Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 70
Filtrar
1.
Nat Commun ; 12(1): 1164, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608517

RESUMO

Understanding how natural selection has shaped genetic architecture of complex traits is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level GWAS data to estimate multiple genetic architecture parameters including selection signature. Here, we present a method (SBayesS) that only requires GWAS summary statistics. We analyse data for 155 complex traits (n = 27k-547k) and project the estimates onto those obtained from evolutionary simulations. We estimate that, on average across traits, about 1% of human genome sequence are mutational targets with a mean selection coefficient of ~0.001. Common diseases, on average, show a smaller number of mutational targets and have been under stronger selection, compared to other traits. SBayesS analyses incorporating functional annotations reveal that selection signatures vary across genomic regions, among which coding regions have the strongest selection signature and are enriched for both the number of associated variants and the magnitude of effect sizes.

2.
Nat Commun ; 12(1): 1050, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594080

RESUMO

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.


Assuntos
Genoma Humano , Filogenia , Adulto , Idoso , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Escolaridade , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Análise de Regressão , Reino Unido
3.
Biol Psychiatry ; 89(1): 11-19, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736793

RESUMO

The genetic contribution to psychiatric disorders is observed through the increased rates of disorders in the relatives of those diagnosed with disorders. These increased rates are observed to be nonspecific; for example, children of those with schizophrenia have increased rates of schizophrenia but also a broad range of other psychiatric diagnoses. While many factors contribute to risk, epidemiological evidence suggests that the genetic contribution carries the highest risk burden. The patterns of inheritance are consistent with a polygenic architecture of many contributing risk loci. The genetic studies of the past decade have provided empirical evidence identifying thousands of DNA variants associated with psychiatric disorders. Here, we describe how these latest results are consistent with observations from epidemiology. We provide an R tool (CHARRGe) to calculate genetic parameters from epidemiological parameters and vice versa. We discuss how the single nucleotide polymorphism-based estimates of heritability and genetic correlation relate to those estimated from family records.

4.
PLoS Genet ; 16(10): e1008718, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33045005

RESUMO

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

5.
Nat Metab ; 2(10): 1126-1134, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33046911

RESUMO

Genome-wide association studies have identified 240 independent loci associated with type 2 diabetes (T2D) risk, but this knowledge has not advanced precision medicine. In contrast, the genetic diagnosis of monogenic forms of diabetes (including maturity-onset diabetes of the young (MODY)) are textbook cases of genomic medicine. Recent studies trying to bridge the gap between monogenic diabetes and T2D have been inconclusive. Here, we show a significant burden of pathogenic variants in genes linked with monogenic diabetes among people with common T2D, particularly in actionable MODY genes, thus implying that there should be a substantial change in care for carriers with T2D. We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. The carriers with T2D are leaner, which evidences a functional metabolic effect of these mutations. Pathogenic variants in actionable MODY genes are more frequent than was previously expected in common T2D. These results open avenues for future interventions assessing the clinical interest of these pathogenic mutations in precision medicine.

6.
Nat Commun ; 11(1): 4799, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968074

RESUMO

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Adulto , Idade de Início , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
PLoS Genet ; 16(9): e1008780, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925905

RESUMO

Genome-Wide Association Studies (GWAS) in large human cohorts have identified thousands of loci associated with complex traits and diseases. For identifying the genes and gene-associated variants that underlie complex traits in livestock, especially where sample sizes are limiting, it may help to integrate the results of GWAS for equivalent traits in humans as prior information. In this study, we sought to investigate the usefulness of results from a GWAS on human height as prior information for identifying the genes and gene-associated variants that affect stature in cattle, using GWAS summary data on samples sizes of 700,000 and 58,265 for humans and cattle, respectively. Using Fisher's exact test, we observed a significant proportion of cattle stature-associated genes (30/77) that are also associated with human height (odds ratio = 5.1, p = 3.1e-10). Result of randomized sampling tests showed that cattle orthologs of human height-associated genes, hereafter referred to as candidate genes (C-genes), were more enriched for cattle stature GWAS signals than random samples of genes in the cattle genome (p = 0.01). Randomly sampled SNPs within the C-genes also tend to explain more genetic variance for cattle stature (up to 13.2%) than randomly sampled SNPs within random cattle genes (p = 0.09). The most significant SNPs from a cattle GWAS for stature within the C-genes did not explain more genetic variance for cattle stature than the most significant SNPs within random cattle genes (p = 0.87). Altogether, our findings support previous studies that suggest a similarity in the genetic regulation of height across mammalian species. However, with the availability of a powerful GWAS for stature that combined data from 8 cattle breeds, prior information from human-height GWAS does not seem to provide any additional benefit with respect to the identification of genes and gene-associated variants that affect stature in cattle.


