Although adolescents frequently engage in a variety of risky behaviors, much remains unknown about the specific etiologies of such tendencies. Candidate genetic variants, such as the COMT Val(158)Met ...polymorphism, may be related to risk-taking propensity, particularly as this variant is linked to functional enzymatic differences influencing dopamine function in regions including the prefrontal cortex. The present study aimed to examine the COMT Val(158)Met variant in relation to risk-taking propensity in a community sample of youth. As part of a larger longitudinal study on adolescent risk behaviors, 223 youths (average age 11.3 years) from the metropolitan Washington D.C. area completed a measure of risk-taking propensity, the Balloon Analog Risk Task-Youth Version (BART-Y), and provided saliva samples for DNA extraction and genotyping. Results indicate that females, but not males, who are carriers of the COMT 158Met allele had higher risk-taking propensity scores on the BART-Y compared to Val homozygotes. Analyses were also conducted in the 111 European American participants, and results were consistent with those of the full sample analyses. This study represents the first investigation of a genetic substrate of risk-taking propensity, measured by a behavioral task, in youth. Results should be taken as quite preliminary, given the small sample. Implications are discussed.
In schizophrenia, genetic predisposition has been linked to chromosome 22q11 and myelin-specific genes are misexpressed in schizophrenia. Nogo-66 receptor 1 (NGR or RTN4R) has been considered to be a ...22q11 candidate gene for schizophrenia susceptibility because it encodes an axonal protein that mediates myelin inhibition of axonal sprouting. Confirming previous studies, we found that variation at the NGR locus is associated with schizophrenia in a Caucasian case-control analysis, and this association is not attributed to population stratification. Within a limited set of schizophrenia-derived DNA samples, we identified several rare NGR nonconservative coding sequence variants. Neuronal cultures demonstrate that four different schizophrenia-derived NgR1 variants fail to transduce myelin signals into axon inhibition, and function as dominant negatives to disrupt endogenous NgR1. This provides the first evidence that certain disease-derived human NgR1 variants are dysfunctional proteins in vitro. Mice lacking NgR1 protein exhibit reduced working memory function, consistent with a potential endophenotype of schizophrenia. For a restricted subset of individuals diagnosed with schizophrenia, the expression of dysfunctional NGR variants may contribute to increased disease risk.
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 remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-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.
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 remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-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.
CONTEXT Although the prevalence of depression among medical interns substantially exceeds that of the general population, the specific factors responsible are not well understood. Recent reports of a ...moderating effect of a genetic polymorphism (5-HTTLPR) in the serotonin transporter protein gene on the likelihood that life stress will precipitate depression may help to understand the development of mood symptoms in medical interns. OBJECTIVES To identify psychological, demographic, and residency program factors that are associated with depression among interns and to use medical internship as a model to study the moderating effects of this polymorphism. DESIGN A prospective cohort study. SETTING Thirteen US hospitals. PARTICIPANTS Seven hundred forty interns entering participating residency programs. MAIN OUTCOME MEASURES Subjects were assessed for depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), a series of psychological traits, and the 5-HTTLPR genotype prior to internship and then assessed for depressive symptoms and potential stressors at 3-month intervals during internship. RESULTS The PHQ-9 depression score increased from 2.4 prior to internship to a mean of 6.4 during internship (P < .001). The proportion of participants who met PHQ-9 criteria for depression increased from 3.9% prior to internship to a mean of 25.7% during internship (P < .001). A series of factors measured prior to internship (female sex, US medical education, difficult early family environment, history of major depression, lower baseline depressive symptom score, and higher neuroticism) and during internship (increased work hours, perceived medical errors, and stressful life events) was associated with a greater increase in depressive symptoms during internship. In addition, subjects with at least 1 copy of a less-transcribed 5-HTTLPR allele reported a greater increase in depressive symptoms under the stress of internship (P = .002). CONCLUSIONS There is a marked increase in depressive symptoms during medical internship. Specific individual, internship, and genetic factors are associated with the increase in depressive symptoms.Published online April 5, 2010 (doi:10.1001/archgenpsychiatry.2010.41).Arch Gen Psychiatry. 2010;67(6):557-565-->
Background: Glutamate neurotransmission plays an important role in a variety of alcohol‐related phenomena, including alcohol self‐administration by both animals and humans. Because the risk for ...alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3′ region of GRIK1, the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD.
Methods: We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3′‐half of GRIK1, which includes 3 differentially spliced exons, in a sample of EA control subjects (n = 507) and subjects with AD (n = 1,057).
Results: We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3′UTR). Empirical p‐value estimation revealed that only rs2832407 was significantly associated to phenotype (p = 0.043).
Discussion: These findings provide support for the hypothesis that variation in the 3′ portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate’s effects in the treatment of AD.
Background
Alcohol dehydrogenase 1B and 1C (ADH1B and ADH1C) variants have been robustly associated with alcohol phenotypes in East Asian populations, but less so in non‐Asian populations where ...prevalence of the most protective ADH1B allele is low (generally <5%). Further, the joint effects of ADH1B and ADH1C on alcohol phenotypes have been unclear. Therefore, we tested the independent and joint effects of ADH1B and ADH1C on alcohol phenotypes in an Israeli sample, with higher prevalence of the most protective ADH1B allele than other non‐Asian populations.
Methods
A structured interview assessed lifetime drinking and alcohol use disorders (AUDs) in adult Israeli household residents. Four single nucleotide polymorphisms (SNPs) were genotyped: ADH1B (rs1229984, rs1229982, and rs1159918) and ADH1C (rs698). Regression analysis examined the association between alcohol phenotypes and each SNP (absence vs. presence of the protective allele) as well as rs698/rs1229984 diplotypes (also indicating absence or presence of protective alleles) in lifetime drinkers (n = 1,129).
Results
Lack of the ADH1B rs1229984 protective allele was significantly associated with consumption‐ and AUD‐related phenotypes (OR = 1.77 for AUD; OR = 1.83 for risk drinking), while lack of the ADH1C rs698 protective allele was significantly associated with AUD‐related phenotypes (OR = 2.32 for AUD). Diplotype analysis indicated that jointly ADH1B and ADH1C significantly influenced AUD‐related phenotypes. For example, among those without protective alleles for ADH1B or ADH1C, OR for AUD was 1.87 as compared to those without the protective allele for ADH1B only and was 3.16 as compared to those with protective alleles for both ADH1B and ADH1C.
Conclusions
This study adds support for the relationship of ADH1B and ADH1C and alcohol phenotypes in non‐Asians. Further, these findings help clarify the mixed results from previous studies by showing that ADH1B and ADH1C jointly effect AUDs, but not consumption. Studies of the association between alcohol phenotypes and either ADH1B or ADH1C alone may employ an oversimplified model, masking relevant information.
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