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1.
Nat Genet ; 51(7): 1137-1148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253982

RESUMO

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.

2.
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.

3.
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
4.
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.

5.
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.

6.
Twin Res Hum Genet ; 20(2): 97-107, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28193307

RESUMO

The monocyte-lymphocyte ratio (MLR) is a useful biomarker for disease development, but little is known about the extent to which genetic and environmental factors influence MLR variation. Here, we study the genetic architecture of MLR and determine the influence of demographic and lifestyle factors on MLR in data from a Dutch non-patient twin-family population. Data were obtained in 9,501 individuals from the Netherlands Twin Register. We used regression analyses to determine the effects of age, sex, smoking, and body mass index (BMI) on MLR and its subcomponents. Data on twins, siblings and parents (N = 7,513) were analyzed by genetic structural equation modeling to establish heritability and genome wide single nucleotide polymorphism (SNP) data from a genotyped subsample (N = 5,892) and used to estimate heritability explained by SNPs. SNP and phenotype data were also analyzed in a genome-wide association study to identify the genes involved in MLR. Linkage disequilibrium (LD) score regression and expression quantitative trait loci (eQTL) analyses were performed to further explore the genetic findings. Results showed that age, sex, and age × sex interaction effects were present for MLR and its subcomponents. Variation in MLR was not related to BMI, but smoking was positively associated with MLR. Heritability was estimated at 40% for MLR, 58% for monocyte, and 58% for lymphocyte count. The Genome-wide association study (GWAS) identified a locus on ITGA4 that was associated with MLR and only marginally significantly associated with monocyte count. For monocyte count, additional genetic variants were identified on ITPR3, LPAP1, and IRF8. For lymphocyte count, GWAS provided no significant findings. Taking all measured SNPs together, their effects accounted for 13% of the heritability of MLR, while all known and identified genetic loci explained 1.3% of variation in MLR. eQTL analyses showed that these genetic variants were unlikely to be eQTLs. In conclusion, variation in MLR level in the general population is heritable and influenced by age, sex, and smoking. We identified gene variants in the ITGA4 gene associated with variation in MLR. The significant SNP-heritability indicates that more genetic variants are likely to be involved.


Assuntos
Estudo de Associação Genômica Ampla , Linfócitos/citologia , Monócitos/citologia , Característica Quantitativa Herdável , Adulto , Índice de Massa Corporal , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Cadeias alfa de Integrinas/genética , Fatores Reguladores de Interferon/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores de Ácidos Lisofosfatídicos/genética , Fumar/efeitos adversos
7.
Am J Med Genet B Neuropsychiatr Genet ; 174(3): 251-260, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27774759

RESUMO

The assessment of children's psychopathology is often based on parental report. Earlier studies have suggested that rater bias can affect the estimates of genetic, shared environmental and unique environmental influences on differences between children. The availability of a large dataset of maternal as well as paternal ratings of psychopathology in 7-year old children enabled (i) the analysis of informant effects on these assessments, and (ii) to obtain more reliable estimates of the genetic and non-genetic effects. DSM-oriented measures of affective, anxiety, somatic, attention-deficit/hyperactivity, oppositional-defiant, conduct, and obsessive-compulsive problems were rated for 12,310 twin pairs from the Netherlands Twin Register by mothers (N = 12,085) and fathers (N = 8,516). The effects of genetic and non-genetic effects were estimated on the common and rater-specific variance. For all scales, mean scores on maternal ratings exceeded paternal ratings. Parents largely agreed on the ranking of their child's problems (r 0.60-0.75). The heritability was estimated over 55% for maternal and paternal ratings for all scales, except for conduct problems (44-46%). Unbiased shared environmental influences, i.e., on the common variance, were significant for affective (13%), oppositional (13%), and conduct problems (37%). In clinical settings, different cutoffs for (sub)clinical scores could be applied to paternal and maternal ratings of their child's psychopathology. Only for conduct problems, shared environmental and genetic influences explain an equal amount in differences between children. For the other scales, genetic factors explain the majority of the variance, especially for the common part that is free of rater bias. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.


