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1.
Biol Psychiatry ; 86(4): 265-273, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31230729

RESUMO

BACKGROUND: A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (ncases = 18,381, ncontrols = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). METHODS: Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression. RESULTS: This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability. CONCLUSIONS: This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.

2.
Exp Neurol ; 316: 20-26, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965038

RESUMO

Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition.

3.
Pharmacogenomics J ; 2019 Jan 31.
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.

4.
PLoS Genet ; 14(12): e1007833, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30507971

RESUMO

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state of the art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.

5.
Genome Biol ; 19(1): 194, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419947

RESUMO

BACKGROUND: Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. RESULTS: We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. CONCLUSIONS: We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.

6.
Commun Biol ; 1: 163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30320231

RESUMO

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

7.
Neuropsychopharmacology ; 43(10): 2146-2153, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29728651

RESUMO

Accumulating evidence suggests that genetic factors have a role in major depressive disorder (MDD). However, only limited MDD risk loci have been identified so far. Here we perform a meta-analysis (a total of 90,150 MDD cases and 246,603 controls) through combing three genome-wide association studies of MDD, including 23andMe (cases were self-reported with a clinical diagnosis or treatment of depression), CONVERGE (cases were diagnosed using the Composite International Diagnostic Interview) and PGC (cases were diagnosed using direct structured diagnostic interview (by trained interviewers) or clinician-administered DSM-IV checklists). Genetic variants from two previously unreported loci (rs10457592 on 6q16.2 and rs2004910 on 12q24.31) showed significant associations with MDD (P < 5 × 10-8) in a total of 336,753 subjects. SNPs (a total of 171) with a P < 1 × 10-7 in the meta-analysis were further replicated in an independent sample (GS:SFHS, 2,659 MDD cases (diagnosed with DSM-IV) and 17,237 controls) and one additional risk locus (rs3785234 on 16p13.3, P = 1.57 × 10-8) was identified in the combined samples (a total of 92,809 cases and 263,840 controls). Risk variants on the identified risk loci were associated with gene expression in human brain tissues and mRNA expression analysis showed that FBXL4 and RSRC1 were significantly upregulated in brains of MDD cases compared with controls, suggesting that genetic variants may confer risk of MDD through regulating the expression of these two genes. Our study identified three novel risk loci (6q16.2, 12q24.31, and 16p13.3) for MDD and suggested that FBXL4 and RSRC1 may play a role in MDD. Further functional characterization of the identified risk genes may provide new insights for MDD pathogenesis.

8.
Transl Psychiatry ; 8(1): 9, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29317602

RESUMO

Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.

9.
Transl Psychiatry ; 7(11): 1263, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29187746

RESUMO

Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18,773), as a discovery cohort with UK Biobank used as a population-based replication cohort (n = 25,035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 × 10-8) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10-7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.


Assuntos
Cromossomos Humanos Par 6 , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Escócia , Reino Unido , Adulto Jovem
10.
Biol Psychiatry ; 82(5): 312-321, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28153336

RESUMO

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


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Proteínas HMGB/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Reino Unido
11.
Biol Psychiatry ; 81(4): 336-346, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27422368

RESUMO

BACKGROUND: Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk. METHODS: We integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested. RESULTS: In GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model. CONCLUSIONS: These post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Fatores de Crescimento Neural/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Netrina-1 , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
Am J Med Genet B Neuropsychiatr Genet ; 174(3): 227-234, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27480393

RESUMO

Type II diabetes (T2D) and major depressive disorder (MDD) are often co-morbid. The reasons for this co-morbidity are unclear. Some studies have highlighted the importance of environmental factors and a causal relationship between T2D and MDD has also been postulated. In the present study we set out to investigate the shared aetiology between T2D and MDD using Mendelian randomization in a population based sample, Generation Scotland: the Scottish Family Health Study (N = 21,516). Eleven SNPs found to be associated with T2D were tested for association with MDD and psychological distress (General Health Questionnaire scores). We also assessed causality and genetic overlap between T2D and MDD using polygenic risk scores (PRS) assembled from the largest available GWAS summary statistics to date. No single T2D risk SNP was associated with MDD in the MR analyses and we did not find consistent evidence of genetic overlap between MDD and T2D in the PRS analyses. Linkage disequilibrium score regression analyses supported these findings as no genetic correlation was observed between T2D and MDD (rG = 0.0278 (S.E. 0.11), P-value = 0.79). As suggested by previous studies, T2D and MDD covariance may be better explained by environmental factors. Future studies would benefit from analyses in larger cohorts where stratifying by sex and looking more closely at MDD cases demonstrating metabolic dysregulation is possible. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.


Assuntos
Transtorno Depressivo Maior/etiologia , Diabetes Mellitus Tipo 2/etiologia , Estudos de Coortes , Comorbidade , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Medição de Risco , Fatores de Risco , Escócia
13.
Biol Psychiatry ; 81(4): 325-335, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27519822

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Idade de Início , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto Jovem
14.
PLoS Med ; 13(8): e1002090, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27529168

RESUMO

BACKGROUND: Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study. METHODS AND FINDINGS: Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum ß = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum ß = 5.68 x 10-2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum ß = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum ß = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes. CONCLUSIONS: Genetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.


Assuntos
Dor Crônica/etiologia , Transtorno Depressivo Maior/etiologia , Adulto , Idoso , Dor Crônica/complicações , Dor Crônica/genética , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Família , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Linhagem , Fatores de Risco , Meio Social , Inquéritos e Questionários , Reino Unido
15.
Addict Biol ; 21(2): 469-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25865819

RESUMO

Alcohol dependence is frequently co-morbid with cognitive impairment. The relationship between these traits is complex as cognitive dysfunction may arise as a consequence of heavy drinking or exist prior to the onset of dependence. In the present study, we tested the genetic overlap between cognitive abilities and alcohol dependence using polygenic risk scores (PGRS). We created two independent PGRS derived from two recent genome-wide association studies (GWAS) of alcohol dependence (SAGE GWAS: n = 2750; Yale-Penn GWAS: n = 2377) in a population-based cohort, Generation Scotland: Scottish Family Health Study (GS:SFHS) (n = 9863). Data on alcohol consumption and four tests of cognitive function [Mill Hill Vocabulary (MHV), digit symbol coding, phonemic verbal fluency (VF) and logical memory] were available. PGRS for alcohol dependence were negatively associated with two measures of cognitive function: MHV (SAGE: P = 0.009, ß = -0.027; Yale-Penn: P = 0.001, ß = -0.034) and VF (SAGE: P = 0.0008, ß = -0.036; Yale-Penn: P = 0.00005, ß = -0.044). VF remained robustly associated after adjustment for education and social deprivation; however, the association with MHV was substantially attenuated. Shared genetic variants may account for some of the phenotypic association between cognitive ability and alcohol dependence. A significant negative association between PGRS and social deprivation was found (SAGE: P = 5.2 × 10(-7) , ß = -0.054; Yale-Penn: P = 0.000012, ß = -0.047). Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking in regions of deprivation. Future work to identify genes which affect both cognitive impairment and alcohol dependence will help elucidate biological processes common to both disorders.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Transtornos Cognitivos/genética , Cognição/fisiologia , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/epidemiologia , Alcoolismo/psicologia , Transtornos Cognitivos/epidemiologia , Estudos de Coortes , Escolaridade , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Fatores de Risco , Escócia/epidemiologia , Fatores Socioeconômicos
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