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Background: We sought to clarify the impact of adolescent alcohol misuse on adult physical health and subjective well‐being. To do so, we investigated both the direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction and the indirect effects on these outcomes attributable to subsequent alcohol problems. Method: The sample included 2733 twin pairs (32% monozygotic; 52% female) from the FinnTwin16 study. Adolescent alcohol misuse was a composite of frequency of drunkenness, frequency of alcohol use, and alcohol problems at ages 16, 17, and 18.5. The early midlife outcomes included somatic symptoms, self‐rated health, and life satisfaction at age 34. The mediators examined as part of the indirect effect analyses included alcohol problems from the Rutgers Alcohol Problem Index at ages 24 and 34. Serial mediation and co‐twin comparison models were applied and included covariates from adolescence and early midlife. Results: There were weak direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction. However, there was stronger evidence for indirect effects, whereby young adult and early midlife alcohol problems serially mediated the relationship between adolescent alcohol misuse and early midlife somatic symptoms (β = 0.03, 95% CI [0.03, 0.04]), self‐rated health (β = −0.02, 95% CI [−0.03, −0.01]), and life satisfaction (β = −0.03, CI [−0.04, −0.02]). These serial mediation effects were robust in co‐twin comparison analyses. Conclusions: These results provide evidence that alcohol problems are a primary driver linking adolescent alcohol misuse and poor health outcomes across the lifespan. [ABSTRACT FROM AUTHOR]

Background: Do drinking patterns in late adolescence/early adulthood predict lifetime childlessness and number of children? Research on this question has been only tangentially relevant and the results inconsistent. The designs used to date have been compromised by genetic and environmental confounds that are poorly controlled; covariate effects of smoking and education that are often ignored; males being understudied; population‐based sampling rare, and long‐term prospective studies with genetically informative designs yet to be reported. Method: In a 33‐year follow‐up, we linked the drinking patterns of >3500 Finnish twin pairs, assessed at ages 18–25, to registry data on their eventual number of children. Analyses distinguished associations of early drinking patterns with lifetime childlessness from those predictive of family size. Within‐twin pair analyses used fixed‐effects regression models to account for shared familial confounds and genetic liabilities. Childlessness was analyzed with Cox proportional hazards models and family size with Poisson regression. Analyses within‐pairs and of twins as individuals were run before and after adjustment for smoking and education, and for oral contraceptive (OC) use in individual‐level analyses of female twins. Results: Baseline abstinence and heavier drinking both significantly predicted lifetime childlessness in individual‐level analyses. Few abstinent women used OCs, but they were nonetheless more often eventually childless; adjusting for smoking and education did not affect this finding. Excluding childless twins, Poisson models of family size showed heavier drinking at 18–25 to be predictive of fewer children in both men and women. Those associations were replicated in within‐pair analyses of dizygotic twins, each level of heavier drinking being associated with smaller families. Among monozygotic twins, associations of drinking with completed family size yielded effects of similar magnitude, reaching significance at the highest levels of consumption, ruling out familial confounds. Conclusions: Compared to moderate levels of drinking, both abstinence and heavier drinking in late adolescence/early adulthood predicted a greater likelihood of lifetime childlessness and eventual number of children. Familial confounds do not fully explain these associations. [ABSTRACT FROM AUTHOR]

Background: DNA methylation may play a role in the progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. We examined the association between alcohol consumption and DNA methylation patterns using 3 approaches: a conventional epigenome‐wide association study (EWAS); a co‐twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption. Methods: Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1,004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome‐wide DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. Results: In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co‐twin comparisons replicated 4 CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker vs. light drinker/abstainer or moderate drinker vs. abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co‐twins. Conclusions: Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood. [ABSTRACT FROM AUTHOR]

Background: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population‐based epidemiological samples. Methods: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment‐seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery–validation pairs), and from meta‐analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. Results: Polygenic scores derived from 1 population‐based sample (ALSPAC) significantly predicted AUD symptoms in another population‐based sample (FT12), but not in either clinically ascertained sample. Trend‐level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. Conclusions: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment‐seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder. [ABSTRACT FROM AUTHOR]

Background: Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene‐by‐environment (G × E) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G × E effects. Methods: We examined these questions in the young adult FinnTwin12 sample (n = 1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p‐value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the G × E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G × E effects in an interaction between romantic relationship status and intoxication frequency. Results: Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per‐SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G × E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. Conclusions: These findings highlight the potential utility of integrating functional genomic annotation information to increase the signal‐to‐noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification. [ABSTRACT FROM AUTHOR]

