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1.  Adolescent Drinking and Motivated Decision-Making: A Cotwin-Control Investigation with Monozygotic Twins 
Behavior genetics  2014;44(4):407-418.
The present study used a monozygotic (MZ) cotwin-control (CTC) design to investigate associations between alcohol use and performance on the Iowa Gambling Task (IGT) in a sample of 96 adolescents (half female). The MZ CTC design is well suited to shed light on whether poor decision-making, as reflected on IGT performance, predisposes individuals to abuse substances or is a consequence of use. Participants completed structural MRI scans as well, from which we derived gray matter volumes for cortical and subcortical regions involved in IGT performance and reduced in adolescents with problematic alcohol use. Drinking was associated with poorer task performance and with reduced volume of the left lateral orbital-frontal cortex. CTC analyses indicated that the former was due to differences between members of twin pairs in alcohol use (suggesting a causal effect of alcohol), whereas the latter was due to factors shared by twins (consistent with a pre-existing vulnerability for use). Although these preliminary findings warrant replication, they suggest that normative levels of alcohol use may diminish the quality of adolescent decision-making and thus have potentially important public health implications.
doi:10.1007/s10519-014-9651-0
PMCID: PMC4058380  PMID: 24676464
Adolescent; drinking; decision-making; cotwin-control; identical twins
2.  Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study 
Behavior genetics  2014;44(4):356-367.
Previous studies have shown associations between SNPs in GABRA2 and adolescent conduct disorder (CD) and alcohol dependence in adulthood, but not adolescent alcohol dependence. The present study was intended as a replication and extension of this work, focusing on adolescent CD, adolescent alcohol abuse and dependence (AAD), and adult AAD. Family based association tests were run using Hispanics and non-Hispanic European American subjects from two independent longitudinal samples. Although the analysis provided nominal support for an association with rs9291283 and AAD in adulthood and CD in adolescence, the current study failed to replicate previous associations between two well replicated GABRA2 NPs and CD and alcohol dependence. Overall, these results emphasize the utility of including an independent replication sample in the study design, so that the results from an individual sample can be weighted in the context of its reproducibility.
doi:10.1007/s10519-014-9653-y
PMCID: PMC4098655  PMID: 24687270
alcohol; association; gamma aminobutyric acid receptor alpha 2; human genetic study; single nucleotide polymorphisms
3.  The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels 
Behavior genetics  2014;44(4):368-382.
The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N∼5000), and conducted an expression QTL (eQTL) analysis to identify SNPs associated with IL6R gene expression. Based on data from 2360 twin families, the broad heritability of sIL-6R was estimated at 72%, and 51% of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3′end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression.
doi:10.1007/s10519-014-9656-8
PMCID: PMC4283105  PMID: 24791950
soluble Interleukin-6 receptor; inflammation; heritability; GWAS; gene expression; eQTL
4.  Polymorphisms in Dopamine Transporter (SLC6A3) are Associated with Stimulant Effects of d-Amphetamine: An Exploratory Pharmacogenetic Study Using Healthy Volunteers 
Behavior genetics  2010;40(2):255-261.
Individuals vary in their subjective responses to stimulant drugs, and these differences are believed to be partially genetic in origin. We evaluated associations between mood, cognitive and cardiovascular responses to d-amphetamine and four polymorphisms in the dopamine transporter (SLC6A3): rs460000, rs3756450, rs37022 and rs6869645. Healthy Caucasian male and female volunteers (N = 152) participated in a double-blind, crossover design study in which they received placebo, 10 and 20 mg of d-amphetamine. We measured self-reported rating of mood, performance on the Digit Symbol Substitution Task, blood pressure and heart rate. Individuals with the C/C genotype at rs460000 (N = 83) reported approximately twofold higher ratings of stimulation and euphoria relative to the A/A+A/C (N = 69) genotype group, at both the 10 and 20 mg doses. No other responses or SNPs showed significant effects. rs460000 is in perfect LD with rs463379 (CEU: D′ = 1; r2 = 1), which was not studied here, but has been associated with etiology of Attention Deficit Hyperactivity Disorder (ADHD). These findings suggest a pleiotropic effect of this polymorphic locus on both ADHD and sensitivity to the subjective effects of amphetamine.
doi:10.1007/s10519-009-9331-7
PMCID: PMC4454285  PMID: 20091113
DAT1; Dopamine transporter; SLC6A3; rs460000; rs463379; Amphetamine; Stimulant response; ADHD
5.  Gender-Specific Gene–Environment Interaction in Alcohol Dependence: The Impact of Daily Life Events and GABRA2 
Behavior genetics  2013;43(5):402-414.
