Jarrod M. Ellingson

Familial Confounding of the Association Between Maternal Smoking During Pregnancy and Offspring Substance Use and Problems

CONTEXT Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring. OBJECTIVE To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design. DESIGN We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding. SETTING Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2). PATIENTS OR OTHER PARTICIPANTS Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1,187,360). MAIN OUTCOME MEASURES Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2). RESULTS The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR](moderate), 1.32 [95% CI, 1.22-1.43]; HR(high), 1.33 [1.17-1.53]) to a narcotics-related conviction (HR(moderate), 2.23 [2.14-2.31]; HR(high), 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant. CONCLUSIONS The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.

A sibling-comparison study of smoking during pregnancy and childhood psychological traits

Prenatal exposure to substances of abuse is associated with numerous psychological problems in offspring, but quasi-experimental studies controlling for co-occurring risk factors suggest that familial factors (e.g., genetic and environmental effects shared among siblings) confound many associations with maternal smoking during pregnancy (SDP). Few of the quasi-experimental studies in this area have explored normative psychological traits in early childhood or developmental changes across the lifespan, however. The current study used multilevel growth curve models with a large, nationally-representative sample in the United States to investigate for potential effects of SDP on the developmental trajectories of cognitive functioning, temperament/personality, and disruptive behavior across childhood, while accounting for shared familial confounds by comparing differentially exposed siblings and statistically controlling for offspring-specific covariates. Maternal SDP predicted the intercept (but not change over time) for all cognitive and externalizing outcomes. Accounting for familial confounds, however, attenuated the association between SDP exposure and all outcomes, except the intercept (age 5) for reading recognition. These findings, which are commensurate with previous quasi-experimental research on more severe indices of adolescent and adult problems, suggest that the associations between SDP and developmental traits in childhood are due primarily to confounding factors and not a causal association.

Measuring historical trauma in an American Indian community sample: Contributions of substance dependence, affective disorder, conduct disorder and PTSD

BACKGROUND The American Indian experience of historical trauma is thought of as both a source of intergenerational trauma responses as well as a potential causative factor for long-term distress and substance abuse among communities. The aims of the present study were to evaluate the extent to which the frequency of thoughts of historical loss and associated symptoms are influenced by: current traumatic events, post traumatic stress disorder (PTSD), cultural identification, percent Native American Heritage, substance dependence, affective/anxiety disorders, and conduct disorder/antisocial personality disorder (ASPD). METHODS Participants were American Indians recruited from reservations that were assessed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), The Historical Loss Scale and The Historical Loss Associated Symptoms Scale (to quantify frequency of thoughts and symptoms of historical loss) the Stressful-Life-Events Scale (to assess experiences of trauma) and the Orthogonal Cultural Identification Scale (OCIS). RESULTS Three hundred and six (306) American Indian adults participated in the study. Over half of them indicated that they thought about historical losses at least occasionally, and that it caused them distress. Logistic regression revealed that significant increases in how often a person thought about historical losses were associated with: not being married, high degrees of Native Heritage, and high cultural identification. Additionally, anxiety/affective disorders and substance dependence were correlated with historical loss associated symptoms. CONCLUSIONS In this American Indian community, thoughts about historical losses and their associated symptomatology are common and the presence of these thoughts are associated with Native American Heritage, cultural identification, and substance dependence.

Does Variance in Drinking Motives Explain the Genetic Overlap Between Personality and Alcohol Use Disorder Symptoms? A Twin Study of Young Women

BACKGROUND Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Although drinking motives have been posited as important mediators of the alcohol-personality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e., abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear. METHODS Using data from 2,904 young adult female twins, the phenotypic and genetic associations between personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen A, 1982 unpublished data], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa and McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested. RESULTS Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant. CONCLUSIONS Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms.

Working memory as a moderator of impulsivity and alcohol involvement: Testing the cognitive-motivational theory of alcohol use with prospective and working memory updating data

Research consistently shows that individuals high in impulsivity are at increased risk for excessive alcohol use and alcohol-related problems including alcohol use disorders (AUDs). Recent theorizing posits that working memory (WM) ability might moderate this association, but extant studies have suffered from methodological shortcomings, particularly mischaracterizing WM as a single, unitary construct and using only cross-sectional designs. This paper reports two studies that attempted to replicate and extend previous investigations of the relationship between WM, impulsivity, and alcohol involvement using two independent samples. Study 1 used a large (N=489 at baseline), prospective cohort of college students at high and low risk for AUD to investigate interactions between WM capacity and impulsivity on cross-sectional and prospective alcohol involvement. Study 2 used a large (N=420), cross-sectional sample of participants in an alcohol challenge study to investigate similar interactions between WM updating and impulsivity on recent alcohol involvement. Whereas Study 1 found that WM capacity moderates the relationship between some measures of impulsivity and alcohol involvement, with effects prospectively predicting alcohol involvement for up to three years, Study 2 did not find similar moderation effects when using measures of WM updating. These findings highlight the multifaceted nature of WM, which is often overlooked in the alcohol and impulsivity literature.

