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1.
Eur J Hum Genet ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558840

RESUMO

Insights into individual differences in gene expression and its heritability (h2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h2total, composed of cis-heritability (h2cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2res, the residual variance explained by all other genome-wide variants). Mean h2total was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h2 = 0.14, p = 6.15 × 10-258). Mean h2cis was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10-308) and with estimates from earlier RNA-Seq-based studies. Mean h2res was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10-3) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10-15), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h2 estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.

2.
Hum Mol Genet ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518406

RESUMO

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. While the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. While it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition towards loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study (GWAS) meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with electronic health record data to conduct a PheWAS with. A genetic predisposition towards loneliness was associated with cardiovascular, psychiatric, and metabolic disorders, and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

3.
Twin Res Hum Genet ; 22(4): 210-219, 2019 Aug.
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.

4.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
5.
Biol Psychiatry ; 85(12): 1065-1073, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31003785

RESUMO

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. METHODS: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. RESULTS: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. CONCLUSIONS: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.

6.
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.

7.
Nat Genet ; 51(3): 445-451, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30643256

RESUMO

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.


Assuntos
Genoma Humano/genética , Encéfalo/fisiologia , Biologia Computacional/métodos , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/fisiologia , Herança Multifatorial/genética , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética
8.
Nat Genet ; 51(2): 237-244, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643251

RESUMO

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fumar/genética , Tabagismo/genética , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Risco , Tabaco/efeitos adversos
9.
Drug Alcohol Depend ; 190: 143-150, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031300

RESUMO

BACKGROUND: Previously reported comorbidity between schizophrenia and substance use may be explained by shared underlying risk factors, such as genetic background. The aim of the present longitudinal study was to investigate how a genetic predisposition to schizophrenia was associated with patterns of substance use (cannabis use, smoking, alcohol use) during adolescence (comparing ages 13-16 with 16-20 years). METHOD: Using piecewise latent growth curve modelling in a longitudinal adolescent cohort (RADAR-Y study, N = 372), we analyzed the association of polygenic risk scores for schizophrenia (PRS; p-value thresholds (pt) < 5e-8 to pt < 0.5) with increase in substance use over the years, including stratified analyses for gender. Significance thresholds were set to adjust for multiple testing using Bonferroni at p ≤ 0.001. RESULTS: High schizophrenia vulnerability was associated with a stronger increase in cannabis use at age 16-20 (PRS thresholds pt < 5e-5 and pt < 5e-4; pt < 5e-6 was marginally significant), whereas more lenient PRS thresholds (PRS thresholds pt < 5e-3 to pt < 0.5) showed the reverse association. For smoking and alcohol, no clear relations were found. CONCLUSIONS: In conclusion, our findings support a relation between genetic risk to schizophrenia and prospective cannabis use patterns during adolescence. In contrast, no relation between alcohol and smoking was established.


Assuntos
Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Fumar Maconha/epidemiologia , Fumar Maconha/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adolescente , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Cannabis , Comorbidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Fumar Maconha/psicologia , Herança Multifatorial , Estudos Prospectivos , Fatores de Risco , Psicologia do Esquizofrênico , Adulto Jovem
10.
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.

11.
Hum Brain Mapp ; 39(11): 4183-4195, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29947131

RESUMO

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1-3.75 Hz, theta 4-7.75 Hz, alpha 8-12.75 Hz, and beta 13-30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2-a known genetic marker for alcohol use disorder and epilepsy-significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q < .05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex-genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

12.
Twin Res Hum Genet ; 21(3): 239-252, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29743129

RESUMO

Twin registers are wonderful research resources for research applications in medical and behavioral genetics, epidemiology, psychology, molecular genetics, and other areas of research. New registers continue to be launched all over the world as researchers from different disciplines recognize the potential to boost and widen their research agenda. In this article, we discuss multiple aspects that need to be taken into account when initiating a register, from its preliminary sketch to its actual development. This encompasses aspects related to the strategic planning and key elements of research designs, promotion and management of a twin register, including recruitment and retaining of twins and family members of twins, phenotyping, database organization, and collaborations between registers. We also present information on questions unique to twin registers and twin-biobanks, such as the assessment of zygosity by SNP arrays, the design of (biomarker) studies involving related participants, and the analyses of clustered data. Altogether, we provide a number of basic guidelines and recommendations for reflection when planning a twin register.