Gender-moderated gene–environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multilevel regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women’s distinct patterns of association.
doi:10.1007/s10519-013-9607-9
PMCID: PMC4441044  PMID: 23974430
Gender; Genetics; Gene–environment interaction; Daily hassles and uplifts; Alcohol dependence
6.  Lindon J. Eaves, Ph.D., M.A. (Oxon), D.Sc. Theory-Model-Data 
Behavior genetics  2014;44(3):183-192.
We begin this special issue by providing a glimpse into the career of Dr. Lindon J. Eaves, from the perspectives of a student, postdoc, instructor, assistant to associate and full professor over the last 20 odd years. We focus primarily on Lindon’s contributions to methodological issues and research designs to address them, in particular those related to models for extended twin-family designs, for the development of adolescent behavior, for genotype-environment covariation and interaction, and their application to the Virginia 30,000 and the Virginia Twin Study of Adolescent Behavioral Development. We then introduce the collection of papers in this special festschrift issue of Behavior Genetics, celebrating Dr. Eaves achievements over the last 40 years.
doi:10.1007/s10519-014-9655-9
PMCID: PMC4289614  PMID: 24816433
twin studies; statistical modeling; intergenerational transmission; development
7.  Combined influences of genes, prenatal environment, cortisol, and parenting on the development of children’s internalizing vs. externalizing problems 
Behavior genetics  2014;45(3):268-282.
Research suggests that genetic, prenatal, endocrine, and parenting influences across development individually contribute to internalizing and externalizing problems in children. The present study tests the combined contributions of genetic risk for psychopathology, prenatal environments (maternal drug use and internalizing symptoms), child cortisol at age 4.5 years, and overreactive parenting influences across childhood on 6-year-old children’s internalizing and externalizing problems. We used data from an adoption design that included 361 domestically adopted children and their biological and adopted parents prospectively followed from birth. Only parenting influences contributed (independently) to externalizing problems. However, genetic influences were indirectly associated with internalizing problems (through increased prenatal risk and subsequent morning cortisol), and parenting factors were both directly and indirectly associated with internalizing problems (through morning cortisol). Results suggest that prenatal maternal drug use/symptoms and children’s morning cortisol levels are mechanisms of genetic and environmental influences on internalizing problems, but not externalizing problems, in childhood.
doi:10.1007/s10519-014-9689-z
PMCID: PMC4416104  PMID: 25355319
adoption; cortisol; externalizing; genetic; internalizing; longitudinal; parenting; prenatal
8.  Sex Differences in Ethanol’s Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice With a Null Mutation of the 5α-Reductase Type 1 Gene 
Behavior genetics  2014;45(3):354-367.
Manipulation of endogenous levels of the GABAergic neurosteroid allopregnanolone alters sensitivity to some effects of ethanol. Chronic ethanol withdrawal decreases activity and expression of 5α-reductase-1, an important enzyme in allopregnanolone biosynthesis encoded by the 5α-reductase-1 gene (Srd5a1). The present studies examined the impact of Srd5a1 deletion in male and female mice on several acute effects of ethanol and on chronic ethanol withdrawal severity. Genotype and sex did not differentially alter ethanol-induced hypothermia, ataxia, hypnosis, or metabolism, but ethanol withdrawal was significantly lower in female versus male mice. On the elevated plus maze, deletion of the Srd5a1 gene significantly decreased ethanol’s effect on total entries versus wildtype (WT) mice and significantly decreased ethanol’s anxiolytic effect in female knockout (KO) versus WT mice. The limited sex differences in the ability of Srd5a1 genotype to modulate select ethanol effects may reflect an interaction between developmental compensations to deletion of the Srd5a1 gene with sex hormones and levels of endogenous neurosteroids.
doi:10.1007/s10519-014-9691-5
PMCID: PMC4417087  PMID: 25355320
neurosteroid; allopregnanolone; GABA; alcohol; hypnosis; metabolism
9.  Multivariate Genetic Analyses in Heterogeneous Populations 
Behavior genetics  2013;44(3):232-239.
