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1.
Genetics ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591132

RESUMO

Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remains significant challenges in gene mapping, including misspecification of the model for the phenotype distribution due to ascertainment. Here, we propose L-BRAT, a retrospective, generalized estimating equations-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.

2.
Transl Psychiatry ; 9(1): 249, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591379

RESUMO

Alcohol-related behaviors are moderately heritable and have ethnic-specific characteristics. At present, genetic studies for alcohol dependence (AD) in Chinese populations are underrepresented. We are the first to conduct a genome-wide association study (GWAS) for AD using 533 male alcoholics and 2848 controls of Han Chinese ethnicity and replicate our findings in 146 male alcoholics and 200 male controls. We then assessed genetic effects on AD characteristics (drinking volume/age onset/Michigan Alcoholism Screening Test (MAST)/Barratt Impulsiveness Scale (BIS-11)), and compared the polygenic risk of AD in Han Chinese with other populations (Thai, European American and African American). We found and validated two significant loci, one located in 4q23, with lead SNP rs2075633*ADH1B (Pdiscovery = 6.64 × 10-16) and functional SNP rs1229984*ADH1B (Pdiscovery = 3.93 × 10-13); and the other located in 12q24.12-12q24.13, with lead SNP rs11066001*BRAP (Pdiscovery = 1.63 × 10-9) and functional SNP rs671*ALDH2 (Pdiscovery = 3.44 × 10-9). ADH1B rs1229984 was associated with MAST, BIS_total score and average drinking volume. Polygenic risk scores from the Thai AD and European American AD GWAS were significantly associated with AD in Han Chinese, which were entirely due to the top two loci, however there was no significant prediction from African Americans. This is the first case-control AD GWAS in Han Chinese. Our findings demonstrate that these variants, which were highly linked with ALDH2 rs671 and ADH1B rs1229984, were significant modulators for AD in our Han Chinese cohort. A larger replication cohort is still needed to validate our findings.

3.
Nat Commun ; 10(1): 4558, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594949

RESUMO

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

5.
J Psychiatry Neurosci ; 44(6): 1-11, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31490055

RESUMO

Background: Phenotypic heterogeneity and complicated gene­environment interplay in etiology are among the primary factors that hinder the identification of genetic variants associated with cocaine use disorder. Methods: To detect novel genetic variants associated with cocaine use disorder, we derived disease traits with reduced phenotypic heterogeneity using cluster analysis of a study sample (n = 9965). We then used these traits in genome-wide association tests, performed separately for 2070 African Americans and 1570 European Americans, using a new mixed model that accounted for the moderating effects of 5 childhood environmental factors. We used an independent sample (918 African Americans, 1382 European Americans) for replication. Results: The cluster analysis yielded 5 cocaine use disorder subtypes, of which subtypes 4 (n = 3258) and 5 (n = 1916) comprised heavy cocaine users, had high heritability estimates (h2 = 0.66 and 0.64, respectively) and were used in association tests. Seven of the 13 identified genetic loci in the discovery phase were available in the replication sample. In African Americans, rs114492924 (discovery p = 1.23 × E−8), a single nucleotide polymorphism in LINC01411, was replicated in the replication sample (p = 3.63 × E−3). In a meta-analysis that combined the discovery and replication results, 3 loci in African Americans were significant genome-wide: rs10188036 in TRAK2 (p = 2.95 × E−8), del-1:15511771 in TMEM51 (p = 9.11 × E−10) and rs149843442 near LPHN2 (p = 3.50 × E−8). Limitations: Lack of data prevented us from replicating 6 of the 13 identified loci. Conclusion: Our results demonstrate the importance of considering phenotypic heterogeneity and gene­environment interplay in detecting genetic variations that contribute to cocaine use disorder, because new genetic loci have been identified using our novel analytic method.

6.
Depress Anxiety ; 36(9): 834-845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385647

RESUMO

BACKGROUND: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. METHODS: We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status. RESULTS: APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). CONCLUSIONS: APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.

7.
Alcohol Clin Exp Res ; 43(10): 2111-2121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31386212

RESUMO

BACKGROUND: Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption. METHOD: Using a high-density methylation array, we characterized epigenome-wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Linear regression was applied in an epigenome-wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length. RESULTS: We found that a total of 70 CpG sites reached EWAS-corrected significance (p < 6E-08) with small effects on alcohol consumption for individual CpG sites, including 64 new CpG sites and 6 CpG sites that were previously reported as associated with alcohol use disorder, liver function, body mass index, and lipid metabolism. The most significant CpG site was located in SLC7A11 (t = -11.34, p = 2.66E-28), a gene involved specifically in cysteine and glutamate transportation. The 70 significant CpG sites were located on 44 genes, including genes involved in amino acid transport and metabolism systems. We identified 68 pathways with a false discovery rate < 0.05. CONCLUSIONS: We identified novel DNA methylation sites associated with alcohol consumption. Results may shed light on peripheral mechanisms of alcohol consumption on adverse health outcomes among heavy drinkers.