The Reliability and Validity of the Family History Method for Assessing Pathological Gambling and Gambling Involvement

The family history (FH) method, which involves the use of an informant to gather information about one or more family members, has been used in a number of previous gambling studies. However, no evaluation of the reliability and validity has been conducted on the use of the FH method for assessing pathological gambling (PG) and gambling involvement. The current study examined the test-retest and inter-rater reliability and the validity of the FH method for assessing PG and gambling involvement among a large community-based sample of adult twins (N = 4,764) reporting on their parents, co-twins, and spouses. The test-retest and inter-rater reliabilities of the FH reports of PG were high. Validity of the FH reports of PG was low, primarily because of substantial underestimation of pathology (low sensitivity). The test-retest and inter-rater reliabilities of the FH reports of gambling involvement (ever gambled, ever gambled monthly, and ever gambled weekly) were moderate and the sensitivities were quite high. The results of this study support the use of the FH method for studies of PG and gambling involvement. A number of potential explanations for the low sensitivity of FH reports of PG are elaborated.

Investigating the influence of prenatal androgen exposure and sibling effects on alcohol use and alcohol use disorder in females from opposite-sex twin pairs.

BACKGROUND There are robust sex differences for alcohol phenotypes, with men reporting more drinking and alcohol use disorder (AUD) symptoms than women. However, the sources of these effects are not completely understood. Sex hormones, a substantial biological sex difference, exert neurobehavioral influences and are candidates for influencing sex differences in alcohol phenotypes. This study investigated the effects of prenatal androgens based on the hypothesis of prenatal hormone transfer, which posits that hormones from one twin influence the development of a cotwin. METHODS This study compared female twins from opposite-sex (OSF) and same-sex (SSF) pairs to investigate associations between prenatal androgens and alcohol phenotypes. Additional analyses distinguished prenatal and postnatal effects by comparing OSFs and SSFs with a close-in-age older (CAO) brother. RESULTS OSFs endorsed more lifetime AUD symptoms than SSFs (d = 0.14). Females with a CAO brother reported greater intoxication frequency (d = 0.35), hangover frequency (d = 0.24), typical drinking quantity (d = 0.33), and max drinks (i.e., the most drinks ever consumed in a 24-hour period; d = 0.29). Controlling for postnatal effects, OSFs still endorsed more lifetime AUD symptoms than SSFs with a CAO brother (d = 0.16). CONCLUSIONS Prenatal exposure to a male cotwin was associated with increases in AUD symptoms, above the effect of postnatal exposure to a male sibling. Prenatal exposure to a male cotwin was not associated with increases in other alcohol-related phenotypes, but postnatal exposure to older male siblings produced medium effect sizes for indicators of alcohol consumption. Sex differences in AUDs, but not alcohol use, may be partially due to the neurodevelopmental effects of prenatal androgens. However, sibling effects may be larger than any effect of prenatal androgen exposure.

Most of the genetic covariation between major depressive and alcohol use disorders is explained by trait measures of negative emotionality and behavioral control

BACKGROUND Mental health disorders commonly co-occur, even between conceptually distinct syndromes, such as internalizing and externalizing disorders. The current study investigated whether phenotypic, genetic, and environmental variance in negative emotionality and behavioral control account for the covariation between major depressive disorder (MDD) and alcohol use disorder (AUD). METHOD A total of 3623 members of a national twin registry were administered structured diagnostic telephone interviews that included assessments of lifetime histories of MDD and AUD, and were mailed self-report personality questionnaires that assessed stress reactivity (SR) and behavioral control (CON). A series of biometric models were fitted to partition the proportion of covariance between MDD and AUD into SR and CON. RESULTS A statistically significant proportion of the correlation between MDD and AUD was due to variance specific to SR (men = 0.31, women = 0.27) and CON (men = 0.20, women = 0.19). Further, genetic factors explained a large proportion of this correlation (0.63), with unique environmental factors explaining the rest. SR explained a significant proportion of the genetic (0.33) and environmental (0.23) overlap between MDD and AUD. In contrast, variance specific to CON accounted for genetic overlap (0.32), but not environmental overlap (0.004). In total, SR and CON accounted for approximately 70% of the genetic and 20% of the environmental covariation between MDD and AUD. CONCLUSIONS This is the first study to demonstrate that negative emotionality and behavioral control confer risk for the co-occurrence of MDD and AUD via genetic factors. These findings are consistent with the aims of NIMHs RDoC proposal to elucidate how transdiagnostic risk factors drive psychopathology.

