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1.
Transl Psychiatry ; 9(1): 219, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488809

RESUMO

Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.

2.
Twin Res Hum Genet ; 22(4): 210-219, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31379313

RESUMO

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

3.
Psychol Med ; 49(7): 1218-1226, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30929657

RESUMO

BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.

4.
Eur J Hum Genet ; 27(6): 970-979, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30760885

RESUMO

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

5.
Eur J Hum Genet ; 27(6): 952-962, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30679814

RESUMO

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

6.
Nat Neurosci ; 21(12): 1656-1669, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30482948

RESUMO

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

7.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

8.
Nicotine Tob Res ; 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29228387

RESUMO

Introduction: The common genetic variant (rs1051730) in the 15q24 nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 was associated with smoking quantity and has been reported to be associated also with reduced ability to quit smoking in pregnant women but results were inconsistent in non pregnant women. The aim of this study was to explore the association between rs1051730 and smoking cessation during pregnancy in a sample of Dutch women. Methods: Data on smoking during pregnancy were available from 1,337 women who ever smoked registered at the Netherlands Twin Register (NTR). Logistic regression was used to assess evidence for association of rs1051730 genotype on smoking during pregnancy. In a subsample of 561 women we investigated the influence of partner's smoking. Educational attainment and year of birth were used as covariates in both analyses. Results: There was evidence for a significant association between having 1 or more T allele's of the rs1051730 polymorphism and the likelihood of smoking during pregnancy (P = 0.03, odds ratio = 1.28, 95% confidence interval: 1.02, 1.61). However, this association attenuated when adjusting for birth cohort and educational attainment (P = 0.37, odds ratio = 1.12, 95% confidence interval: 0.87, 1.43). In the subsample, Smoking spouse was highly associated with smoking during pregnancy, even when educational attainment and birth cohort were included in the model. Conclusions: Our results did not support a strong association between this genetic variant and smoking during pregnancy. However, a strong association was observed with smoking behavior of the partner, regardless of the genotype of the women. Implications: The present study emphasizes the importance of social influences like spousal smoking on smoking behavior of pregnant women. Further research is needed to address the role of rs1051730 genetic variant in influencing smoking cessation and the interaction with important environmental factors like smoking behavior of the partner.

9.
Twin Res Hum Genet ; 20(4): 267-270, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28540843

RESUMO

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10-8) and gene-based (p = 1.48 × 10-7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.


Assuntos
Proteínas do Citoesqueleto/genética , Transtorno Depressivo Maior/genética , Neuropeptídeos/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino
10.
Biol Psychiatry ; 82(5): 312-321, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28153336

RESUMO

BACKGROUND: Major depressive disorder (MDD) is the second largest cause of global disease burden. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by common variants within haplotype blocks, integrating the effects of multiple variants, and may be more powerful for identifying MDD-associated genomic regions. METHODS: We applied HRHM to Generation Scotland: The Scottish Family Health Study, a large family- and population-based Scottish cohort (N = 19,896). Single-single nucleotide polymorphism (SNP) and haplotype-based association tests were used to localize the association signal within the regions identified by HRHM. Functional prediction was used to investigate the effect of MDD-associated SNPs within the regions. RESULTS: A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific long noncoding RNA RP1-269M15.3 in frontal cortex and nucleus accumbens basal ganglia, respectively, were significantly regulated by MDD-associated SNPs within this region. Both the regional heritability and single-SNP associations within this block were replicated in the UK-Ireland group of the most recent release of the Psychiatric Genomics Consortium (PGC), the PGC2-MDD (Major Depression Dataset). The SNP association was also replicated in a depressive symptom sample that shares some individuals with the PGC2-MDD. CONCLUSIONS: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Proteínas HMGB/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Reino Unido
11.
Proc Natl Acad Sci U S A ; 113(50): 14372-14377, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27911795

RESUMO

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified ß-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). ß-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific ß-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/fisiopatologia , Fatores de Crescimento de Fibroblastos/fisiologia , Proteínas de Membrana/genética , Animais , Comportamento Animal/fisiologia , Encéfalo/fisiopatologia , Emoções/fisiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fígado/fisiopatologia , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único
12.
Twin Res Hum Genet ; 19(5): 418-21, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27406421

RESUMO

In a recent GWAS of spontaneous dizygotic twinning, Mbarek et al. (The American Journal of Human Genetics, 2016, Vol 98, pp. 898-908) identified two SNPs, rs11031006 (near FSHB) and rs17293443 (in SMAD3). In the present note, we address the question how to present the results in terms of effect sizes in a manner that is comprehensible to the general audience (e.g., mothers of twins, readership of newspapers). We propose to avoid the standard effect sizes such as odds ratios and relative risk as these require some knowledge of probability theory. Rather, we convey the results in terms of the conditional probabilities, but expressed in natural language.


Assuntos
Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gêmeos Dizigóticos/genética , Feminino , Humanos , Masculino
13.
Am J Hum Genet ; 98(5): 898-908, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27132594

RESUMO

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.


Assuntos
Fertilidade/genética , Variação Genética/genética , Síndrome do Ovário Policístico/genética , Gêmeos Dizigóticos/genética , Ansiedade/genética , Estudos de Casos e Controles , Depressão/genética , Família , Feminino , Hormônio Foliculoestimulante/sangue , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Mães , Síndrome do Ovário Policístico/sangue , Gravidez
14.
Eur J Hum Genet ; 24(10): 1488-95, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27142678

RESUMO

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.


Assuntos
Antígenos Nucleares/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Sono/genética , Encéfalo/metabolismo , Humanos , Transmissão Sináptica/genética
15.
J Med Genet ; 53(7): 441-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27036123

RESUMO

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.