Martin & Eaves (1977) proposed a multivariate model for twin and family data in order to investigate potential differences in the genetic and environmental architecture of multivariate phenotypes. The general form of the model is the independent pathway model, which differentiates between genetic and environmental influences at the item level, and therefore permits the decomposition to differ across items. A restricted version is the common pathway model, where the decomposition takes place at the factor level. The paper has spurred numerous studies, and evidence for differences in genetic and environmental architecture has been established for personality and several other psychiatric phenotypes by showing a better fit of the independent pathway model compared to the common pathway model. We show that genome-wide association studies (GWAS) that use an aggregate score computed from multiple questionnaire items as a univariate phenotype implicitly assume a similar structure as the common pathway model. It has been shown that in case of a differential genetic and environmental architecture, multivariate GWAS methods can outperform the univariate GWAS approach. However, current multivariate methods rely on the assumptions of phenotypic and genetic homogeneity, that is, item responses are assumed to have the same means and covariances, and genetic effects are assumed to be the same for all subjects. We describe a distance-based regression technique that is designed to account for subgroups in the population, and that therefore can account for differential genetic effects. A first evaluation with simulated data shows a substantial increase of power compared to univariate GWAS.
doi:10.1007/s10519-013-9631-9
PMCID: PMC4024325  PMID: 24311199
10.  Latent Classiness and Other Mixtures 
Behavior genetics  2014;44(3):205-211.
The aim of this article is to laud Lindon Eaves’ role in the development of mixture modeling in genetic studies. The specification of models for mixture distributions was very much in its infancy when Professor Eaves implemented it in his own FORTRAN programs, and extended it to data collected from relatives such as twins. It was his collaboration with the author of this article which led to the first implementation of mixture distribution modeling in a general-purpose structural equation modeling program, Mx, resulting in a 1996 article on linkage analysis in Behavior Genetics. Today, the popularity of these methods continues to grow, encompassing methods for genetic association, latent class analysis, growth curve mixture modeling, factor mixture modeling, regime switching, marginal maximum likelihood, genotype by environment interaction, variance component twin modeling in the absence of zygosity information, and many others. This primarily historical article concludes with some consideration of some possible future developments.
doi:10.1007/s10519-013-9637-3
PMCID: PMC4024345  PMID: 24477932
mixture distribution; conditional likelihood; latent class analysis; genetic analysis; twins
11.  Genetic Influences on Political Ideologies: Twin Analyses of 19 Measures of Political Ideologies from Five Democracies and Genome-Wide Findings from Three Populations 
Behavior genetics  2014;44(3):282-294.
Almost forty years ago, evidence from large studies of adult twins and their relatives suggested that between 30-60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase “Left-Right”. We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one’s genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits.
doi:10.1007/s10519-014-9648-8
PMCID: PMC4038932  PMID: 24569950
Ideology; Politics; GWAS; Attitudes; Authoritarianism
12.  Estimating the Sex-Specific Effects of Genes on Facial Attractiveness and Sexual Dimorphism 
Behavior genetics  2013;44(3):270-281.
Human facial attractiveness and facial sexual dimorphism (masculinity–femininity) are important facets of mate choice and are hypothesized to honestly advertise genetic quality. However, it is unclear whether genes influencing facial attractiveness and masculinity–femininity have similar, opposing, or independent effects across sex, and the heritability of these phenotypes is poorly characterized. To investigate these issues, we assessed facial attractiveness and facial masculinity–femininity in the largest genetically informative sample (n = 1,580 same- and opposite-sex twin pairs and siblings) to assess these questions to date. The heritability was ~0.50–0.70 for attractiveness and ~0.40–0.50 for facial masculinity– femininity, indicating that, despite ostensible selection on genes influencing these traits, substantial genetic variation persists in both. Importantly, we found evidence for intralocus sexual conflict, whereby alleles that increase masculinity in males have the same effect in females. Additionally, genetic influences on attractiveness were shared across the sexes, suggesting that attractive fathers tend to have attractive daughters and attractive mothers tend to have attractive sons.
doi:10.1007/s10519-013-9627-5
PMCID: PMC4096150  PMID: 24213680
Facial attractiveness; Masculinity–femininity; Mate choice; Sexual selection; Intralocus sexual conflict; Evolutionary genetics; Twin and family studies; Sex limitation
13.  POPULATION FREQUENCIES OF THE TRIALLELIC 5HTTLPR IN SIX ETHNICIALLY DIVERSE SAMPLES FROM NORTH AMERICA, SOUTHEAST ASIA, AND AFRICA 
Behavior genetics  2015;45(2):255-261.