13.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

14.
Nicotine Tob Res ; 20(7): 836-842, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-28575460

RESUMO

Introduction: Classical twin studies show that smoking is heritable. To determine if shared family environment plays a role in addition to genetic factors, and if they interact (G×E), we use a children-of-twins design. In a second sample, we measure genetic influence with polygenic risk scores (PRS) and environmental influence with a question on exposure to smoking during childhood. Methods: Data on smoking initiation were available for 723 children of 712 twins from the Netherlands Twin Register (64.9% female, median birth year 1985). Children were grouped in ascending order of risk, based on smoking status and zygosity of their twin-parent and his/her co-twin: never smoking twin-parent with a never smoking co-twin; never smoking twin-parent with a smoking dizygotic co-twin; never smoking twin-parent with a smoking monozygotic co-twin; and smoking twin-parent with a smoking or never smoking co-twin. For 4072 participants from the Netherlands Twin Register (67.3% female, median birth year 1973), PRS for smoking were computed and smoking initiation, smoking heaviness, and exposure to smoking during childhood were available. Results: Patterns of smoking initiation in the four group children-of-twins design suggested shared familial influences in addition to genetic factors. PRS for ever smoking were associated with smoking initiation in all individuals. PRS for smoking heaviness were associated with smoking heaviness in individuals exposed to smoking during childhood, but not in non-exposed individuals. Conclusions: Shared family environment influences smoking, over and above genetic factors. Genetic risk of smoking heaviness was only important for individuals exposed to smoking during childhood, versus those not exposed (G×E). Implications: This study adds to the very few existing children-of-twins (CoT) studies on smoking and combines a CoT design with a second research design that utilizes polygenic risk scores and data on exposure to smoking during childhood. The results show that shared family environment affects smoking behavior over and above genetic factors. There was also evidence for gene-environment interaction (G×E) such that genetic risk of heavy versus light smoking was only important for individuals who were also exposed to (second-hand) smoking during childhood. Together, these findings give additional incentive to recommending parents not to expose their children to cigarette smoking.

15.
Drug Alcohol Depend ; 183: 7-12, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220643

RESUMO

BACKGROUND: Genetic and environmental factors contribute about equally to alcohol-related phenotypes in adulthood. In the present study, we examined whether more stress at home or low satisfaction with life might be associated with heavier drinking or more alcohol-related problems in individuals with a high genetic susceptibility to alcohol use. METHODS: Information on polygenic scores and drinking behavior was available in 6705 adults (65% female; 18-83 years) registered with the Netherlands Twin Register. Polygenic risk scores (PRSs) were constructed for all subjects based on the summary statistics of a large genome-wide association meta-analysis on alcohol consumption (grams per day). Outcome measures were quantity of alcohol consumption and alcohol-related problems assessed with the Alcohol Use Disorders Identification Test (AUDIT). Stress at home and life satisfaction were moderating variables whose significance was tested by Generalized Estimating Equation analyses taking familial relatedness, age and sex into account. RESULTS: PRSs for alcohol were significantly associated with quantity of alcohol consumption and alcohol-related problems in the past year (R2=0.11% and 0.10% respectively). Participants who reported to have experienced more stress in the past year and lower life satisfaction, scored higher on alcohol-related problems (R2=0.27% and 0.29 respectively), but not on alcohol consumption. Stress and life satisfaction did not moderate the association between PRSs and the alcohol outcome measures. CONCLUSIONS: There were significant main effects of polygenic scores and of stress and life satisfaction on drinking behavior, but there was no support for PRS-by-stress or PRS-by-life satisfaction interactions on alcohol consumption and alcohol-related problems.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Herança Multifatorial/genética , Satisfação Pessoal , Estresse Psicológico/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/complicações , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Fatores de Risco , Estresse Psicológico/complicações , Adulto Jovem
16.
Med Sci Sports Exerc ; 50(4): 700-708, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29135816

