Criança , Pré-Escolar , Escolaridade , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Matemática , Polimorfismo de Nucleotídeo Único/genética
18.
Genet Epidemiol ; 37(8): 846-59, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24186853

RESUMO

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.


Assuntos
Predisposição Genética para Doença , Família Multigênica/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Fumar/genética , Adolescente , Idade de Início , Cotinina/metabolismo , Feminino , Loci Gênicos/genética , Humanos , Internacionalidade , Desequilíbrio de Ligação/genética , Masculino , Proteínas do Tecido Nervoso/genética , Fenótipo , Tabagismo/genética
19.
Proc Natl Acad Sci U S A ; 110(24): 9692-7, 2013 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-23708117

RESUMO

Subjective well-being (SWB) is a major topic of research across the social sciences. Twin and family studies have found that genetic factors may account for as much as 30-40% of the variance in SWB. Here, we study genetic contributions to SWB in a pooled sample of ≈ 11,500 unrelated, comprehensively-genotyped Swedish and Dutch individuals. We apply a recently developed method to estimate "common narrow heritability": the fraction of variance in SWB that can be explained by the cumulative additive effects of genetic polymorphisms that are common in the population. Our estimates are 5-10% for single-question survey measures of SWB, and 12-18% after correction for measurement error in the SWB measures. Our results suggest guarded optimism about the prospects of using genetic data in SWB research because, although the common narrow heritability is not large, the polymorphisms that contribute to it could feasibly be discovered with a sufficiently large sample of individuals.


Assuntos
Felicidade , Satisfação Pessoal , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Polimorfismo de Nucleotídeo Único , Sistema de Registros/estatística & dados numéricos , Inquéritos e Questionários , Suécia
20.
PLoS One ; 8(4): e60542, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593239

RESUMO

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σ(g)(2)/σ(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10(-5) were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.


Assuntos
Emprego , Estudo de Associação Genômica Ampla , Herança Multifatorial , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Inteligência , Masculino , Modelos Teóricos , Personalidade , Polimorfismo de Nucleotídeo Único , Sistema de Registros , Gêmeos Dizigóticos , Gêmeos Monozigóticos
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