Background: Twin studies demonstrate that measures of alcohol consumption (AC) show evidence of genetic influence, suggesting they may be useful in gene identification efforts. The extent to which ...these phenotypes will be informative in identifying susceptibility genes involved in alcohol dependence depends on the extent to which genetic influences are shared across measures of AC and alcohol problems. Previous studies have demonstrated that AC reported for the period of heaviest lifetime drinking shows a large degree of genetic overlap with alcohol dependence; however, many studies with genetic material assess current AC. Further, there are many different aspects of AC that can be assessed (e.g., frequency of use, quantity of use, and frequency of intoxication).
Methods: Here, we use data from 2 large, independent, population‐based twin samples, FinnTwin 16 and The Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, to examine the extent to which genetic influences are shared across many different measures of AC and alcohol problems.
Results: Genetic correlations across current AC measures and alcohol problems were high across both samples. However, both samples suggest a complex genetic architecture with many different genetic factors influencing various aspects of current AC and problems.
Conclusions: These results suggest that careful attention must be paid to the phenotype in efforts to “replicate” genetic effects across samples or combine samples for meta‐analyses of genetic effects influencing susceptibility to alcohol‐related outcomes.
Dating several people in emerging adulthood has been associated with higher alcohol use compared with being single or being in an exclusive relationship. As a follow-up to that report, we examined ...whether romantic relationship status is part of a pathway of risk between antecedent alcohol use risk factors and subsequent alcohol outcomes. Participants were 4,410 emerging adults assessed at 2 time-points during their first year of college. We found that a parental history of alcohol problems was indirectly related to dating several people via 2 modestly correlated pathways. The first pathway was through conduct problems. The second pathway was through positive urgency (i.e., a positive emotion-based predisposition to rash action). In turn, dating several people was associated with higher alcohol use. Our results suggest that these familial and individual-level alcohol risk factors are related to emerging adults' selection into subsequent romantic relationship experiences that are associated with higher alcohol use. These findings have implications for how romantic relationship experiences may fit into developmental models of the etiology of alcohol use.
Alcohol Dependence in Men: Reliability and Heritability Ystrom, Eivind; Reichborn-Kjennerud, Ted; Aggen, Steven H. ...
Alcoholism, clinical and experimental research,
September 2011, Letnik:
35, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background: The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM‐IV) life‐time history of alcohol dependence (LTH‐AD) has been found to be moderately ...reliable and substantially heritable. However, in studies of the heritability of LTH‐AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH‐AD in a population based sample, (ii) identify characteristics of LTH‐AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH‐AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH‐AD correcting for measurement error.
Methods: An unselected sample of 4,203 male twins was interviewed twice approximately 1‐year apart assessing DSM‐IV LTH‐AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH‐AD. Genetic and environmental influences on reliable LTH‐AD were examined using structural equation models.
Results: Reliability of the diagnosis of LTH‐AD was moderate (κ = 0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM‐IV AD criterion #5). Using an index of caseness, heritability of LTH‐AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH‐AD increased from 55 to 71%.
Conclusions: Reliably diagnosed LTH‐AD can be predicted by characteristics relevant to the disorder. LTH‐AD appears to be a moderately reliable disorder of high heritability.
Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as ...results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length–polymorphism markers and of 17 SNP markers implicated two regions, separated by ∼7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene
DTNBP1 (
dys
trobrevi
n-binding
protein
1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical
P values produced by the program TRANSMIT were significant (
P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (
P=.008–.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.
Abstract Background We consider the strength of the relationship between types of conduct problems in early life and pattern of alcohol use during adolescence. Methods Children from the Avon ...Longitudinal Study of Parents and Children, a UK birth-cohort, had their level of conduct problems assessed repeatedly from 4 to 13 years using the maternal report Strengths and Difficulties Questionnaire. Developmental trajectories derived from these data were subsequently related to (i) patterns of alcohol use from 13 to 15 years, and (ii) hazardous alcohol used at age 16. Results Boys with ‘Adolescent Onset’ or ‘Early Onset Persistent’ conduct problems were much more likely to be high frequency drinkers between 13 and 15 years (OR 5.00 95% CI = 2.4, 10.6 and 3.9 95% CI = 2.1, 7.3 respectively) compared with those with Low or ‘Childhood Limited’ conduct. Adolescent Onset/Early Onset Persistent girls also had greater odds of this high-alcohol frequency drinking pattern (2.67 1.4, 5.0 and 2.14 1.2, 4.0 respectively). Associations were more moderate for risk of hazardous alcohol use at age 16. Compared to 32% among those with low conduct problems, over 40% of young people classified as showing Adolescent Onset/Early Onset Persistent conduct problems were drinking hazardously (OR 1.52 1.09, 2.11 and 1.63 1.22, 2.18 respectively). Conclusions Whilst persistent conduct problems greatly increase the risk of adolescent alcohol problems, the majority of adolescents reporting hazardous use at age 16 lack such a history. It is important, therefore, to undertake alcohol prevention among all young people as a priority, as well as target people with manifest conduct problems.