8.
AIDS Behav ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435887

RESUMO

We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the characteristics of people living with HIV (PLWH), and matched uninfected individuals, by levels of alcohol use and types of abstinence. We then identified factors that differentiate abstinence and determined whether the association with an alcohol biomarker or a genetic polymorphism is improved by differentiating abstinence. Among abstainers, 34% of PLWH and 38% of uninfected were Q-AP; 53% and 53% were Q-OR; and 12% and 10% were LTA. Logistic regression models found smoking, alcohol, cocaine, and hepatitis C increased odds of Q-AP, whereas smoking and marijuana decreased odds of LTA. Differentiating types of abstinence improved association. Q-APs and LTAs can be readily differentiated by an alcohol biomarker and genetic polymorphism. Differentiating type of abstinence may enhance understanding of alcohol health effects.

9.
AIDS Behav ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31317364

RESUMO

A better understanding of predisposition to transition to high-dose, long-term opioid therapy after initial opioid receipt could facilitate efforts to prevent opioid use disorder (OUD). We extracted data on 69,268 patients in the Veterans Aging Cohort Study who received any opioid prescription between 1998 and 2015. Using latent growth mixture modelling, we identified four distinguishable dose trajectories: low (53%), moderate (29%), escalating (13%), and rapidly escalating (5%). Compared to low dose trajectory, those in the rapidly escalating dose trajectory were proportionately more European-American (59% rapidly escalating vs. 38% low); had a higher prevalence of HIV (31% vs. 29%) and hepatitis C (18% vs. 12%); and during follow-up, had a higher incidence of OUD diagnoses (13% vs. 3%); were hospitalised more often [18.1/100 person-years (PYs) vs. 12.5/100 PY]; and had higher all-cause mortality (4.7/100 PY vs. 1.8/100 PY, all p < 0.0001). These measures can potentially be used in future prevention research, including genetic discovery.

10.
Nat Neurosci ; 22(9): 1394-1401, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358989

RESUMO

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10-10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.

11.
Addict Biol ; : e12811, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362332

RESUMO

The United States is experiencing the worst opioid overdose (OpOD) crisis in its history. We carried out a genome-wide association study on OpOD severity among 3 477 opioid-exposed individuals, 1 019 of whom experienced OpODs, including 2 032 European Americans (EAs) (653 overdose cases), and 1 445 African Americans (AAs) (366 overdose cases). Participants were scored 1 to 4 based on their reported overdose status and the number of times that medical treatment was required. Genome-wide association study (GWAS) of EAs and AAs separately resulted in two genome-wide significant (GWS) signals in AAs but none in EAs. The first signal was represented by three closely mapped variants (rs115208233, rs116181528, and rs114077267) located near mucolipin 1 (MCOLN1) and patatin-like phospholipase domain containing 6 (PNPLA6), and the other signal was represented by rs369098800 near dead-box helicase 18 (DDX18). There were no additional GWS signals in the trans-population meta-analysis, so that post-GWAS analysis focused on these loci. In network analysis, MCOLN1 was coexpressed with PNPLA6, but only MCOLN1-associated genes were enriched in functional categories relevant to OpOD, including calcium and cation channel activities; no enrichment was observed for PNPLA6-associated genes. Drug repositioning analysis was carried out in the connectivity map (CMap) database for MCOLN1 (PNPLA6 was not available in CMap) and showed that the opioid agonist drug-induced expression profile is similar to that of MCOLN1 overexpression and yielded the highest-ranked expression profile of 83 drug classes. Thus, MCOLN1 may be a risk gene for OpOD, but replication is needed. This knowledge could be helpful in the identification of drug targets for preventing OpOD.

12.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

13.
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.

14.
Biol Psychiatry ; 86(5): 365-376, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151762

RESUMO

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS: The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

15.
Nat Commun ; 10(1): 2275, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101824

RESUMO

The original version of this Article omitted the following from the Acknowledgements: 'Supported by the Mental Illness Research, Education and Clinical Center of the Veterans Integrated Service Network 4 of the Department of Veterans Affairs.' This has now been corrected in both the PDF and HTML versions of the Article.

