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Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; M(age) = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.

Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7,568; African ancestry = 3,274). We performed a family-based genome-wide association study (GWAS) on externalizing scores derived from criterion counts of five DSM disorders (alcohol dependence, alcohol abuse, illicit drug dependence, illicit drug abuse, and either antisocial personality disorder or conduct disorder). We meta analyzed these results with a similar measure of externalizing in an independent sample, Spit for Science (combined sample N = 15,112). We did not discover any robust genome-wide significant signals. Polygenic scores derived from the ancestry-specific GWAS summary statistics predicted externalizing problems in an independent European ancestry sample, but not in those of African ancestry. However, these PRS were no longer significant after adjusting for multiple testing. Larger samples with deep phenotyping are necessary for the discovery of SNPs related to externalizing problems.

We analyzed how the effects of genetic and environmental factors on the perceptions of family interaction change from early to late adolescence. The data were collected by postal surveys on Finnish twins (N = 4808) at 12, 14 and 17 years of age and analyzed using genetic twin modeling. Additive genetic factors explained a modest share of the variation in perceived relational support (a2 = 0.30 in boys and 0.18 in girls) and relational tensions (a2 = 0.13 and 0.14, respectively) at 12 years of age, with the proportions becoming larger through 17 years of age (a2 = 0.53 in boys and 0.49 in girls for relational support; a2 = 0.35 in boys and 0.33 in girls for relational tensions). Simultaneously, the role of environment shared by co-twins decreased. These findings suggest that the associations between perceived family interaction and other factors in adulthood should be interpreted with caution, because they partly reflect genetic background, whereas in childhood, they may provide more reliable information on parental characteristics. Electronic supplementary material The online version of this article (10.1007/s10519-019-09960-z) contains supplementary material, which is available to authorized users.

Twin studies indicate that latent genetic factors overlap across comorbid psychiatric disorders. In this study, we used a novel approach to elucidate shared genetic factors across psychiatric outcomes by clustering single nucleotide polymorphisms based on their genome-wide association patterns. We applied latent profile analysis (LPA) to p-values resulting from genome-wide association studies across three phenotypes: symptom counts of alcohol dependence (AD), antisocial personality disorder (ASP), and major depression (MD), using the European-American case-control genome-wide association study subsample of the collaborative study on the genetics of alcoholism (N = 1399). In the 3-class model, classes were characterized by overall low associations (85.6% of SNPs), relatively stronger association only with MD (6.8%), and stronger associations with AD and ASP but not with MD (7.6%), respectively. These results parallel the genetic factor structure identified in twin studies. The findings suggest that applying LPA to association results across multiple disorders may be a promising approach to identify the specific genetic etiologies underlying shared genetic variance.

The article "Genetics of Perceived Family Interaction From 12 to 17 Years of Age", written by Karri Silventoinen, Jinni Su, Lea Pulkkinen, Peter Barr, Richard J. Rose, Danielle M. Dick, Jaakko Kaprio, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 24 May 2019 without open access.

The Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes.

Depressive symptoms and alcohol use are frequently positively associated during adolescence. This study aimed to assess the heritability of each phenotype across adolescence; to assess potential shared liabilities; to examine changes in the nature of shared liabilities across adolescence; and to investigate potential causal relationships between depressive symptoms and alcohol use. We studied a longitudinally assessed sample of adolescent Finnish twins (N = 1,282) to test hypotheses about genetic and environmental influences on these phenotypes within and across ages, using data from assessments at ages 12, 14, and 17.5 years. The heritability of depressive symptoms is consistent across adolescence (~40–50%), with contributions from common and unique environmental factors. The heritability of alcohol use varies across time (a2 = .25–.44), and age 14 alcohol use is heavily influenced by shared environmental factors. Genetic attenuation and innovation were observed across waves. Modest to moderate genetic (rA = .26–.59) and environmental (rC = .30–.63) correlations between phenotypes exist at all ages, but decrease over time. Tests for causal relationships between traits differed across ages and sexes. Intrapair MZ difference tests provided evidence for reciprocal causation in girls at ages 14 and 17.5. Formal causal models suggested significant causal relationships between the variables in both boys and girls. The association between depressive symptoms and alcohol use during adolescence is likely due to a combination of shared genetic and environmental influences and causal influences. These influences are also temporally dynamic, complicating efforts to understand factors contributing to the relationship between these outcomes. peerReviewed

We report genetic linkage and association findings which implicate the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) in the modulation of a scalp-recorded electrophysiological phenotype. The P3 (P300) response was evoked using a three-stimulus visual oddball paradigm and a phenotype that relates to the energy in the theta band (4-5 Hz) was analyzed. Studies have shown that similar electrophysiological measures represent cognitive correlates of attention, working memory, and response selection; a role has been suggested for the ascending cholinergic pathway in the same functions. The results of our genetic association tests, combined with knowledge regarding the presence of presynaptic cholinergic M2 autoreceptors in the basal forebrain, indicate that the cognitive processes required by the experiment may in part be mediated by inhibitory neural networks. These findings underscore the utility of electrophysiology and neurogenetics in the understanding of cognitive function and the study of brain-related disorders.

