John Myers

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50–60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 × 10−6, at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0–2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Parenting and adult mood, anxiety and substance use disorders in female twins: an epidemiological, multi-informant, retrospective study

BACKGROUND Although parenting has long been considered an important risk factor for subsequent psychopathology, most investigations of this question have studied a single informant, clinical populations, one or a few disorders and did not consider relevant covariates. METHODS Three dimensions of parenting (coldness, protectiveness and authoritarianism) were measured by combining the retrospective reports from adult female twins, their co-twins, and their mothers and fathers. We assessed by personal interview, lifetime history in the twins of eight common psychiatric and substance abuse disorders and a range of predictors of parenting. Analyses were performed using logistic regression. RESULTS Examined individually, high levels of coldness and authoritarianism were modestly but significantly associated with increased risk for nearly all disorders, while the impact of protectiveness was more variable. These associations declined modestly when putative predictors of parenting were added as covariates. Maternal and paternal parenting were equally associated with outcomes in adult daughters. When coldness, protectiveness and authoritarianism were examined together, nearly all significant associations were seen solely with coldness. Few significant interactions were found between maternal and paternal parenting or between coldness, protectiveness and authoritarianism. The shared experience of these three dimensions of parenting predicts a quite small correlation in liability to these disorders in dizygotic twin pairs (e.g. r < 0.04). CONCLUSION In women, parenting behaviour, especially levels of coldness, is probably causally related to risk for a broad range of adult psychiatric disorders. The impact of parenting on substance use disorders may be largely mediated through their co-morbidity with major depression, phobias and generalized anxiety disorder. In general population samples, the association of poor parenting with psychiatric illness is modest, largely non-specific and explains little of the observed aggregation of these disorders in families.

Early Smoking Onset and Risk for Subsequent Nicotine Dependence: A Monozygotic Co-Twin Control Study

OBJECTIVE Early onset of regular smoking is associated with an elevated risk for later nicotine dependence. Whether or not this association is causal is unknown and has substantial public policy implications. METHOD The authors used a monozygotic co-twin control study design. Pairs were selected from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders for discordance in age at onset of regular smoking. Nicotine dependence was measured by the Fagerström test for nicotine dependence and level of craving. RESULTS The authors identified 175 male-male and 69 female-female monozygotic twin pairs who differed by at least 2 years in age at onset of regular smoking. During their period of heaviest smoking, the twin who began smoking earlier had significantly higher Fagerström test scores in both the male-male (Cohens d=0.20) and female-female twin pairs (d=0.26). Craving for cigarettes when unable to smoke was also higher in the early-onset member in both groups (male pairs, d=0.38; female pairs, d=0.25). The early-onset smoking twin did not differ from the later-onset twin in symptoms of alcohol or cannabis abuse or dependence, current alcohol use, or maximal level of cannabis, sedative, stimulant, or cocaine use. CONCLUSIONS Controlling for genetic and familial-environmental effects, age at onset of regular smoking predicted level of nicotine dependence. Consistent with the animal literature, these findings suggest that in humans, early nicotine exposure directly increases level of later nicotine dependence. These results should be interpreted in the context of the methodological strengths and limitations of the monozygotic co-twin design.

The heritability of cluster A personality disorders assessed by both personal interview and questionnaire