Genetic differences between populations are a potentially an important contributor to health disparities around the globe. As differences in gene frequencies influence study design, it is important to have a thorough understanding of the natural variation of the genetic variant(s) of interest. Along these lines, we characterized the variation of the 5HTTLPR and rs25531 polymorphisms in six samples from North America, Southeast Asia, and Africa (Cameroon) that differ in their racial and ethnic composition. Allele and genotype frequencies were determined for 24,066 participants. Results indicated higher frequencies of the rs25531 G-allele among Black and African populations as compared with White, Hispanic and Asian populations. Further, we observed a greater number of ‘extra-long’ (‘XL’) 5HTTLPR alleles than have previously been reported. Extra-long alleles occurred almost entirely among Asian, Black and Non-White Hispanic populations as compared with White and Native American populations where they were completely absent. Lastly, when considered jointly, we observed between sample differences in the genotype frequencies within racial and ethnic populations. Taken together, these data underscore the importance of characterizing the L-G allele to avoid misclassification of participants by genotype and for further studies of the impact XL alleles may have on the transcriptional efficiency of SLC6A4.
doi:10.1007/s10519-014-9703-5
PMCID: PMC4348250  PMID: 25564228
5HTTLPR; Serotonin Transporter; rs25531; Hispanics; Add Health; population genetics
14.  Natural Genetic Variation Underlying Differences in Peromyscus Repetitive & Social/Aggressive Behaviors 
Behavior genetics  2014;44(2):126-135.
Peromyscus maniculatus (BW) and P. polionotus (PO) are interfertile North American species that differ in many characteristics. For example, PO exhibit monogamy and BW animals are susceptible to repetitive behaviors and thus a model for neurobehavioral disorders such as Autism. We analyzed these two stocks as well as their hybrids, a BW YPO consomic line (previously shown to alter glucose homeostasis) and a natural P. maniculatus agouti variant (ANb = wide band agouti). We show that PO animals engage in far less repetitive behavior than BW animals, that this trait is dominant, and that trait distribution in both species is bi-modal. The ANb allele also reduces such behaviors, particularly in females. PO, F1, and ANb animals all dig significantly more than BW. Increased self-grooming is also a PO dominant trait, and there is a bimodal trait distribution in all groups except BW. The inter-stock differences in self-grooming are greater between males, and the consomic data suggest the Y chromosome plays a role. The monogamous PO animals engage in more social behavior than BW; hybrid animals exhibit intermediate levels. Surprisingly, ANb animals are also more social than BW animals, although ANb interactions led to aggressive interactions at higher levels than any other group. PO animals exhibited the lowest incidence of aggressive behaviors, while the hybrids exhibited BW levels. Thus this group exhibits natural, genetically tractable variation in several biomedically relevant traits.
doi:10.1007/s10519-013-9640-8
PMCID: PMC3951310  PMID: 24407381
stereotypies; aggression; social interaction; Y chromosome; Peromyscus
15.  Epigenetic Analysis of Neurocognitive Development at 1 year of Age in a Community-Based Pregnancy Cohort 
Behavior genetics  2014;44(2):113-125.
Multiple studies show that molecular genetic changes and epigenetic modifications affect the risk of cognitive disability or impairment. However, the role of epigenetic variation in cognitive development of neurotypical young children remains largely unknown. Using data from a prospective, community-based study of mother-infant pairs, we investigated the association of DNA methylation patterns in neonatal umbilical cord blood with cognitive and language development at 1 year of age. No CpG loci achieved genome-wide significance, although a small number of weakly suggestive associations with Bayley-III Receptive Communication scales were noted. While umbilical cord blood is a convenient resource for genetic analyses of birth outcomes, our results do not provide conclusive evidence that its use for DNA methylation profiling yields epigenetic markers that are directly related to postnatal neurocognitive outcomes at 1 year of age.
doi:10.1007/s10519-014-9641-2
PMCID: PMC3989106  PMID: 24452678
Genome-wide association study; DNA methylation; Neurocognitive development; Umbilical cord blood
16.  Testing for Measured Gene-Environment Interaction: Problems with the use of Cross-Product Terms and a Regression Model Reparameterization Solution 
Behavior genetics  2014;44(2):165-181.