RESUMO

PURPOSE: Most candidate gene studies on the neurobiology of voluntary exercise behavior have focused on the dopaminergic signaling pathway and its role in the mesolimbic reward system. We hypothesized that dopaminergic candidate genes may influence exercise behavior through additional effects on executive functioning and that these effects are only detected when the types of exercise activity are taken into account. METHODS: Data on voluntary exercise behavior and at least one single-nucleotide polymorphism/variable number of tandem repeat (VNTR) were available for 12,929 participants of the Netherlands Twin Registry. Exercise activity was classified as externally paced if a high level of executive function skill was required. The total volume of voluntary exercise (minutes per week) as well as the volume specifically spent on externally paced activities were tested for association with nine functional dopaminergic polymorphisms (DRD1: rs265981, DRD2/ANKK1: rs1800497, DRD3: rs6280, DRD4: VNTR 48 bp, DRD5: VNTR 130-166 bp, DBH: rs2519152, DAT1: VNTR 40 bp, COMT: rs4680, MAOA: VNTR 30 bp), a polygenic score (PGS) based on nine alleles leading to lower dopamine responsiveness, and a PGS based on three alleles associated with both higher reward sensitivity and better executive functioning (DRD2/ANKK1: "G" allele, COMT: Met allele, DAT1: 440-bp allele). RESULTS: No association with total exercise volume or externally paced exercise volume was found for individual alleles or the nine-allele PGS. The volume of externally paced exercise behavior was significantly associated with the reward and executive function congruent PGS. This association was driven by the DAT1 440-bp and COMT Met allele, which acted as increaser alleles for externally paced exercise behavior. CONCLUSIONS: Taking into account the types of exercise activity may increase the success of identifying genetic variants and unraveling the neurobiology of voluntary exercise behavior.

17.
Behav Genet ; 48(1): 1-11, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29043520

RESUMO

For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of 253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568-1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.


Assuntos
Doenças em Gêmeos/genética , Neuroticismo/fisiologia , Gêmeos/genética , Família/psicologia , Feminino , Humanos , Masculino , Modelos Genéticos , Países Baixos/epidemiologia , Linhagem , Sistema de Registros , Meio Social , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
18.
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.

19.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
J Hum Genet ; 62(11): 979-988, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29066854

RESUMO

Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are important biomarkers for disease development and progression. To gain insight into the genetic causes of variance in NLR and PLR in the general population, we conducted genome-wide association (GWA) analyses and estimated SNP heritability in a sample of 5901 related healthy Dutch individuals. GWA analyses identified a new genome-wide significant locus on the HBS1L-MYB intergenic region for PLR, which replicated in a sample of 2538 British twins. For platelet count, we replicated three known genome-wide significant loci in our cohort (at CCDC71L-PIK3CG, BAK1 and ARHGEF3). For neutrophil count, we replicated the PSMD3 locus. For the identified top SNPs, we found significant cis and trans expression quantitative trait loci effects for several loci involved in hematological and immunological pathways. Linkage Disequilibrium score (LD) regression analyses for PLR and NLR confirmed that both traits are heritable, with a polygenetic SNP heritability for PLR of 14.1%, and for NLR of 2.4%. Genetic correlations were present between ratios and the constituent counts, with the genetic correlation (r=0.45) of PLR with platelet count reaching statistical significance. In conclusion, we established that two important biomarkers have a significant heritable SNP component, and identified the first genome-wide locus for PLR.


Assuntos
Biomarcadores/sangue , Plaquetas , Proteínas de Ligação ao GTP/genética , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP70/genética , Fatores de Alongamento de Peptídeos/genética , Locos de Características Quantitativas/genética , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Estudos de Coortes , Feminino , Humanos , Desequilíbrio de Ligação/genética , Linfócitos/metabolismo , Masculino , Neutrófilos/metabolismo , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único/genética , Complexo de Endopeptidases do Proteassoma/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética
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