Large-scale mental health surveys screen participants for the presence of the core diagnostic criteria of a mental disorder such as major depressive disorder (MDD). Only participants who screen ...positive are administered the full diagnostic module; the remainder "skip-out." Although this procedure adheres faithfully to the psychiatric classification of mental disorders, it limits the use of the resulting survey data for conducting high-quality research of importance to scientists, clinicians, and policymakers. Here, we conduct a series of exploratory analyses using the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD) data, a unique survey which suspended the skip-out procedure for assessing past-year MDD. Adult twins (N = 8,980) born between 1930 and 1974 were recruited from a multiple-birth record database established in 1980 and interviewed in mid-adulthood between 1987 and 1996. We compared the: (a) prevalence and levels of impairment of the diagnostic criteria (and disaggregated symptom items) of adults screening positive/negative and (b) patterns of associations between MDD diagnostic criteria (and disaggregated symptom items) under three conditions: (a) full data; (b) "skip-out" data substituted with zeros; and (c) "skip-out" data treated via listwise deletion. Important differences in the patterns of associations between diagnostic criteria and disaggregated symptom sets emerged which changed the statistical evidence regarding the dimensionality of the criteria/symptom items (i.e., Condition C). An ill-defined correlation matrix which was unsuitable for statistical analysis was produced (i.e., Condition B). Given the problems with these widely used approaches, we offer researchers and data analysts practical alternatives to using the skip-out procedure in future surveys.
General Scientific SummaryThe use of "skip-out" procedures in diagnostic modules in national mental health surveys results in substantial proportions of missing data, causing theoretical and methodological challenges. Researchers need to think carefully about how best to treat this missing data because common methods to overcome this issue (e.g., complete case analyses, substitution with zero values) cause difficulties when analyzing this data using traditional statistical models.
Results from previous studies on DSM-IV and DSM-5 Antisocial Personality Disorder (ASPD) have suggested that the construct is etiologically multidimensional. To our knowledge, however, the structure ...of genetic and environmental influences in ASPD has not been examined using an appropriate range of biometric models and diagnostic interviews. The 7 ASPD criteria (section A) were assessed in a population-based sample of 2794 Norwegian twins by a structured interview for DSM-IV personality disorders. Exploratory analyses were conducted at the phenotypic level. Multivariate biometric models, including both independent and common pathways, were compared. A single phenotypic factor was found, and the best-fitting biometric model was a single-factor common pathway model, with common-factor heritability of 51% (95% CI 40–67%). In other words, both genetic and environmental correlations between the ASPD criteria could be accounted for by a single common latent variable. The findings support the validity of ASPD as a unidimensional diagnostic construct.
Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable ...success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.
We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.
Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.
These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.
Motivation: During the past decade, we have seen an exponential growth of vast amounts of genetic data generated for complex disease studies. Currently, across a variety of complex biological ...problems, there is a strong trend towards the integration of data from multiple sources. So far, candidate gene prioritization approaches have been designed for specific purposes, by utilizing only some of the available sources of genetic studies, or by using a simple weight scheme. Specifically to psychiatric disorders, there has been no prioritization approach that fully utilizes all major sources of experimental data. Results: Here we present a multi-dimensional evidence-based candidate gene prioritization approach for complex diseases and demonstrate it in schizophrenia. In this approach, we first collect and curate genetic studies for schizophrenia from four major categories: association studies, linkage analyses, gene expression and literature search. Genes in these data sets are initially scored by category-specific scoring methods. Then, an optimal weight matrix is searched by a two-step procedure (core genes and unbiased P-values in independent genome-wide association studies). Finally, genes are prioritized by their combined scores using the optimal weight matrix. Our evaluation suggests this approach generates prioritized candidate genes that are promising for further analysis or replication. The approach can be applied to other complex diseases. Availability: The collected data, prioritized candidate genes, and gene prioritization tools are freely available at http://bioinfo.mc.vanderbilt.edu/SZGR/. Contact: zhongming.zhao@vanderbilt.edu Supplementary information:Supplementary data are available at Bioinformatics online.
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