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1.
Nat Commun ; 10(1): 5086, 2019 Nov 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.

2.
Nat Hum Behav ; 2019 Oct 21.
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.

3.
Nat Commun ; 10(1): 3719, 2019 Sep 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.

5.
Sci Rep ; 9(1): 9439, 2019 Jul 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.

6.
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
7.
Nat Commun ; 9(1): 4953, 2018 Nov 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.

8.
Lipids ; 53(8): 797-807, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30334266

RESUMO

It has been reported that polymorphisms within the gene-encoding enzymes related to alcohol metabolism are associated with levels of serum HDL-cholesterol (HDL-C) in East Asian populations. We evaluated the effects of genetic variants within the aldehyde dehydrogenase-2 (ALDH2) gene and the alcohol dehydrogenase-1B (ADH1B) gene on changes in the lipid profile in an 11-year longitudinal study. We genotyped rs1229984 within ADH1B and rs671 within ALDH2. We combined the genetic data with longitudinal clinical and biochemical data from 2002 to 2013 and designed a retrospective longitudinal study of 1436 Japanese males. There were significant negative relationships between rs671 within ALDH2 and HDL-C levels according to multiple linear regression analysis. Next, we assessed the association between the development of hypo-HDL cholesterolemia and rs1229984 within ADH1B or rs671 within ALDH2. In logistic regression analysis, rs671 A allele homozygote carriers have 2.65 times higher risk of developing hypo-HDL cholesterolemia than G allele homozygote carriers. Even after adjusting for possible confounding factors, a significant association was observed. However, no association between rs1229984 within ADH1B and the development of hypo-HDL cholesterolemia was observed. Rs671 within ALDH2 but not rs1229984 within ADH1B was associated with lower HDL-C levels in Japanese males.

9.
Theor Popul Biol ; 124: 51-60, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30316741

RESUMO

Mate choice through direct assortment on heritable traits, assortative mating (AM), is predicted in theory to inflate the genetic variance in a population and the correlation between relatives. Here, we revisit the theory of AM, first established in the landmark 1918 paper from RA Fisher, and provide new theory and analytical results. In particular, we shed light on inconsistencies in the literature regarding the correlation between double first cousins under AM and provide a solution. We derive new theory for AM due to X-chromosome loci. We show in the latter case that the inflation of genetic variance induced under AM is twice as large in females compared to males. These two theoretical contributions are verified and illustrated through simulations. We also provide a more general unified framework for the correlation between relatives in a non-inbred population.

10.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
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).

11.
Hum Mol Genet ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30239722

RESUMO

One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (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.

12.
Hum Mol Genet ; 27(20): 3641-3649, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30124842

RESUMO

Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N âˆ¼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P < 1 × 10-8), including 1185 height-associated SNPs and 751 BMI-associated SNPs located within loci not previously identified by these two GWAS. The near-independent genome-wide significant SNPs explain ∼24.6% of the variance of height and ∼6.0% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were ∼0.44 and ∼0.22, respectively. From analyses of integrating GWAS and expression quantitative trait loci (eQTL) data by summary-data-based Mendelian randomization, we identified an enrichment of eQTLs among lead height and BMI signals, prioritizing 610 and 138 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by the discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow-up studies.

13.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

15.
Nat Commun ; 9(1): 2941, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054458

RESUMO

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

16.
Nat Commun ; 9(1): 2282, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891976

RESUMO

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples ([Formula: see text] for cis-eQTLs and [Formula: see text] for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.

17.
JAMA Psychiatry ; 75(9): 901-910, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29936532

RESUMO

Importance: Urban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas. Objective: To assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk. Design, Setting, and Participants: Four large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018. Exposures: Polygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models. Main Outcomes and Measures: Population density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested. Results: The QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations. Conclusions and Relevance: The results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.

18.
Diabetes ; 67(7): 1310-1321, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728363

RESUMO

In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor α) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA-blocking antibodies, PDGF receptor inhibitors, and by metformin, opening therapeutic avenues. Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and possibly NAFLD.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Adulto , Estudos de Casos e Controles , Células Cultivadas , Metilação de DNA , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Epigênese Genética/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Transdução de Sinais/genética , Regulação para Cima/genética
19.
Nat Genet ; 50(5): 746-753, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29662166

RESUMO

We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.

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