Assuntos
Angiopoietinas/genética , Éxons/genética , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína 4 Semelhante a Angiopoietina , Jejum/fisiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
16.
Circ Cardiovasc Genet ; 8(6): 832-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26538566

RESUMO

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.


Assuntos
Alelos , Pressão Sanguínea/genética , Frequência Cardíaca/genética , Hipertensão , Fumar , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Fumar/efeitos adversos , Fumar/genética , Fumar/fisiopatologia
17.
Am J Med Genet B Neuropsychiatr Genet ; 168(8): 739-48, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26365420

RESUMO

Alcohol dependence (AD) is among the most common and costly public health problems contributing to morbidity and mortality throughout the world. In this study, we investigate the genetic basis of AD in a Dutch population using data from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety (NESDA). The presence of AD was ascertained via the Alcohol Use Disorders Identification Test (AUDIT) applying cut-offs with good specificity and sensitivity in identifying those at risk for AD. Twin-based heritability of AD-AUDIT was estimated using structural equation modeling of data in 7,694 MZ and DZ twin pairs. Variance in AD-AUDIT explained by all SNPs was estimated with genome-wide complex trait analysis (GCTA). A genome-wide association study (GWAS) was performed in 7,842 subjects. GWAS SNP effect concordance analysis was performed between our GWAS and a recent AD GWAS using DSM-IV diagnosis. The twin-based heritability of AD-AUDIT was estimated at 60% (55-69%). GCTA showed that common SNPs jointly capture 33% (SE = 0.12, P = 0.002) of this heritability. In the GWAS, the top hits were positioned within four regions (4q31.1, 2p16.1, 6q25.1, 7p14.1) with the strongest association detected for rs55768019 (P = 7.58 × 10(-7) ). This first GWAS of AD using the AUDIT measure found results consistent with previous genetic studies using DSM diagnosis: concordance in heritability estimates and direction of SNPs effect and overlap with top hits from previous GWAS. Thus, the use of appropriate questionnaires may represent cost-effective strategies to phenotype samples in large-scale biobanks or other population-based datasets.


Assuntos
Alcoolismo/genética , Gêmeos/genética , Adulto , Alcoolismo/epidemiologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Nat Commun ; 6: 7846, 2015 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-26242864

RESUMO

Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.


Assuntos
Troca Genética , Idade Materna , Recombinação Genética , Aneuploidia , Teorema de Bayes , Estudos de Coortes , Humanos , Modelos Lineares , Modelos Genéticos
19.
Genes (Basel) ; 6(3): 559-76, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26184321

RESUMO

Hair color is one of the most visible and heritable traits in humans. Here, we estimated heritability by structural equation modeling (N = 20,142), and performed a genome wide association (GWA) analysis (N = 7091) and a GCTA study (N = 3340) on hair color within a large cohort of twins, their parents and siblings from the Netherlands Twin Register (NTR). Self-reported hair color was analyzed as five binary phenotypes, namely "blond versus non-blond", "red versus non-red", "brown versus non-brown", "black versus non-black", and "light versus dark". The broad-sense heritability of hair color was estimated between 73% and 99% and the genetic component included non-additive genetic variance. Assortative mating for hair color was significant, except for red and black hair color. From GCTA analyses, at most 24.6% of the additive genetic variance in hair color was explained by 1000G well-imputed SNPs. Genome-wide association analysis for each hair color showed that SNPs in the MC1R region were significantly associated with red, brown and black hair, and also with light versus dark hair color. Five other known genes (HERC2, TPCN2, SLC24A4, IRF4, and KITLG) gave genome-wide significant hits for blond, brown and light versus dark hair color. We did not find and replicate any new loci for hair color.

20.
Behav Genet ; 45(5): 503-13, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25987507

RESUMO

Prior searches for genetic variants (GVs) implicated in initiation of cannabis use have been limited to common single nucleotide polymorphisms (SNPs) typed in HapMap samples. Denser SNPs are now available with the completion of the 1000 Genomes and the Genome of the Netherlands projects. More densely distributed SNPs are expected to track the causal variants better. Therefore we extend the search for variants implicated in early stages of cannabis use to previously untagged common and low-frequency variants. We run heritability, SNP and gene-based analyses of initiation and age at onset. This is the first genome-wide study of age at onset to date. Using GCTA and a sample of distantly related individuals from the Netherlands Twin Register, we estimated that the currently measured (and tagged) SNPs collectively explain 25 % of the variance in initiation (SE = 0.088; P = 0.0016). Chromosomes 4 and 18, previously linked with cannabis use and other addiction phenotypes, account for the largest amount of variance in initiation (6.8 %, SE = 0.025, P = 0.002 and 3.6 %, SE = 0.01, P = 0.012, respectively). No individual SNP- or gene-based test reached genomewide significance in the initiation or age at onset analyses. Our study detected association signal in the currently measured SNPs. A comparison with prior SNP-heritability estimates suggests that at least part of the signal is likely coming from previously untyped common and low frequency variants. Our results do not rule out the contribution of rare variants of larger effect-a plausible source of the difference between the twin-based heritability estimate and that from GCTA. The causal variants are likely of very small effect (i.e., <1 % explained variance) and are uniformly distributed over the genome in proportion to chromosomes' length. Similar to other complex traits and diseases, detecting such small effects is to be expected in sufficiently large samples.


Assuntos
Predisposição Genética para Doença/genética , Fumar Maconha/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Idade de Início , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Modelos de Riscos Proporcionais , Sistema de Registros
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