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1.
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.

2.
Science ; 365(6456)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31467194

RESUMO

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.

3.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

4.
Behav Genet ; 49(4): 349-365, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31111357

RESUMO

Studies testing the effect of single genetic variants on substance use have had modest success. This paper reviewed 39 studies using polygenic measures to test interaction with any type of environmental exposure (G×E) in alcohol, tobacco, and cannabis use. Studies using haplotype combinations, sum scores of candidate-gene risk alleles, and polygenic scores (PS) were included. Overall study quality was moderate, with lower ratings for the polygenic methods in the haplotype and candidate-gene score studies. Heterogeneity in investigated environmental exposures, genetic factors, and outcomes was substantial. Most studies (N = 30) reported at least one significant G×E interaction, but overall evidence was weak. The majority (N = 26) found results in line with differential susceptibility and diathesis-stress frameworks. Future studies should pay more attention to methodological and statistical rigor, and focus on replication efforts. Additional work is needed before firm conclusions can be drawn about the importance of G×E in the etiology of substance use.

6.
J Res Adolesc ; 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30697859

RESUMO

Not much is known regarding underlying biological pathways to adolescents' loneliness. Insight in underlying molecular mechanisms could inform intervention efforts aimed at reducing loneliness. Using latent growth curve modeling, baseline levels and development of loneliness were studied in two longitudinal adolescent samples. Genes (OXTR, OXT, AVPR1A, AVPR1B) were examined using SNP-based, gene-based, and polygenic risk score (PRS) approaches. In both samples, SNP- and gene-based tests showed involvement of the OXTR gene in development of loneliness, though, significance levels did not survive correction for multiple testing. The PRS approach provided no evidence for relations with loneliness. We recommend alternative phenotyping methods, including environmental factors, to consider epigenetic studies, and to examine possible endophenotypes in relation to adolescents' loneliness.

7.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

9.
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.

10.
J Pers ; 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29752830

RESUMO

OBJECTIVE: Loneliness is an aversive response to a discrepancy between desired and actual social relationships and correlates with personality. We investigate the relationship of loneliness and personality in twin family and molecular genetic data. METHOD: Phenotypic correlations between loneliness and the Big Five personality traits were estimated in 29,625 adults, and in a group with genome-wide genotype data (N = 4,222), genetic correlations were obtained. We explored whether genetic correlations may reflect causal relationships by investigating within monozygotic twin pair differences (Npairs = 2,662), by longitudinal within-subject changes in personality and loneliness (N = 4,260-9,238 longitudinal comparisons), and by longitudinal cross-lagged panel analyses (N = 15,628). Finally, we tested whether genetic correlations were due to cross-trait assortative mating (Nspouse pairs = 4,436). RESULTS: The strongest correlations with loneliness were observed for Neuroticism (r = .55) and Extraversion (r = -.33). Only Neuroticism showed a high correlation with loneliness independent of other personality traits (r = .50), so follow-up analyses focused on Neuroticism. The genetic correlation between loneliness and Neuroticism from genotyped variants was .71; a significant reciprocal causal relationship and nonsignificant cross-trait assortative mating imply that this is at least partly due to mediated pleiotropy. CONCLUSIONS: We show that the relationship between loneliness and personality is largely explained by its relationship with Neuroticism, which is substantially genetic in nature.

11.
J Epidemiol Community Health ; 72(8): 708-710, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29666151

RESUMO

BACKGROUND: Body mass index (BMI) is correlated negatively with subjective well-being and positively with depressive symptoms. Whether these associations reflect causal effects is unclear. METHODS: We examined bidirectional, causal effects between BMI and mental health with Mendelian randomisation using summary-level data from published genome-wide association studies (BMI: n=339 224; subjective well-being: n=204 966; depressive symptoms: n=161 460). Genetic variants robustly related to the exposure variable acted as instrumental variable to estimate causal effects. We combined estimates of individual genetic variants with inverse-variance weighted meta-analysis, weighted median regression and MR-Egger regression. RESULTS: There was evidence for a causal, increasing effect of BMI on depressive symptoms and suggestive evidence for a decreasing effect of BMI on subjective well-being. We found no evidence for causality in the other direction. CONCLUSION: This study provides support for a higher BMI causing poorer mental health. Further research should corroborate these findings and explore mechanisms underlying this potential causality.

12.
Drug Alcohol Depend ; 187: 296-299, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29702338

RESUMO

BACKGROUND: There is high comorbidity between antisocial behaviour (ASB) and substance use, and twin studies have shown that part of the covariation is due to overlapping genetic influences. Here we used measured genetic effects to estimate the genetic correlations of ASB with nicotine, alcohol, and cannabis use. METHODS: We meta-analysed data from two genome-wide association studies for ASB and used existing summary statistics from the largest genome-wide association studies into substance use (ever smoking, cigarettes smoked per day, weekly alcohol consumption, and lifetime cannabis use). We performed cross-trait LD-score regression to estimate genetic correlations between ASB and substance use phenotypes explained by all single nucleotide polymorphisms (SNPs). When significant, we tested whether the signs of the regression coefficients of SNPs from the ASB and substance use phenotypes were in the same direction across multiple p-value thresholds and examined enrichment in overlap of the strongest associated SNPs. RESULTS: We found nominally significant genetic correlations of ASB with lifetime cannabis use (rg = 0.69, p=.016) and cigarettes per day (rg = 0.59, p = 0.036) but not with weekly alcohol consumption or ever smoking. Sign-tests revealed consistent directions of effect of SNPs for ASB and cannabis use for all p-value thresholds except the most stringent one, whereas for ASB with cigarettes per day no consistent evidence was found. We found no evidence of enrichment in overlap of the most associated SNPs across these traits. CONCLUSION: Using measured genetic variants, we found preliminary support for a genetic correlation of ASB with lifetime cannabis use and cigarettes per day.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Transtorno da Personalidade Antissocial/genética , Abuso de Maconha/genética , Fumar/genética , Tabagismo/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/psicologia , Transtorno da Personalidade Antissocial/psicologia , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Abuso de Maconha/psicologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Fumar/psicologia , Tabagismo/psicologia , Adulto Jovem
14.
Addiction ; 113(7): 1333-1338, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29334416