Results from twin studies suggest that overlapping genetic factors influence alcohol dependence and illicit drug dependence. Using data from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined the association between 69 SNPs in the GABAA receptor gene cluster on chromosome 4 and marijuana and illicit drug dependence, individually, and as co-occurring phenotypes with alcohol dependence. Results suggested association between marijuana dependence and illicit drug dependence with SNPs in the GABRA2 gene. Interestingly, the evidence for association previously observed with alcohol dependence came only from individuals with comorbid illicit drug dependence. There was no association with other genes in the GABAA cluster on chromosome 4 with illicit drug dependence.

We use findings from the behavior genetics literature about how genetic factors (latently) influence alcohol dependence and related disorders to develop and test hypotheses about the risk associated with a specific gene, GABRA2, across different developmental stages. This gene has previously been associated with adult alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA) sample [Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. K., Nurnberger Jr., J. I., O'Connor, S. J., Reich, T., Rice, J., Schuckit, M., Porjesz, B., Foroud, T., and Begleiter, H. (2004). Am. J. Hum. Genet. 74:705-714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B:104-109; Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., and Gelernter, J. (2005). Alcohol. Clin. Exp. Res. 29:493-498]. In a sample of children and adolescents ascertained as part of the COGA project, we find that GABRA2 is significantly associated with childhood conduct disorder symptoms, but not with childhood alcohol dependence symptoms. A consistent elevation in risk for alcohol dependence associated with GABRA2 is not evident until the mid-20s and then remains throughout adulthood. GABRA2 is also associated with other drug dependence in our sample, both in adolescence and adulthood.

Intelligence, as measured by standardized psychological tests, has been shown to be highly heritable, though identifying specific genes influencing general intelligence has proven difficult. We conducted genome-wide linkage analyses to identify chromosomal regions containing genes influencing intelligence, as measured by WAIS full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ). Non-parametric multipoint linkage analyses were conducted with Merlin-regress software, using a sample of 1,111 genotyped and phenotyped individuals from 201 families, ascertained as part of the Collaborative Study on the Genetics of Alcoholism (COGA). The strongest evidence of linkage was obtained for FSIQ on chromosome 6 (LOD=3.28, 12 cM) near the marker D6S1006. This region was also implicated with suggestive linkage in a recently published genome screen of IQ in Australian and Dutch twin pairs, and it has been implicated in linkage studies of developmental dyslexia. Our findings provide further support that chromosome 6p contains gene(s) affecting intelligence.

Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that (1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and (2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.

The cholinergic neurotransmitter system is thought to be involved in many aspects of memory, attention, and higher cognition. In the Collaborative Study on the Genetics of Alcoholism (COGA) sample, we have previously reported linkage and association to the cholinergic muscarinic 2 receptor gene (CHRM2) on chromosome 7 with evoked EEG oscillations (Jones et al. 2004), providing evidence that this gene may be involved in human brain dynamics and cognition. In addition, a small number of genetic markers were genotyped in CHRM2 in the Minnesota Twin and Family Study (Comings et al. 2003) and a Dutch family study (Gosso et al. 2006, in press) and both research groups found evidence that this gene may be involved in intelligence. In the COGA sample, we have extensively genotyped SNPs within and flanking the CHRM2 gene. We find evidence of association with multiple SNPs across CHRM2 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R). These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample.

The progression to alcohol dependence unfolds across multiple stages, including the decision to initiate use, the development of regular patterns of use, and (for some individuals) the subsequent development of problems associated with alcohol use. Using data from two population-based, longitudinal twin studies, FinnTwin16 (FT16) and FinnTwin12 (FT12), we applied multiple stage genetic models (Heath et al., Twin Res. 5 (2002) 113) to better understand the extent to which genetic and environmental influences impact the initiation of alcohol use, frequency of use in adolescence and young adulthood, and alcohol problems in young adulthood. Shared environmental factors played a large role in initiation, and a more moderate role on frequency of use, and it was largely the same influences acting across these stages of use. However, there was no significant evidence of shared environmental influences on alcohol problems in early adulthood. Problems were largely influenced by genetic factors that overlapped with genetic influences on frequency of use. Unique environmental factors were largely specific to each stage, with some overlap between alcohol problems and frequency of use at age 25.

The use of endophenotypes has been proposed as a strategy to aid gene identification efforts for complex phenotypes [Gottesman, I. I., and Shields J. (1972). Schizophrenia and Genetics: A Twin Study Vantage Point. London: Academic]. As part of the Collaborative Study of the Genetics of Alcoholism (COGA) project, we have analyzed electrophysiological endophenotypes, in addition to clinical diagnoses, as part of our effort to identify genes involved in the predisposition to alcohol dependence. In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence [GABRA2 (Edenberg et al., (2004). Am. J. Hum. Genet. 74:705-714) and CHRM2 (Wang et al., (2004). Hum. Mol. Genet. 13:1903-1911)]. Our experience in the COGA project has been that the analysis of endophenotypes provides several advantages over diagnostic phenotypes, including the strength and localization of the linkage signal. Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972.