Background: Regular drinking by age 14 years is a significant risk factor for alcoholism, and genetically informative data suggest that whether a young adolescent abstains or drinks is largely attributable to familial (or other shared) environmental factors. Methods: Three consecutive birth cohorts of Finnish twins, enrolled into a longitudinal study at age 11 to 12 years, completed a follow-up questionnaire within 3 months of their 14th birthdays. The sample included 1380 twin sisters and 1330 twin brothers at age 14, and at that age, 35.4% reported using alcohol. Genetic analyses (model-fitting of twin pair data) and epidemiological analyses (logistical regressions of data from individual twins) were conducted to examine predictive factors of drinking versus abstinence at age 14. Results: Polychoric correlations were substantial across all same-sex twin pairs but were lower for brother-sister twins, suggesting significant influences of common environments, with some sex-specific effects. Common environmental effects were equivalent in male and female adolescents and accounted for 76% of the total variation in abstinence/drinking. Logistical regression analyses among 2206 individual twins with complete data on risk-relevant measures at both baseline and follow-up identified significant predictors of drinking or abstaining at age 14, including female sex, twin sibling of the opposite sex, accelerated pubertal development, and the twins' assessments, made at age 12, of reduced parental monitoring and a less supportive home atmosphere; drinking at age 14 was also predicted by behaviors rated by the twins' classroom teachers 2 years earlier, increasing with rated behavioral problems but decreasing with rated emotional problems. Conclusions: Our results show that environmental factors shared by twin siblings account for most of the variance in abstaining or drinking at age 14. We identify predictors of drinking in the adolescent twins' home environments and in their dispositional behaviors, sibling interactions, and pubertal timing. [ABSTRACT FROM AUTHOR]

Background: Drinking frequency escalates rapidly during adolescence. Abstinence declines markedly, and drinking monthly or more often becomes normative. Individual differences in adolescent drinking patterns are large, and some patterns are predictive of subsequent drinking problems; little, however, is known of the gene-environment interactions that create them. Methods: Five consecutive and complete birth cohorts of Finnish twins, born 1975-1979, were enrolled sequentially into a longitudinal study and assessed, with postal questionnaires, at ages 16, 17, and 18.5 years. The sample included 1786 same-sex twin pairs, of whom 1240 pairs were concordantly drinking at age 16. Maximum likelihood models were fit in longitudinal analyses of the three waves of drinking data to assess changes in genetic and environmental influences on alcohol use across adolescence. Secondary analyses contrasted twin pairs residing in rural versus those in urban environments to investigate gene-environment interactions. Results: Longitudinal analyses revealed that genetic factors influencing drinking patterns increased in importance across the 30-month period, and effects arising from common environmental influences declined. Distributions of drinking frequencies in twins residing in urban and rural environments were highly similar, but influences on drinking varied between the two environments. Genetic factors assumed a larger role among adolescents residing in urban areas, while common environmental influences were more important in rural settings. Formal modeling of the data established a significant gene-environment interaction. Conclusions: The results document the changing impact of genetic and environmental influences on alcohol use across adolescence. Importantly, the results also reveal a significant gene-environment interaction in patterns of adolescent drinking and invite more detailed analyses of the pathways and mechanisms by which environments modulate genetic effects. [ABSTRACT FROM AUTHOR]

In 1975 and again in 1981, all adult twins in the population-based Finnish Twin Cohort were administered postal questionnaires yielding data on self-reported frequency and quantity of alcohol use. The longitudinal results provide information on the age-to-age stability of social drinking patterns among 13,404 (twin) individuals aged 18 to 43 at baseline; model-fitting the cross-temporal consistency of the twins' reported alcohol use yields unique estimates of the contribution of genetic and environmental factors to their individual age-to-age stabilities. Mean consumption levels did not change between 1975 and 1981. Patterns of social drinking were more stable in older (aged 24-43 at baseline) than younger (aged 18-23 at baseline) adult twins, and were more stable among men than women. Heritabilities were significant at both baseline and follow-up for all three alcohol measures in both genders and both age groups, with a median magnitude of 0.48. Both longitudinal genetic and environmental covariances were significant, and both were generally higher among older pairs. Genetic covariances (median magnitude = 0.68) were significantly higher than environmental covariances (median = 0.36). Analyses of absolute changes in alcohol use revealed heritable influences on the disposition to change. We conclude that genes contribute to both consistency and change in patterns of alcohol use from early to midadulthood. [ABSTRACT FROM AUTHOR]

To evaluate genetic influences on the use and abuse of alcohol, we compared questionnaire measures of the frequency, quantity, and density of social drinking, and the frequency of alcohol-induced passouts self-reported by 879 monozygotic (MZ) and 1940 dizygotic (DZ) pairs of twin brothers, aged 24-49 yr. The measures of frequency, quantity, and density (heavy drinking once or more a month) significantly intercorrelate, and the self-reported alcohol consumption by this sample is satisfactorily stable and consistent with nationwide sales figures. None of the drinking measures was associated with twin type (zygosity), and only density correlated with age. Similarity of drinking habits among twin brothers was evaluated as a function of their genetic resemblance and age, the frequency of their social contact with one another, and the interactions of these terms. The effects were estimated from hierarchical linear regressions of a double-entry data matrix from which each twin's drinking was predicted from that of his twin brother, and that pair's age, zygosity, cohabitation status, and frequency of social contact. Significant genetic variance was found for each of the drinking measures with heritability estimates ranging from 0.36 to 0.40. Co-twins in more frequent social contact with one another reported greater similarity in their use of alcohol, but heritable variance remained after the effects of age and social contact were removed from both mean levels and co-twin resemblance. Reported frequency of pass-outs yielded significant, but equivalent, correlations in both MZ and DZ twins and no evidence of genetic influence. [ABSTRACT FROM AUTHOR]