Genetic confounds in the study of sexual orientation: comment on Roberts, Glymour, and Koenen (2014).

Roberts, Glymour, and Koenen (2013) presented evidence that childhood maltreatment is related to adult homosexuality, using an instrumental variables regression analysis. Briefly, several instrumentalvariables—presenceofa stepparent,poverty,parental alcohol abuse, and parental mental illness—were related to adult homosexuality, but these relations were statistically mediated by childhood maltreatment. Roberts et al. concluded that childhood maltreatment causes adult homosexuality. We criticized the statistical approach of Roberts et al. (2013), arguing that the assumptions of both instrumental variables regression and mediation analysis were almost certainly violated (Bailey & Bailey, 2013). The instruments—stepparent presence, poverty, parental alcohol abuse, and parental mental illness—are complex in their causes and effects, and might be correlated with adult sexual orientation, through a multitude of complex pathways that do not require adult sexual orientation to be caused by the instruments via childhood maltreatment. The study falls far short of being a‘‘natural experiment,’’on which the instrumental variables regression approach is designed to capitalize, despite Roberts et al.’s characterization of their study as such. If an unmeasured third variable can cause both the instruments and outcome, the results from instrumental variables regression and mediation analyses cannot be taken as evidence for the causal pathways tested in these models. We proposed that the findings from Roberts et al. (2013) were equally consistent with an alternative causal explanation of adult sexualorientation,wheregenesthat influenceanindividual’ssexual orientation also influence an individual’s personality. Both neuroticism (Zietsch, Verweij, Bailey, Wright, & Martin, 2011) and depression (Zietsch et al., 2012) have been found to correlate at the genetic level with adult sexual orientation. Therefore, parents with these genes may be more likely to divorce (resulting in stepparent presence), live in poverty, abuse alcohol, be diagnosed with mental illness, and to have children who are maltreated. Under this model, Roberts et al.’s instrumental variables regression and mediation analyses would yield apparent evidence for an influence of childhood maltreatment on adult sexual orientation, even though maltreatment does not cause adult sexual orientation. Roberts, Glymour, and Koenen (2014) criticized our reply, stating that‘‘no genetic research supports [the] possibility’’that genes associated with sexual orientation may also be related to parental relationship instability, mental illness, alcohol use, and poverty.Further, theyclaimthat, for thehypothesisweproposed toaccountfor theirfindings,homosexualityandneuroticismmust both be caused by an allele of very large effect (accounting for 14 % of the variance in mother’s neuroticism and 15 % of the variance inchild’s sexualorientation).Robertsetal. asserted that these effects ‘‘are stronger, by an order of magnitude, than any established genetic determinant for any mental health or complex behavioral outcome.’’ Ifweunderstand‘‘establishedgeneticdeterminant’’asasingle gene, then we agree with Roberts et al. (2014). To date, there have been no replicable findings of genes with effects of this magnitude (i.e., 14 % of the variance in neuroticism and 15 % of the variance in sexual orientation). However, our argument does not rely on the assumption that the genetic correlation is due to a D. H. Bailey Department of Psychology, Carnegie Mellon University, Pittsburgh, PA, USA

The family history method in disordered gambling research: A comparison of reports obtained from discordant twin pairs

The purpose of this study was to examine potential biases in family history reports of problem gambling and gambling frequency. Same-sex twin pairs discordant for a history of problem (n = 230 pairs) and pathological gambling (n = 48 pairs) and for three indexes of gambling frequency (ever gambling, monthly gambling, and weekly gambling; n = 44-517 pairs) were identified from a large Australian national twin study. The problem gambling affected twin was significantly more likely to endorse paternal problem gambling than the problem gambling unaffected cotwin (OR = 5.5), and similar findings were obtained for family history reports of gambling frequency (OR = 2.0-2.8). These results could not be explained by differences between the discordant pairs in whether they had spent time gambling with the parents; there was no association between a history of problem, monthly or weekly gambling and having gambled with the parents among discordant twin pairs. The results of this study suggest that relying solely on family history assessments of disordered gambling and gambling involvement can lead to incorrect estimates of the strength of the family history effect.