Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Are the symptoms of cannabis use disorder best accounted for by dimensional, categorical, or factor mixture models? A comparison of male and female young adults.

Despite the consensus that criteria for cannabis abuse and dependence and symptoms of withdrawal are best explained by a single latent liability, it remains unknown whether alternative models provide a better explanation of these criteria. A series of latent factor, latent class, and hybrid factor mixture models were fitted to data from 872 recent cannabis users from the Minnesota Twin Family Study who completed Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised, and 4th ed.) diagnostic criteria for cannabis abuse, dependence, and symptoms of withdrawal. Despite theoretical appeal, results did not support latent class or factor mixture modeling. Instead, symptoms of abuse, dependence, and withdrawal were better summarized by a single latent factor Cannabis Use Disorder (CUD) for male and female young adults. An almost 2-fold sex difference in item endorsement was best explained by a single mean difference on the CUD factor, indicating that young men have a greater latent liability toward expressing CUD.

An assessment of the individual and collective effects of variants on height using twins and a developmentally informative study design.

In a sample of 3,187 twins and 3,294 of their parents, we sought to investigate association of both individual variants and a genotype-based height score involving 176 of the 180 common genetic variants with adult height identified recently by the GIANT consortium. First, longitudinal observations on height spanning pre-adolescence through adulthood in the twin sample allowed us to investigate the separate effects of the previously identified SNPs on pre-pubertal height and pubertal growth spurt. We show that the effect of SNPs identified by the GIANT consortium is primarily on prepubertal height. Only one SNP, rs7759938 in LIN28B, approached a significant association with pubertal growth. Second, we show how using the twin data to control statistically for environmental variance can provide insight into the ultimate magnitude of SNP effects and consequently the genetic architecture of a phenotype. Specifically, we computed a genetic score by weighting SNPs according to their effects as assessed via meta-analysis. This weighted score accounted for 9.2% of the phenotypic variance in height, but 14.3% of the corresponding genetic variance. Longitudinal samples will be needed to understand the developmental context of common genetic variants identified through GWAS, while genetically informative designs will be helpful in accurately characterizing the extent to which these variants account for genetic, and not just phenotypic, variance.

A Twin and Adoption Study of Reading Achievement: Exploration of Shared-Environmental and Gene-Environment-Interaction Effects.

Existing behavior-genetic research implicates substantial influence of heredity and modest influence of shared environment on reading achievement and reading disability. Applying DeFries-Fulker analysis to a combined sample of twins and adoptees (N = 4,886, including 266 reading-disabled probands), the present study replicates prior findings of considerable heritability for both reading achievement and reading disability. A simple biometric model adequately described parent and offspring data (combined N = 9,430 parents and offspring) across differing types of families present in the sample Analyses yielded a high heritability estimate (around 0.70) and a negligible shared-environmentality estimate for both reading achievement and reading disability. No evidence of gene × environment interaction was found for parental reading ability and parental educational attainment, the two moderators analyzed.

Locating eating pathology within an empirical diagnostic taxonomy: evidence from a community-based sample.

Existing structural models of psychopathology need to be expanded to include additional diagnostic constructs beyond mood, anxiety, substance use, and antisocial behavior disorders. The goal of this study was to locate eating disorders within a hierarchical structural model of psychopathology that is anchored by broad Internalizing and Externalizing factors. Participants were female adolescent twins (N = 1,434) from the Minnesota Twin Family Study. The authors compared the fit of 4 models in which eating disorders (a) defined their own diagnostic class, (b) represented a subclass within Internalizing, (c) formed a subclass within Externalizing, and (d) were allowed to cross-load on both Internalizing and Externalizing. In the best fitting model, eating disorders formed a subfactor within Internalizing. These findings underscore the value of developing more comprehensive empirically based models of psychopathology to increase researchers' understanding of diverse mental disorders.

The enrichment study of the Minnesota twin family study: increasing the yield of twin families at high risk for externalizing psychopathology.

The Enrichment Study (ES) was designed to extend the Minnesota Twin Family Study (MTFS) by oversampling 11-year-old twins at especially high risk for substance use disorders by virtue of having a childhood disruptive disorder. The sample was ascertained from Minnesota birth records. To identify high-risk twins, we conducted telephone screening interviews for parent-reported symptoms of attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) as well as indications of academic disengagement. Twins who exceeded a predetermined threshold were invited to participate. To facilitate comparison with the previously ascertained MTFS participants, a random sample of 11-year-old twins was also recruited. As part of the ES study, 499 twin pairs, and their parents, visited the University of Minnesota, where each participant completed a clinical interview, psychophysiological evaluation, and thorough assessment of environmental risk. We were highly successful in recruiting at-risk twins; 52% of the screened male twins and 41% of the screened females met criteria for a diagnosis of ADHD, CD, or oppositional defiant disorder (ODD). At the pair level, 63% of the screened pairs had at least one member with a childhood disruptive disorder. This article provides an overview of the study design and includes a review of recent findings using this sample of twins.

