Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 74
Filtrar
1.
PLoS Med ; 17(12): e1003410, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33275596

RESUMO

BACKGROUND: Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. METHODS AND FINDINGS: Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 × 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 × 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 × 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 × 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 × 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P value = 5.56 × 10-4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10-6), CHD (OR = 1.64, 95% CI, 1.28-2.09, P value = 8.07 × 10-5), heart failure (HF) (OR = 1.61, 95% CI, 1.32-1.95, P value = 1.9 × 10-6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41-4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10-2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14-2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38-4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations. CONCLUSIONS: Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk.

2.
Lancet Psychiatry ; 7(12): 1032-1045, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33096046

RESUMO

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

3.
Alzheimers Dement (Amst) ; 12(1): e12078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32789163

RESUMO

Introduction: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants. Methods: Associations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland. Results: AD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption. Discussion: Dementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.

4.
Mol Psychiatry ; 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523041

RESUMO

Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (ß = 0.338, p = 1.17 × 10-7) and remained associated after adjustment for lifestyle factors (ß = 0.219, p = 0.001, R2 = 0.68%). When modelled alongside PRS (ß = 0.384, p = 4.69 × 10-9) the MRS remained associated with MDD (ß = 0.327, p = 5.66 × 10-7). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (ß = 0.193, p = 0.016, R2 = 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (ß = 0.440, p ≤ 2 × 10-16). After removing smokers from the training set, the MRS strongly associated with BMI (ß = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.

5.
Mol Psychiatry ; 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398718

RESUMO

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10-24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.

6.
Nat Commun ; 11(1): 2301, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385265

RESUMO

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (ß: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (ß: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.


Assuntos
Depressão/genética , Córtex Pré-Frontal/metabolismo , Idoso , Bancos de Espécimes Biológicos , Depressão/metabolismo , Depressão/patologia , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neuroimagem/métodos , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/patologia , Fatores de Risco
7.
Transl Psychiatry ; 10(1): 163, 2020 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448866

RESUMO

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup.

8.
Nat Neurosci ; 23(7): 809-818, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451486

RESUMO

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Consumo de Bebidas Alcoólicas/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial
9.
Nat Genet ; 52(4): 437-447, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231276

RESUMO

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Transtorno Bipolar/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e Especificidade
10.
Eur Psychiatry ; 63(1): e28, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32189608

RESUMO

BACKGROUND: Cognitive impairment associated with lifetime major depressive disorder (MDD) is well-supported by meta-analytic studies, but population-based estimates remain scarce. Previous UK Biobank studies have only shown limited evidence of cognitive differences related to probable MDD. Using updated cognitive and clinical assessments in UK Biobank, this study investigated population-level differences in cognitive functioning associated with lifetime MDD. METHODS: Associations between lifetime MDD and cognition (performance on six tasks and general cognitive functioning [g-factor]) were investigated in UK Biobank (N-range 7,457-14,836, age 45-81 years, 52% female), adjusting for demographics, education, and lifestyle. Lifetime MDD classifications were based on the Composite International Diagnostic Interview. Within the lifetime MDD group, we additionally investigated relationships between cognition and (a) recurrence, (b) current symptoms, (c) severity of psychosocial impairment (while symptomatic), and (d) concurrent psychotropic medication use. RESULTS: Lifetime MDD was robustly associated with a lower g-factor (ß = -0.10, PFDR = 4.7 × 10-5), with impairments in attention, processing speed, and executive functioning (ß ≥ 0.06). Clinical characteristics revealed differential profiles of cognitive impairment among case individuals; those who reported severe psychosocial impairment and use of psychotropic medication performed worse on cognitive tests. Severe psychosocial impairment and reasoning showed the strongest association (ß = -0.18, PFDR = 7.5 × 10-5). CONCLUSIONS: Findings describe small but robust associations between lifetime MDD and lower cognitive performance within a population-based sample. Overall effects were of modest effect size, suggesting limited clinical relevance. However, deficits within specific cognitive domains were more pronounced in relation to clinical characteristics, particularly severe psychosocial impairment.

11.
Mol Psychiatry ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32203157

RESUMO

Excessive alcohol intake is associated with 5.9% of global deaths. However, this figure is especially acute in men such that 7.6% of deaths can be attributed to alcohol intake. Previous studies identified a significant interaction between genotypes of the galanin (GAL) gene with anxiety and alcohol abuse in different male populations but were unable to define a mechanism. To address these issues the current study analysed the human UK Biobank cohort and identified a significant interaction (n = 115,865; p = 0.0007) between allelic variation (GG or CA genotypes) in the highly conserved human GAL5.1 enhancer, alcohol intake (AUDIT questionnaire scores) and anxiety in men. Critically, disruption of GAL5.1 in mice using CRISPR genome editing significantly reduced GAL expression in the amygdala and hypothalamus whilst producing a corresponding reduction in ethanol intake in KO mice. Intriguingly, we also found the evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans from our UK Biobank studies. Using bioinformatic analysis and co-transfection studies we further identified the EGR1 transcription factor, that is co-expressed with GAL in amygdala and hypothalamus, as being important in the protein kinase C (PKC) supported activity of the GG genotype of GAL5.1 but less so in the CA genotype. Our unique study uses a novel combination of human association analysis, CRISPR genome editing in mice, animal behavioural analysis and cell culture studies to identify a highly conserved regulatory mechanism linking anxiety and alcohol intake that might contribute to increased susceptibility to anxiety and alcohol abuse in men.