Assuntos
Viés , Psicologia da Criança/métodos , Criança , Pai , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Epidemiologia Molecular/métodos , Mães , Países Baixos , Pais , Psicopatologia/métodos , Reprodutibilidade dos Testes , Inquéritos e Questionários , Gêmeos/psicologia
8.
Behav Genet ; 47(2): 152-163, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27796610

RESUMO

In studies of child psychopathology, phenotypes of interest are often obtained by parental ratings. When behavioral ratings are obtained in the context of a twin study, this allows for the decomposition of the phenotypic variance, into a genetic and a non-genetic part. If a phenotype is assessed by a single rater, heritability is based on the child's behavior as expressed in the presence of that particular rater, whereas heritability based on assessments by multiple raters allows for the estimation of the heritability of the phenotype based on rater agreement, as well as the heritability of the rater specific view of the behavior. The aim of this twin study was to quantify the rater common and rater specific contributions to the variation in children's behavioral problems. We estimated the heritability of maternal and paternal ratings of the Child Behavior Checklist (CBCL) 6-18 empirical emotional and behavioral problem scales in a large sample of 12,310 7-year old Dutch twin pairs. Between 30 and 59% of variation in the part of the phenotype parents agree upon was explained by genetic effects. Common environmental effects that make children in the same family similar explained less variance, ranging between 0 and 32%. For unique views of their children's behavioral problems, heritability ranged between 0 and 20% for maternal and between 0 and 22% for paternal views. Between 7 and 24% of the variance was accounted for by common environmental factors specific to mother and father's views. The proportion of rater shared and rater specific heritability can be translated into genetic correlations between parental views and inform the design and interpretation of results of molecular genetic studies. Genetic correlations were nearly or above 0.7 for all CBCL based psychopathology scales. Such large genetic correlations suggest two practical guidelines for genome-wide association studies (GWAS): when studies have collected data from either fathers or mothers, the shared genetic aetiology in parental ratings indicates that is possible to analyze paternal and maternal assessments in a single GWAS or meta-analysis. Secondly, if a study has collected information from both parents, a gain in statistical power may be realized in GWAS by the simultaneous analysis of the data.


Assuntos
Transtornos do Comportamento Infantil/genética , Psicometria/métodos , Criança , Comportamento Infantil/psicologia , Transtornos do Comportamento Infantil/psicologia , Pai/psicologia , Feminino , Humanos , Masculino , Modelos Genéticos , Mães/psicologia , Países Baixos , Pais/psicologia , Comportamento Problema/psicologia , Reprodutibilidade dos Testes , Inquéritos e Questionários , Gêmeos/genética , Gêmeos/psicologia
9.
Eur J Hum Genet ; 25(2): 267-270, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27876820

RESUMO

As an example of optimizing population-specific genotyping assays using a whole-genome sequence reference set, we detail the approach that followed to design the Axiom-NL array which is characterized by an improved imputation backbone based on the Genome of the Netherlands (GoNL) reference sequence and, compared with earlier arrays, a more comprehensive inclusion of SNPs on chromosomes X, Y, and the mitochondria. Common variants on the array were selected to be compatible with the Illumina Psych Array and the Affymetrix UK Biobank Axiom array. About 3.5% of the array (23 977 markers) represents SNPs from the GWAS catalog, including SNPs at FTO, APOE, Ion-channels, killer-cell immunoglobulin-like receptors, and HLA. Around 26 000 markers associated with common psychiatric disorders are included, as well as 6705 markers suggested to be associated with fertility and twinning. The platform can thus be used for risk profiling, detection of new variants, as well as ancestry determination. Results of coverage tests in 249 unrelated subjects with GoNL-based sequence data show that after imputation with 1000G as a reference, the median concordance between original and imputed genotypes is above 98%. The median imputation quality R2 for MAF thresholds of 0.001, 0.01, 0.05, and >0.05 are 0.05, 0.28, 0.80, 0.99, respectively, for the 1000G imputed SNPs, with a similar quality for the autosomes and X chromosome, showing a good genome-wide coverage for association studies after imputation.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Estudo de Associação Genômica Ampla/normas , Técnicas de Genotipagem/normas , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/normas , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
10.
J Am Acad Child Adolesc Psychiatry ; 55(10): 896-905.e6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27663945

RESUMO

OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Humanos , Masculino
11.
Behav Genet ; 46(2): 170-82, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26362575

RESUMO

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.