Assuntos
Estatura/genética , Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Animais , Cruzamento/métodos , Bases de Dados Genéticas , Variação Genética/genética , Humanos , Gado/genética , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
8.
Nat Commun ; 11(1): 3865, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737319

RESUMO

Polygenic scores (PGS) have been widely used to predict disease risk using variants identified from genome-wide association studies (GWAS). To date, most GWAS have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European ancestry populations. Here, we derive a theoretical model of the relative accuracy (RA) of PGS across ancestries. We show through extensive simulations that the RA of PGS based on genome-wide significant SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of causal SNP effects and heritability. We find that LD and MAF differences between ancestries can explain between 70 and 80% of the loss of RA of European-based PGS in African ancestry for traits like body mass index and type 2 diabetes. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWAS are mostly shared across continents.


Assuntos
Asma/genética , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Modelos Genéticos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , África/epidemiologia , Idoso , Alelos , Ásia/epidemiologia , Asma/diagnóstico , Asma/epidemiologia , Asma/etnologia , Índice de Massa Corporal , Colesterol/sangue , Simulação por Computador , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etnologia , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etnologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Prognóstico , Característica Quantitativa Herdável , Risco
9.
Sleep ; 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32671396

RESUMO

STUDY OBJECTIVES: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. METHODS: We computed whole-genome Polygenic Risk Scores (PRS) for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation and extended sleep opportunity, in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. RESULTS: AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with large slow wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. CONCLUSIONS: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.

10.
Hum Brain Mapp ; 41(14): 4062-4076, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32687259

RESUMO

The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.

11.
Behav Genet ; 50(1): 67-71, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31713005

RESUMO

Using data from 5500 adolescents from the National Longitudinal Study of Adolescent to Adult Health, Domingue et al. (Proc Natl Acad Sci 25:256., 2018) claimed to show that friends are genetically more similar to one another than randomly selected peers, beyond the confounding effects of population stratification by ancestry. The authors also claimed to show 'social-genetic' effects, whereby individuals' educational attainment (EA) is influenced by their friends' genes. We argue that neither claim is justified by the data. Mathematically we show that (1) the genetic similarity reported between friends is far larger than theoretically possible if it was caused by phenotypic assortment as the authors claim; uncontrolled population stratification is a likely reason for the genetic similarity they observed, and (2) significant association between individuals' EA and their friends' polygenic scores for EA is a necessary consequence of EA similarity among friends, and does not provide evidence for social-genetic effects. Going forward, we urge caution in the analysis and interpretation of data at the intersection of human genetics and the social sciences.


Assuntos
Comportamento do Adolescente/psicologia , Amigos/psicologia , Genótipo , Adolescente , Escolaridade , Feminino , Humanos , Masculino , Modelos Teóricos , Grupo Associado , Polimorfismo de Nucleotídeo Único/genética , Comportamento Social , Meio Social , Integração Social , Ciências Sociais/métodos , Ciências Sociais/tendências
12.
Nat Commun ; 10(1): 5086, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704910

RESUMO

Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R2 by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.