The study of gene-environment interaction (G × E) has garnered widespread attention. The most common way to assess interaction effects is in a regression model with a G × E interaction term that is a product of the values specified for the genotypic (G) and environmental (E) variables. In this paper we discuss the circumstances under which interaction can be modeled as a product term and cases in which use of a product term is inappropriate and may lead to erroneous conclusions about the presence and nature of interaction effects. In the case of a binary coded genetic variant (as used in dominant and recessive models, or where the minor allele occurs so infrequently that it is not observed in the homozygous state), the regression coefficient corresponding to a significant interaction term reflects a slope difference between the two genotype categories and appropriately characterizes the statistical interaction between the genetic and environmental variables. However, when using a three-category polymorphic genotype, as is commonly done when modeling an additive effect, both false positive and false negative results can occur, and the nature of the interaction can be misrepresented. We present a reparameterized regression equation that accurately captures interaction effects without the constraints imposed by modeling interactions using a single cross-product term. In addition, we provide a series of recommendations for making conclusions about the presence of meaningful G × E interactions, which take into account the nature of the observed interactions and whether they map onto sensible genotypic models.
doi:10.1007/s10519-014-9642-1
PMCID: PMC4004105  PMID: 24531874
Genes; Environment; Modeling; Regression; Cross-product
17.  Preference on Cash-Choice Task Predicts Externalizing Outcomes in 17-Year-Olds 
Behavior genetics  2014;44(2):102-112.
doi:10.1007/s10519-013-9638-2
PMCID: PMC4032562  PMID: 24442381
18.  Genetics of Wellbeing and Its Components Satisfaction with Life, Happiness, and Quality of Life: A Review and Meta-analysis of Heritability Studies 
Behavior Genetics  2015;45(2):137-156.
Wellbeing is a major topic of research across several disciplines, reflecting the increasing recognition of its strong value across major domains in life. Previous twin-family studies have revealed that individual differences in wellbeing are accounted for by both genetic as well as environmental factors. A systematic literature search identified 30 twin-family studies on wellbeing or a related measure such as satisfaction with life or happiness. Review of these studies showed considerable variation in heritability estimates (ranging from 0 to 64 %), which makes it difficult to draw firm conclusions regarding the genetic influences on wellbeing. For overall wellbeing twelve heritability estimates, from 10 independent studies, were meta-analyzed by computing a sample size weighted average heritability. Ten heritability estimates, derived from 9 independent samples, were used for the meta-analysis of satisfaction with life. The weighted average heritability of wellbeing, based on a sample size of 55,974 individuals, was 36 % (34–38), while the weighted average heritability for satisfaction with life was 32 % (29–35) (n = 47,750). With this result a more robust estimate of the relative influence of genetic effects on wellbeing is provided.
doi:10.1007/s10519-015-9713-y
PMCID: PMC4346667  PMID: 25715755
Wellbeing; Satisfaction with life; Happiness; Twin; Heritability; Review; Meta-analysis; Genetics; Genes
19.  Childhood ODD and ADHD Behavior: The Effect of Classroom Sharing, Gender, Teacher Gender and Their Interactions 
Behavior Genetics  2015;45(4):394-408.
One criterion for a diagnostic and statistical manual of mental disorders (DSM-IV) diagnosis of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) is that symptoms are present in at least two settings, and often teacher ratings are taken into account. The short Conners’ Teacher Rating Scales—Revised (CTRS-R) is a widely used standardized instrument measuring ODD and ADHD behavior in a school setting. In the current study CTRS-R data were available for 7, 9 and 12-year-old twins from the Netherlands Twin Register. Measurement invariance (MI) across student gender and teacher gender was established for three of the four scales (Oppositional Behavior, Hyperactivity and ADHD Index) of the CTRS-R. The fourth scale (ATT) showed an unacceptable model fit even without constraints on the data and revision of this scale is recommended. Gene-environment (GxE) interaction models revealed that heritability was larger for children sharing a classroom. There were some gender differences in the heritability of ODD and ADHD behavior and there was a moderating effect of teacher’s gender at some of the ages. Taken together, this indicates that there was evidence for GxE interaction for classroom sharing, gender of the student and gender of the teacher.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-015-9712-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s10519-015-9712-z
PMCID: PMC4458263  PMID: 25711757
ODD; ADHD; Conners’ Teacher Rating Scales; Measurement invariance; Heritability
20.  Longitudinal Development of Hormone Levels and Grey Matter Density in 9 and 12-Year-Old Twins 
Behavior Genetics  2015;45(3):313-323.