16.
Biol Psychiatry ; 85(11): 889-890, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31122339
17.
Epigenomics ; 11(7): 739-749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140863

RESUMO

Aim: Salivary miRNA can be easily accessible biomarkers of alcohol dependence (AD). Materials & methods: The miRNA transcriptome in the saliva of 56 African-Americans (AAs; 28 AD patients/28 controls) and 64 European-Americans (EAs; 32 AD patients/32 controls) was profiled using small RNA sequencing. Differentially expressed miRNAs were identified. Salivary miRNAs were used to predict the AD presence using machine learning with Random Forests. Results: Seven miRNAs were differentially expressed in AA AD patients, and five miRNAs were differentially expressed in EA AD patients. The AD prediction accuracy based on top five miRNAs (ranked by Gini index) was 79.1 and 72.2% in AAs and EAs, respectively. Conclusion: This study provided the first evidence that salivary miRNAs are AD biomarkers.

18.
JAMA Netw Open ; 2(5): e193447, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050786

RESUMO

Importance: There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood. Objectives: To investigate the association of PTSD with traits related to EA. Design, Setting, and Participants: Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018. Main Outcomes and Measures: Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR. Results: Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (rg = -0.26; SE = 0.05; P = 4.60 × 10-8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (ß = -0.23; 95% CI, -0.07 to -0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA (trauma exposure: ß = 0.37; 95% CI, 0.19 to 0.52; P = 2.57 × 10-5; risk-taking: ß = 0.76; 95% CI, 0.38 to 1.13; P = 1.13 × 10-4), while income may mediate the association of EA with PSTD (MR income: ß = -0.18; 95% CI, -0.29 to -0.07; P = .001; MR EA: ß = -0.23; 95% CI, -0.39 to -0.07; P = .004; multivariable MR income: ß = -0.32; 95% CI, -0.57 to 0.07; P = .02; multivariable MR EA: ß = -0.04; 95% CI, -0.29 to 0.21; SE, 0.13; P = .79). Conclusions and Relevance: Large-scale genomic data sets add further evidence to the negative association of EA with PTSD, also supporting the role of economic status as a mediator in the association observed.

19.
Am J Med Genet B Neuropsychiatr Genet ; 180(5): 310-319, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31081985

RESUMO

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome-wide association studies (GWASs) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self-assessed resilience (N = 11,492) was found to have significant common-variant heritability (h2 = 0.162, se = 0.050, p = 5.37 × 10-4 ), and to be significantly negatively genetically correlated with neuroticism (rg = -0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome-wide significant locus on an intergenic region on Chr 4 upstream from doublecortin-like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10-9 ] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch-like family member 36 (KLHL36) was detected at gene-wise genome-wide significance [p = 1.89 × 10-6 ]. A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genome-wide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10-8 ]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and point to new avenues for therapeutic intervention.

20.
Alcohol Clin Exp Res ; 43(7): 1462-1477, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31009096

RESUMO

BACKGROUND: The underlying molecular mechanisms associated with alcohol use disorder (AUD) risk have only been partially revealed using traditional approaches such as univariate genomewide association and linkage-based analyses. We therefore aimed to identify gene clusters related to Electroencephalograms (EEG) neurobiological phenotypes distinctive to individuals with AUD using a multivariate approach. METHODS: The current project adopted a bimultivariate data-driven approach, parallel independent component analysis (para-ICA), to derive and explore significant genotype-phenotype associations in a case-control subset of the Collaborative Study on the Genetics of Alcoholism (COGA) dataset. Para-ICA subjects comprised N = 799 self-reported European Americans (367 controls and 432 AUD cases), recruited from COGA, who had undergone resting EEG and genotyping. Both EEG and genomewide single nucleotide polymorphism (SNP) data were preprocessed prior to being subjected to para-ICA in order to derive genotype-phenotype relationships. RESULTS: From the data, 4 EEG frequency and 4 SNP components were estimated, with 2 significantly correlated EEG-genetic relationship pairs. The first such pair primarily represented theta activity, negatively correlated with a genetic cluster enriched for (but not limited to) ontologies/disease processes representing cell signaling, neurogenesis, transmembrane drug transportation, alcoholism, and lipid/cholesterol metabolism. The second component pair represented mainly alpha activity, positively correlated with a genetic cluster with ontologies similarly enriched as the first component. Disease-related enrichments for this component revealed heart and autoimmune disorders as top hits. Loading coefficients for both the alpha and theta components were significantly reduced in cases compared to controls. CONCLUSIONS: Our data suggest plausible multifactorial genetic components, primarily enriched for neuronal/synaptic signaling/transmission, immunity, and neurogenesis, mediating low-frequency alpha and theta abnormalities in alcohol addiction.

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