Assuntos
Teorema de Bayes , Herança Multifatorial/genética , Análise de Regressão , Tecido Adiposo , Alopecia/genética , Metabolismo Basal/genética , Bancos de Espécimes Biológicos , Peso ao Nascer/genética , Composição Corporal/genética , Estatura/genética , Índice de Massa Corporal , Densidade Óssea/genética , Diabetes Mellitus Tipo 2/genética , Volume Expiratório Forçado/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Estatística como Assunto , Capacidade Vital/genética , Relação Cintura-Quadril
13.
Nat Hum Behav ; 3(12): 1332-1342, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636407

RESUMO

Human DNA polymorphisms vary across geographic regions, with the most commonly observed variation reflecting distant ancestry differences. Here we investigate the geographic clustering of common genetic variants that influence complex traits in a sample of ~450,000 individuals from Great Britain. Of 33 traits analysed, 21 showed significant geographic clustering at the genetic level after controlling for ancestry, probably reflecting migration driven by socioeconomic status (SES). Alleles associated with educational attainment (EA) showed the most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals who leave coal mining areas carry more EA-increasing alleles on average than those in the rest of Great Britain. The level of geographic clustering is correlated with genetic associations between complex traits and regional measures of SES, health and cultural outcomes. Our results are consistent with the hypothesis that social stratification leaves visible marks in geographic arrangements of common allele frequencies and gene-environment correlations.


Assuntos
Escolaridade , Emigração e Imigração , Grupo com Ancestrais do Continente Europeu/genética , Herança Multifatorial/genética , Classe Social , Tecido Adiposo , Alelos , Estatura/genética , Índice de Massa Corporal , Análise por Conglomerados , Mapeamento Geográfico , Nível de Saúde , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Reino Unido
14.
Nat Commun ; 10(1): 3719, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481654

RESUMO

In most human societies, there are taboos and laws banning mating between first- and second-degree relatives, but actual prevalence and effects on health and fitness are poorly quantified. Here, we leverage a large observational study of ~450,000 participants of European ancestry from the UK Biobank (UKB) to quantify extreme inbreeding (EI) and its consequences. We use genotyped SNPs to detect large runs of homozygosity (ROH) and call EI when >10% of an individual's genome comprise ROHs. We estimate a prevalence of EI of ~0.03%, i.e., ~1/3652. EI cases have phenotypic means between 0.3 and 0.7 standard deviation below the population mean for 7 traits, including stature and cognitive ability, consistent with inbreeding depression estimated from individuals with low levels of inbreeding. Our study provides DNA-based quantification of the prevalence of EI in a European ancestry sample from the UK and measures its effects on health and fitness traits.


Assuntos
Consanguinidade , Grupo com Ancestrais do Continente Europeu/genética , Nível de Saúde , Aptidão Física/fisiologia , Família , Feminino , Genética Populacional , Genoma Humano/genética , Homozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
16.
Sci Rep ; 9(1): 9439, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.


Assuntos
Glicemia/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Glicemia/análise , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
Nat Commun ; 10(1): 1891, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015401

RESUMO

Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10-8/23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).


Assuntos
Uso de Medicamentos/estatística & dados numéricos , Genoma Humano , Estudo de Associação Genômica Ampla , Testes Farmacogenômicos/estatística & dados numéricos , Medicamentos sob Prescrição/uso terapêutico , Idoso , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Bases de Dados Factuais , Feminino , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologia , Loci Gênicos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/fisiopatologia , Autoadministração , Autorrelato , Reino Unido
18.
Hum Mol Genet ; 28(1): 166-174, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239722

RESUMO

More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.


Assuntos
Adiposidade/genética , Distribuição da Gordura Corporal/métodos , Obesidade/genética , Tecido Adiposo/fisiologia , Adulto , Alelos , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Relação Cintura-Quadril
19.
Nat Commun ; 9(1): 4953, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459399

RESUMO

The original version of this Article contained an error in the spelling of the author Julia Sidorenko, which was incorrectly given as Julia Sirodenko. This has now been corrected in both the PDF and HTML versions of the Article. Further, the sixth sentence of the second paragraph of the Correspondence and the legend to Fig. 1 incorrectly omitted citation of work by Heilmann-Helmbach, S. et al. This has now been corrected in both the PDF and HTML versions of the Article.

20.
Nat Genet ; 50(11): 1505-1513, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).


Assuntos
Mapeamento Cromossômico/métodos , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Genoma Humano/genética , Ilhotas Pancreáticas/metabolismo , Polimorfismo de Nucleotídeo Único , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ensaios de Triagem em Larga Escala/métodos , Humanos , Ilhotas Pancreáticas/patologia , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Fatores Sexuais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA