K. K. Bucholz

Bio: K. K. Bucholz is an academic researcher from Washington University in St. Louis. The author has contributed to research in topics: Alcohol dependence & Poison control. The author has an hindex of 30, co-authored 40 publications receiving 5675 citations.

A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA.

Abstract: Within- and cross-center test-retest studies were conducted to study the reliability of a new, semistructured, comprehensive, polydiagnostic psychiatric interview being used in a multisite genetic linkage study of alcoholism. Findings from both studies indicated that reliability for the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was high for DSM-III-R substance dependence disorders, but less so for substance abuse disorders. Reliability of depression was good in both studies, but mixed for antisocial personality disorder (ASP). Findings are presented in terms of specific substance dependence and abuse diagnoses, as well as for depression and ASP. Criterion-specific reliabilities are examined by type of substance used. Although SSAGA was designed to provide for broad phenotyping of alcoholism, review of its new features suggests its suitability for a variety of family studies, not just those focusing on substance abuse.

Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men

Abstract: Background. Genetic influences on alcoholism risk are well-documented in men, but uncertain in women. We tested for gender differences in genetic influences on, and risk-factors for, DSM-III-R alcohol dependence (AD).Method. Diagnostic follow-up interviews were conducted in 1992–3 by telephone with twins from an Australian twin panel first surveyed in 1980–82 (N=5889 respondents). Data were analysed using logistic regression models.Results. Significantly higher twin pair concordances were observed in MZ compared to DZ same-sex twin pairs in women and men, even when data were weighted to adjust for over-representation of well-educated respondents, and for selective attrition. AD risk was increased in younger birth cohorts, in Catholic males or women reporting no religious affiliation, in those reporting a history of conduct disorder or major depression and in those with high Neuroticism, Social Non-conformity, Toughmindedness, Novelty-Seeking or (in women only) Extraversion scores; and decreased in ‘Other Protestants’, weekly church attenders, and university-educated males. Controlling for these variables, however, did not remove the significant association with having an alcoholic MZ co-twin, implying that much of the genetic influence on AD risk remained unexplained. No significant gender difference in the genetic variance in AD was found (64% heritability, 95% confidence interval 32–73%).Conclusions. Genetic risk-factors play as important a role in determining AD risk in women as in men. With the exception of certain sociocultural variables such as religious affiliation, the same personality, sociodemographic and axis I correlates of alcoholism risk are observed in women and men.

Early sexual abuse and lifetime psychopathology: a co-twin-control study.

Abstract: Background. This study was designed to determine lifetime prevalence of psychiatric disorders among twins who reported childhood sexual abuse (CSA), and to compare these rates with those among non-abused co-twins. The contribution of familial and individual-specific factors to reported sexual abuse was also examined. Method. Information about lifetime psychopathology and substance use was obtained by structured telephone interviews with 5995 Australian twins. Twins who reported a history of childhood sexual abuse (CSA) were contrasted on lifetime psychopathology with subjects without such a history; in addition, comparisons were made between same-sex twin pairs discordant for CSA. Results. A history of CSA was reported by 5‐9% of the women and 2‐5% of the men. In the sample as a whole, those reporting CSA were more likely to receive lifetime diagnoses of major depression, conduct disorder, panic disorder and alcoholism, and were more likely to report suicidal ideation and a history of suicide attempt. Abused women, but not men, were also more likely to report social phobia. When comparisons were restricted to non-abused co-twins, no dierences in psychopathology were seen. However, rates of major depression, conduct disorder and suicidal ideation were higher if both co-twins were abused than if the respondent alone reported CSA. Model-fitting indicated that shared environmental factors influenced risk for reported CSA in women, but not in men. Conclusion. The association between CSA and psychopathology arises at least in part through the influence of shared familial factors on both risk of victimization and risk of psychopathology.

Genetic differences in alcohol sensitivity and the inheritance of alcoholism risk.

Abstract: Background. Substantial evidence exists for an important genetic contribution to alcohol dependence risk in women and men. It has been suggested that genetically determined differences in alcohol sensitivity may represent one pathway by which an increase in alcohol dependence risk occurs. Methods. Telephone interview follow-up data were obtained on twins from male, female and unlike­ sex twin pairs who had participated in an alcohol challenge study in 1979-81, as well as other pairs from the same Australian twin panel surveyed by mail in 1980-82. Results. At follow-up, alcohol challenge men did not differ from other male twins from the same age cohort on measures of lifetime psychopathology or drinking habits; but alcohol challenge women were on average heavier drinkers than other women. A composite alcohol sensitivity measure, combining subjective intoxication and increase in body-sway after alcohol challenge in 1979-81, exhibited high heritability (60 %). Parental alcoholism history was weakly associated with decreased alcohol sensitivity in women, but not after adjustment for baseline drinking history, or in men. High alcohol sensitivity in men was associated with substantially reduced alcohol dependence risk (OR = 0'05, 95 % CI 0'01-0'39). Furthermore, significantly decreased (i.e. low) alcohol sensitivity was observed in non-alcoholic males whose MZ co-twin had a history of alcohol dependence, compared to other non-alcoholics. These associations remained significant in conservative analyses that controlled for respondents' alcohol consumption levels and alcohol problems in 1979-81. Conclusions. Men (but not women) at increased genetic risk of alcohol dependence (assessed by MZ co-twin's history of alcohol dependence) exhibited reduced alcohol sensitivity. Associations with parental alcoholism were inconsistent.

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence

Abstract: Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

Deciding on the Number of Classes in Latent Class Analysis and Growth Mixture Modeling: A Monte Carlo Simulation Study

Abstract: Mixture modeling is a widely applied data analysis technique used to identify unobserved heterogeneity in a population. Despite mixture models' usefulness in practice, one unresolved issue in the application of mixture models is that there is not one commonly accepted statistical indicator for deciding on the number of classes in a study population. This article presents the results of a simulation study that examines the performance of likelihood-based tests and the traditionally used Information Criterion (ICs) used for determining the number of classes in mixture modeling. We look at the performance of these tests and indexes for 3 types of mixture models: latent class analysis (LCA), a factor mixture model (FMA), and a growth mixture models (GMM). We evaluate the ability of the tests and indexes to correctly identify the number of classes at three different sample sizes (n = 200, 500, 1,000). Whereas the Bayesian Information Criterion performed the best of the ICs, the bootstrap likelihood ratio test ...

Integrative analysis of 111 reference human epigenomes

Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.