RESUMO

BACKGROUND AND AIMS: Epidemiological studies consistently show co-occurrence of use of different addictive substances. Whether these associations are causal or due to overlapping underlying influences remains an important question in addiction research. Methodological advances have made it possible to use published genetic associations to infer causal relationships between phenotypes. In this exploratory study, we used Mendelian randomization (MR) to examine the causality of well-established associations between nicotine, alcohol, caffeine and cannabis use. METHODS: Two-sample MR was employed to estimate bidirectional causal effects between four addictive substances: nicotine (smoking initiation and cigarettes smoked per day), caffeine (cups of coffee per day), alcohol (units per week) and cannabis (initiation). Based on existing genome-wide association results we selected genetic variants associated with the exposure measure as an instrument to estimate causal effects. Where possible we applied sensitivity analyses (MR-Egger and weighted median) more robust to horizontal pleiotropy. RESULTS: Most MR tests did not reveal causal associations. There was some weak evidence for a causal positive effect of genetically instrumented alcohol use on smoking initiation and of cigarettes per day on caffeine use, but these were not supported by the sensitivity analyses. There was also some suggestive evidence for a positive effect of alcohol use on caffeine use (only with MR-Egger) and smoking initiation on cannabis initiation (only with weighted median). None of the suggestive causal associations survived corrections for multiple testing. CONCLUSIONS: Two-sample Mendelian randomization analyses found little evidence for causal relationships between nicotine, alcohol, caffeine and cannabis use.

15.
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.

16.
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
18.
Methods Mol Biol ; 1666: 171-194, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28980246

RESUMO

This chapter describes how the heritability of a trait can be estimated using data collected from pairs of twins. The principles of the classical twin design are described, followed by the assumptions, and some possible extensions of the design. In the second part of this chapter, two example scripts are presented and the basic steps for estimating heritability using the statistical program OpenMx are explained. OpenMx and the scripts used for this chapter can be downloaded so that readers can adapt and use the scripts for their own purposes.


Assuntos
Genótipo , Fenótipo , Gêmeos , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Padrões de Herança , Masculino , Modelos Genéticos , Software
19.
Proc Biol Sci ; 284(1862)2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28904145

RESUMO

Higher paternal age at offspring conception increases de novo genetic mutations. Based on evolutionary genetic theory we predicted older fathers' children, all else equal, would be less likely to survive and reproduce, i.e. have lower fitness. In sibling control studies, we find support for negative paternal age effects on offspring survival and reproductive success across four large populations with an aggregate N > 1.4 million. Three populations were pre-industrial (1670-1850) Western populations and showed negative paternal age effects on infant survival and offspring reproductive success. In twentieth-century Sweden, we found minuscule paternal age effects on survival, but found negative effects on reproductive success. Effects survived tests for key competing explanations, including maternal age and parental loss, but effects varied widely over different plausible model specifications and some competing explanations such as diminishing paternal investment and epigenetic mutations could not be tested. We can use our findings to aid in predicting the effect increasingly older parents in today's society will have on their children's survival and reproductive success. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time periods.


Assuntos
Aptidão Genética , Idade Paterna , Reprodução , Pai , Humanos , Masculino , Idade Materna , Suécia
20.
Drug Alcohol Depend ; 178: 66-69, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28641132

RESUMO

BACKGROUND: Ecstasy is a widely used psychoactive drug that users often take because they experience positive effects such as increased euphoria, sociability, elevated mood, and heightened sensations. Ecstasy use is not harmless and several immediate and long term side effects have been identified. Lifetime ecstasy use is likely to be partly influenced by genetic factors, but no twin study has determined the heritability. Here, we apply a classical twin design to a large sample of twins and siblings to estimate the heritability of lifetime ecstasy use. METHODS: The sample comprised 8500 twins and siblings aged between 18 and 45 years from 5402 families registered at the Netherlands Twin Registry. In 2013-2014 participants filled out a questionnaire including a question whether they had ever used ecstasy. We used the classical twin design to partition the individual differences in liability to ecstasy use into that due to genetic, shared environmental, and residual components. RESULTS: Overall, 10.4% of the sample had used ecstasy during their lifetime, with a somewhat higher prevalence in males than females. Twin modelling indicated that individual differences in liability to lifetime ecstasy use are for 74% due to genetic differences between individuals, whereas shared environmental and residual factors explain a small proportion of its liability (5% and 21%, respectively). Although heritability estimates appeared to be higher for females than males, this difference was not significant. CONCLUSIONS: Lifetime ecstasy use is a highly heritable trait, which indicates that some people are genetically more vulnerable to start using ecstasy than others.


Assuntos
N-Metil-3,4-Metilenodioxianfetamina/química , Psicotrópicos/farmacologia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Gêmeos/genética , Meio Ambiente , Feminino , Humanos , Masculino , Países Baixos , Prevalência , Psicotrópicos/química , Sistema de Registros , Irmãos , Inquéritos e Questionários
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