12.
Transl Psychiatry ; 10(1): 55, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066731

RESUMO

Expression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity. Using large-scale eQTL mapping studies, we computed 6457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA = 14,518) and mean diffusivity (NMD = 14,485), representing white matter structural integrity. We found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (ßabsolute FA = 0.0339-0.0453; MD = 0.0308-0.0381) and individual tracts (ßabsolute FA = 0.0320-0.0561; MD = 0.0295-0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson's disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C). Our findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these results suggest it may be possible, in future, to map potential trait- and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.

13.
Psychol Med ; : 1-10, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31955720

RESUMO

BACKGROUND: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. METHODS: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. RESULTS: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16). CONCLUSIONS: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

14.
Biol Psychiatry ; 87(7): 609-618, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733789

RESUMO

Alcohol use disorder (AUD) is defined by several symptom criteria, which can be dissected further at the genetic level. Over the past several years, our understanding of the genetic factors influencing alcohol use and abuse has progressed tremendously; numerous loci have been implicated in different aspects of alcohol use. Previously known associations with alcohol-metabolizing enzymes (ADH1B, ALDH2) have been replicated definitively. In addition, novel associations with loci containing the genes KLB, GCKR, CRHR1, and CADM2 have been reported. Downstream analyses have leveraged these genetic findings to reveal important relationships between alcohol use behaviors and both physical and mental health. AUD and aspects of alcohol misuse have been shown to overlap strongly with psychiatric disorders, whereas aspects of alcohol consumption have shown stronger links to metabolism. These results demonstrate that the genetic architecture of alcohol consumption only partially overlaps with the genetics of clinically defined AUD. We discuss the limitations of using quantitative measures of alcohol use as proxy measures for AUD, and we outline how future studies will require careful phenotype harmonization to properly capture the genetic liability to AUD.

15.
Pharmacogenomics J ; 20(2): 329-341, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700811

RESUMO

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.

16.
Int J Epidemiol ; 49(2): 410-421, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263887

RESUMO

BACKGROUND: People who opt to participate in scientific studies tend to be healthier, wealthier and more educated than the broader population. Although selection bias does not always pose a problem for analysing the relationships between exposures and diseases or other outcomes, it can lead to biased effect size estimates. Biased estimates may weaken the utility of genetic findings because the goal is often to make inferences in a new sample (such as in polygenic risk score analysis). METHODS: We used data from UK Biobank, Generation Scotland and Partners Biobank and conducted phenotypic and genome-wide association analyses on two phenotypes that reflected mental health data availability: (i) whether participants were contactable by e-mail for follow-up; and (ii) whether participants responded to follow-up surveys of mental health. RESULTS: In UK Biobank, we identified nine genetic loci associated (P <5 × 10-8) with e-mail contact and 25 loci associated with mental health survey completion. Both phenotypes were positively genetically correlated with higher educational attainment and better health and negatively genetically correlated with psychological distress and schizophrenia. One single nucleotide polymorphism association replicated along with the overall direction of effect of all association results. CONCLUSIONS: Re-contact availability and follow-up participation can act as further genetic filters for data on mental health phenotypes.

17.
Psychol Med ; 50(10): 1653-1662, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31317844

RESUMO

BACKGROUND: Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ. METHODS: The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants. RESULTS: There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (ß = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (ß = 0.098, p = 0.026), compared to a negative association among controls (ß = -0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons. CONCLUSIONS: Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.

18.
PLoS Genet ; 15(11): e1008104, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738745

RESUMO

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.


Assuntos
Envelhecimento/genética , Epigênese Genética , Predisposição Genética para Doença , Longevidade/genética , Envelhecimento/patologia , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
Mol Psychiatry ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767999

RESUMO

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18 and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use associations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). No significant association between partner polygenic risk scores were observed. Associations between an individual's alcohol PRS (b = 0.05, S.E. = 0.006, p < 2 × 10-16) and smoking status PRS (b = 0.05, S.E. = 0.005, p < 2 × 10-16) were found with their partner's phenotype. In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

20.
Psychol Med ; : 1-10, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31576797

RESUMO

BACKGROUND: Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. METHODS: We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu. RESULTS: We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education. CONCLUSION: Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...