Assuntos
Extroversão (Psicologia) , Estudo de Associação Genômica Ampla , Personalidade/genética , Estudos de Coortes , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
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
13.
J Am Acad Child Adolesc Psychiatry ; 54(9): 737-44, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26299295

RESUMO

OBJECTIVE: Genetic factors contribute to individual differences in behavior problems. In children, genome-wide association studies (GWAS) have yielded the first suggestive results when aiming to identify genetic variants that explain heritability, but the proportion of genetic variance that can be attributed to common single nucleotide polymorphisms (SNPs) remains to be determined, as only a few studies have estimated SNP heritability, with diverging results. METHOD: Genomic-relationship-matrix restricted maximum likelihood (GREML) as implemented in the software Genome-Wide Complex Trait Analysis (GCTA) was used to estimate SNP heritability (SNP h(2)) for multiple phenotypes within 4 broad domains of children's behavioral problems (attention-deficit/hyperactivity symptoms, internalizing, externalizing, and pervasive developmental problems) and cognitive function. We combined phenotype and genotype data from 2 independent, population-based Dutch cohorts, yielding a total number of 1,495 to 3,175 of 3-, 7-, and 9-year-old children. RESULTS: Significant SNP heritability estimates were found for attention-deficit/hyperactivity symptoms (SNP h(2) = 0.37-0.71), externalizing problems (SNP h(2) = 0.44), and total problems (SNP h(2) = 0.18), rated by mother or teacher. Sensitivity analyses with exclusion of extreme cases and quantile normalization of the phenotype data decreased SNP h(2) as expected under genetic inheritance, but they remained statistically significant for most phenotypes. CONCLUSION: We provide evidence of the influence of common SNPs on child behavior problems in an ethnically homogenous sample. These results support the continuation of large GWAS collaborative efforts to unravel the genetic basis of complex child behaviors.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Polimorfismo de Nucleotídeo Único , Comportamento Problema/psicologia , Escala de Avaliação Comportamental , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Países Baixos , Escalas de Graduação Psiquiátrica , Característica Quantitativa Herdável , Software
14.
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.

15.
Behav Genet ; 45(5): 514-28, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26036992

RESUMO

Combining genotype data across cohorts increases power to estimate the heritability due to common single nucleotide polymorphisms (SNPs), based on analyzing a Genetic Relationship Matrix (GRM). However, the combination of SNP data across multiple cohorts may lead to stratification, when for example, different genotyping platforms are used. In the current study, we address issues of combining SNP data from different cohorts, the Netherlands Twin Register (NTR) and the Generation R (GENR) study. Both cohorts include children of Northern European Dutch background (N = 3102 + 2826, respectively) who were genotyped on different platforms. We explore imputation and phasing as a tool and compare three GRM-building strategies, when data from two cohorts are (1) just combined, (2) pre-combined and cross-platform imputed and (3) cross-platform imputed and post-combined. We test these three strategies with data on childhood height for unrelated individuals (N = 3124, average age 6.7 years) to explore their effect on SNP-heritability estimates and compare results to those obtained from the independent studies. All combination strategies result in SNP-heritability estimates with a standard error smaller than those of the independent studies. We did not observe significant difference in estimates of SNP-heritability based on various cross-platform imputed GRMs. SNP-heritability of childhood height was on average estimated as 0.50 (SE = 0.10). Introducing cohort as a covariate resulted in ≈2 % drop. Principal components (PCs) adjustment resulted in SNP-heritability estimates of about 0.39 (SE = 0.11). Strikingly, we did not find significant difference between cross-platform imputed and combined GRMs. All estimates were significant regardless the use of PCs adjustment. Based on these analyses we conclude that imputation with a reference set helps to increase power to estimate SNP-heritability by combining cohorts of the same ethnicity genotyped on different platforms. However, important factors should be taken into account such as remaining cohort stratification after imputation and/or phenotypic heterogeneity between and within cohorts. Whether one should use imputation, or just combine the genotype data, depends on the number of overlapping SNPs in relation to the total number of genotyped SNPs for both cohorts, and their ability to tag all the genetic variance related to the specific trait of interest.


Assuntos
Estatura/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Criança , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Análise de Componente Principal , Característica Quantitativa Herdável
16.
JAMA Psychiatry ; 72(7): 642-50, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25993607

RESUMO

IMPORTANCE: Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases). OBJECTIVES: To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES: Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS: A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P < .05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE: This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.


Assuntos
Transtornos de Ansiedade/genética , Moléculas de Adesão Celular Neuronais/genética , Transtorno Depressivo Maior/genética , Personalidade/genética , Transtornos de Ansiedade/psicologia , Transtorno Depressivo Maior/psicologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Neuroticismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
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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