BACKGROUND Personality disorders (PDs) as assessed by questionnaires and personal interviews are heritable. However, we know neither how much unreliability of measurement impacts on heritability estimates nor whether the genetic and environmental risk factors assessed by these two methods are the same. We wish to know whether the same set of PD vulnerability factors are assessed by these two methods. METHOD A total of 3334 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP) completed a questionnaire containing 91 PD items. One to 6 years later, 1386 of these pairs were interviewed with the Structured Interview for DSM-IV Personality (SIDP-IV). Self-report items predicting interview results were selected by regression. Measurement models were fitted using Mx. RESULTS In the best-fit models, the latent liabilities to paranoid personality disorder (PPD), schizoid personality disorder (SPD) and schizotypal personality disorder (STPD) were all highly heritable with no evidence of shared environmental effects. For PPD and STPD, only unique environmental effects were specific to the interview measure whereas both environmental and genetic effects were found to be specific to the questionnaire assessment. For SPD, the best-fit model contained genetic and environmental effects specific to both forms of assessment. CONCLUSIONS The latent liabilities to the cluster A PDs are highly heritable but are assessed by current methods with only moderate reliability. The personal interviews assessed the genetic risk for the latent trait with excellent specificity for PPD and STPD and good specificity for SPD. However, for all three PDs, the questionnaires were less specific, also indexing an independent set of genetic risk factors.

A genetically informative developmental study of the relationship between conduct disorder and peer deviance in males

BACKGROUND Conduct disorder (CD) and peer deviance (PD) both powerfully predict future externalizing behaviors. Although levels of CD and PD are strongly correlated, the causal relationship between them has remained controversial and has not been examined by a genetically informative study. METHOD Levels of CD and PD were assessed in 746 adult male-male twin pairs at personal interview for ages 8-11, 12-14 and 15-17 years using a life history calendar. Model fitting was performed using the Mx program. RESULTS The best-fit model indicated an active developmental relationship between CD and PD including forward transmission of both traits over time and strong causal relationships between CD and PD within time periods. The best-fit model indicated that the causal relationship for genetic risk factors was from CD to PD and was constant over time. For common environmental factors, the causal pathways ran from PD to CD and were stronger in earlier than later age periods. CONCLUSION A genetically informative model revealed causal pathways difficult to elucidate by other methods. Genes influence risk for CD, which, through social selection, impacts on the deviance of peers. Shared environment, through family and community processes, encourages or discourages adolescent deviant behavior, which, via social influence, alters risk for CD. Social influence is more important than social selection in childhood, but by late adolescence social selection becomes predominant. These findings have implications for prevention efforts for CD and associated externalizing disorders.

Caffeine intake, toxicity and dependence and lifetime risk for psychiatric and substance use disorders : an epidemiologic and co-twin control analysis

BACKGROUND Although caffeine is the most commonly used psychoactive substance and often produces symptoms of toxicity and dependence, little is known, especially in community samples, about the association between caffeine use, toxicity and dependence and risk for common psychiatric and substance use disorders. METHOD Assessments of lifetime maximal caffeine use and symptoms of caffeine toxicity and dependence were available on over 3600 adult twins ascertained from the population-based Virginia Twin Registry. Lifetime histories of major depression (MD), generalized anxiety disorder (GAD) and panic disorder, alcohol dependence, adult antisocial behavior and cannabis and cocaine abuse/dependence were obtained at personal interview. Logistic regression analyses in the entire sample and within monozygotic (MZ) twin pairs were conducted in SAS. RESULTS In the entire sample, measures of maximal caffeine use, heavy caffeine use, and caffeine-related toxicity and dependence were significantly and positively associated with all seven psychiatric and substance use disorders. However, within MZ twin pairs, controlling for genetic and family environmental factors, these associations, while positive, were all non-significant. These results were similar when excluding twins who denied regular caffeine use. CONCLUSIONS Maximal lifetime caffeine intake and caffeine-associated toxicity and dependence are moderately associated with risk for a wide range of psychiatric and substance use disorders. Analyses of these relationships within MZ twin pairs suggest that most of the observed associations are not causal. Rather, familial factors, which are probably in part genetic, predispose to both caffeine intake, toxicity and dependence and the risk for a broad array of internalizing and externalizing disorders.