Parental alcohol dependence and the transmission of adolescent behavioral disinhibition: a study of adoptive and non-adoptive families.

AIM: To examine the genetic and environmental influences of parental alcoholism on offspring disinhibited behavior. DESIGN: We compared the effect of parental alcoholism history on offspring in adoptive and non-adoptive families. In families with a history of parental alcohol dependence, we examined the effect of exposure to parental alcoholism symptoms during the life-time of the adolescent. Setting Assessments occurred at the University of Minnesota from 1998 to 2004. PARTICIPANTS: Adolescents adopted in infancy were ascertained systematically from records of three private Minnesota adoption agencies; non-adopted adolescents were ascertained from Minnesota birth records. Adolescents and their rearing parents participated in in-person assessments. MEASUREMENTS: For adolescents, measures included self- reports of delinquency, deviant peers, substance use, antisocial attitudes and personality. For parents, we conducted DSM-IV clinical assessments of alcohol abuse and dependence. FINDINGS: A history of parental alcohol dependence was associated with higher levels of disinhibition only when adolescents were related biologically to their rearing parents. Within families with a history of parental alcoholism, exposure to parental alcohol misuse during the life-time of the adolescent was associated with increased odds of using alcohol in adopted adolescents only. CONCLUSIONS: These findings suggest that the association between a history of parental alcohol dependence and adolescent offspring behavioral disinhibition is attributable largely to genetic rather than environmental transmission. We also obtained some evidence for parental alcohol misuse as a shared environmental risk factor in adoptive families.

Self-esteem, negative emotionality, and depression as a common temperamental core: a study of mid-adolescent twin girls.

We tested the structure and magnitude of genetic and environmental influences on the overlap among self-esteem, negative emotionality, and major depression symptoms in adolescent girls (N=706) from the Minnesota Twin Family Study. Genetic and environmental influences on all three operated via a general, heritable factor. Genetic influences explained the majority of overlap among the three constructs, as well as most of the variance in self-esteem and negative emotionality. Genetic influences on depression were more modest and largely due to genetic factors specific to depression. These findings support the theory that self-esteem, depression, and neuroticism represent aspects of a common temperamental core. The interrelations among the three constructs in mid-adolescence is consistent with their interrelations in adulthood.

Parental smoking and adolescent problem behavior: an adoption study of general and specific effects.

OBJECTIVE: It is essential to understand the effect of parental smoking on offspring tobacco use. In biologically related families, parents who smoke may transmit a nonspecific genetic risk for offspring disinhibited behavior, including tobacco use. Studying adoptive families allows one to control for genetic confounding when examining the environmental effect of exposure to parental smoking. The purpose of this study was to examine the genetic and environmental contributions to the risk represented by exposure to parental smoking and to assess the specificity of that risk. METHODS: Adolescents adopted in infancy were systematically ascertained from records of three private Minnesota adoption agencies; nonadopted adolescents were ascertained from Minnesota birth records. Adolescents and their rearing parents participated in all assessments in person. The main outcome measures were self-reports of behavioral deviance, substance use, and personality, as well as DSM-IV clinical assessments of childhood disruptive disorders. RESULTS: The data from adoptive families suggest that exposure to parental smoking represents an environmental risk for substance use in adolescent offspring. In biologically related families, the effect of exposure to parental smoking is larger and more diverse, including substance use, disruptive behavior disorders, delinquency, deviant peer affiliations, aggressive attitudes, and preference for risk taking. CONCLUSIONS: This study provides evidence for an environmentally mediated pathway by which parental smoking increases risk specifically for substance use in adolescent offspring. The data are also consistent with a genetically mediated pathway by which nonadoptive parents who smoke may also transmit a nonspecific genetic risk to their offspring for disinhibited behavior.

The heritability of life events: an adolescent twin and adoption study.

Although life events are often conceptualized as reflecting exogenous risk factors for psychopathology, twin studies have suggested they are heritable. We undertook a mixed twin/adoption study to further explore genetic and environmental contributions to individual differences in the experience of life events. Specifically, a sample of 618 pairs of like-sex adolescent twins, 244 pairs of like-sex adopted adolescent and young adult siblings, and 128 pairs of like-sex biological siblings completed a life events interview. Events were classified as independent (not likely to have been influenced by respondent's behavior), dependent (likely to have been influenced by respondent's behavior), or familial (experienced by a family member), and then summed to form three life event scales. Variance on the scales was assumed to be a function of four factors: additive genetic effects (a2), shared environmental effects (c2), twin-specific effects (t2), and nonshared environmental effects (e2). Data were analyzed using standard biometrical models. Shared environmental effects were found to be the largest contributor to variance in familial events (c2 = .71; 95% confidence interval of .65, .76); additive genetic effects were the largest contributor to dependent events (a2 = .45; CI = .31, .58); and nonshared environmental effects were found to be the largest contributor independent events (e2 = .57; CI = .51, .64). A significant twin-specific effect was also found for independent life events, indicating that twins are more likely to be exposed to such events than non-twin biological siblings. Findings are discussed in terms of their implication for understanding the nature of psychosocial risk.