A Developmental Twin Study of Church Attendance and Alcohol and Nicotine Consumption: A Model for Analyzing the Changing Impact of Genes and Environment

OBJECTIVE Church attendance is one of the most consistent predictors of alcohol and nicotine consumption. The authors sought to clarify changes in the role of genetic and environmental factors in influencing church attendance and the interrelationship between church attendance and alcohol and nicotine use from early adolescence into adulthood. METHOD The authors used data from two interview waves 6 years apart of 1,796 male twins from a population-based register, in which respondents were asked about current and past church attendance and psychoactive drug use. Structural twin models were fitted and tested using the Mx software program. RESULTS As twins developed from childhood through adulthood, the influence of shared environmental factors on church attendance declined dramatically while genetic factors increased. In early and late adolescence, the negative correlations between church attendance and alcohol and nicotine consumption resulted largely from shared environmental factors. In adulthood, the inverse relationship between church attendance and substance use became stronger and arose largely from genetic factors. CONCLUSIONS As individuals mature, they increasingly shape their own social environment in large part as a result of their genetically influenced temperament. When individuals are younger and living at home, frequent church attendance reflects a range of familial and social-environmental influences that reduce levels of substance use. In adulthood, by contrast, high levels of church attendance largely index genetically influenced temperamental factors that are protective against substance use. Using genetically informative designs such as twin studies, it is possible to show that the causes of the relationship between social risk factors and substance use can change dramatically over development.

Borderline personality disorder traits and their relationship with dimensions of normative personality: a web-based cohort and twin study.

Kendler KS, Myers J, Reichborn‐Kjennerud T. Borderline personality disorder traits and their relationship with dimensions of normative personality: a web‐based cohort and twin study.

The Relationship Between the Genetic and Environmental Influences on Common Internalizing Psychiatric Disorders and Mental Well-Being

To determine the relationship between the genetic and environmental risk factors for common internalizing psychopathology (IP) and mental well-being (MWB), we examined detailed measures of emotional, social and psychological well-being, and a history of major depression (MD), generalized anxiety disorder (GAD) and panic attacks in the last year, in 1,386 twins from same-sex pairs from the MIDUS national USA sample assessed in 1995 and then again in 2005. Statistical analyses were performed with the Mx program. In the 1995 data, the best fit model contained one substantially heritable common factor for MD, GAD and panic attacks, and one strongly heritable common factor for the three well-being measures. Genetic and environmental risk factors for IP accounted for, respectively, 50 and 5%, of the genetic and environmental influences on MWB. We then constructed, using 1995 and 2005 data, two common factors that reflected temporally stable influences on (i) MD and GAD, and (ii) on emotional and psychological well-being. Genetic and environmental risk factors for the stable liability to IP accounted for 41 and 29% of the stable genetic and environmental influences, respectively, on MWB. This study suggests that genetic risk factors for IP make up 41–50% of the genetic influences on MWB. The overlap of environmental risk factors is more modest. Although low levels of IP on average reflect a high genetic propensity for MWB, other independent genetic influences play an important role in producing good mental health.

The Relationship Between Genetic Influences on Alcohol Dependence and on Patterns of Alcohol Consumption

BACKGROUND Genetic factors impact substantially both on alcohol consumption (AC) and on the risk for alcohol dependence (AD). However, we know little about the degree to which measures of AC index the genetic risk for AD. METHODS We assessed a lifetime history of AD by DSM-IV criteria and four measures of AC at the time of heaviest drinking (drink frequency, regular quantity, maximum quantity, and drunk frequency) in 5,073 adult twins from same-sex pairs from the Virginia Twin Registry. Structural models were fitted using Mx. RESULTS We found evidence for different genetic structure in the sexes. In women, genetic risk for AD and for the four measures of AC was entirely shared. In men, the AC measures captured 85% of the genetic risk for AD. In women, the genetic relationship with AD was strongest for drunk frequency and in men for both drunk frequency and regular quantity. CONCLUSIONS In a population-based sample of twins, four relatively simple measures of AC obtained for the time of lifetime heaviest drinking were able to capture all (in women) or a very large proportion (in men) of the genetic risk for the complex multi-dimensional construct of AD. If replicated, these results have practical implications for studies aiming to assess genetic risk for AD.