Puberty is characterized by major changes in hormone levels and structural changes in the brain. To what extent these changes are associated and to what extent genes or environmental influences drive such an association is not clear. We acquired circulating levels of luteinizing hormone, follicle stimulating hormone (FSH), estradiol and testosterone and magnetic resonance images of the brain from 190 twins at age 9 [9.2 (0.11) years; 99 females/91 males]. This protocol was repeated at age 12 [12.1 (0.26) years] in 125 of these children (59 females/66 males). Using voxel-based morphometry, we tested whether circulating hormone levels are associated with grey matter density in boys and girls in a longitudinal, genetically informative design. In girls, changes in FSH level between the age of 9 and 12 positively associated with changes in grey matter density in areas covering the left hippocampus, left (pre)frontal areas, right cerebellum, and left anterior cingulate and precuneus. This association was mainly driven by environmental factors unique to the individual (i.e. the non-shared environment). In 12-year-old girls, a higher level of circulating estradiol levels was associated with lower grey matter density in frontal and parietal areas. This association was driven by environmental factors shared among the members of a twin pair. These findings show a pattern of physical and brain development going hand in hand.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-015-9708-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10519-015-9708-8
PMCID: PMC4422848  PMID: 25656383
Longitudinal; Twins; Puberty; Grey matter; Hormones; FSH; Estradiol
21.  Genetic and Environmental Risk Factors for Illicit Substance Use and Use Disorders: Joint Analysis of Self and Co-twin Ratings 
Behavior genetics  2013;44(1):1-13.
The specificity of genetic and environmental risk factors for illicit substance use and substance use disorders (SUD) was investigated by utilizing self and co-twin reports in 1,791 male twins. There was a high rate of comorbidity between both use of, and SUD from, different classes of illicit substances. For substance use, the model that included one common genetic, one shared environmental, and one individual-specific (i.e., unique) environmental factor, along with substance-specific effects that were attributed entirely to genetic factors fit the data best. For illicit SUD, one common genetic and one common unique environmental risk factor, and substance specific shared environmental and unique environmental risk factors were identified. Risk factors for illicit substance use and SUD are mainly non-specific to substance class. Co-twin rating of illicit substance use and SUD was a reliable source of information, and by taking account of random and systematic measurement error, environmental exposures unique to the individual were of lesser importance than found in earlier studies.
doi:10.1007/s10519-013-9626-6
PMCID: PMC3893354  PMID: 24196977
Illicit drugs; Substance use; Substance abuse; Comorbidity; Rater bias; Co-twin report
22.  A Twin-Sibling Study on the Relationship Between Exercise Attitudes and Exercise Behavior 
Behavior genetics  2013;44(1):45-55.
Social cognitive models of health behavior propose that individual differences in leisure time exercise behavior are influenced by the attitudes towards exercise. At the same time, large scale twin-family studies show a significant influence of genetic factors on regular exercise behavior. This twin–sibling study aimed to unite these findings by demonstrating that exercise attitudes can be heritable themselves. Secondly, the genetic and environmental cross-trait correlations and the monozygotic (MZ) twin intrapair differences model were used to test whether the association between exercise attitudes and exercise behavior can be causal. Survey data were obtained from 5,095 twins and siblings (18–50 years). A genetic contribution was found for exercise behavior (50 % in males, 43 % in females) and for the six exercise attitude components derived from principal component analysis: perceived benefits (21, 27 %), lack of skills, support and/or resources (45, 48 %), time constraints (25, 30 %), lack of energy (34, 44 %), lack of enjoyment (47, 44 %), and embarrassment (42, 49 %). These components were predictive of leisure time exercise behavior (R2 = 28 %). Bivariate modeling further showed that all the genetic (0.36 <|rA| <0.80) and all but two unique environmental (0.00 <|rE| <0.27) correlations between exercise attitudes and exercise behavior were significantly different from zero, which is a necessary condition for the existence of a causal effect driving the association. The correlations between the MZ twins’ difference scores were in line with this finding. It is concluded that exercise attitudes and exercise behavior are heritable, that attitudes and behavior are partly correlated through pleiotropic genetic effects, but that the data are compatible with a causal association between exercise attitudes and behavior.
doi:10.1007/s10519-013-9617-7
PMCID: PMC3893360  PMID: 24072598
Twin-sibling design; Twins; Correlational approach; Physical activity; Heritability
23.  A sibling-comparison study of smoking during pregnancy and childhood psychological traits 
Behavior genetics  2013;44(1):25-35.
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.
doi:10.1007/s10519-013-9618-6
PMCID: PMC3947202  PMID: 24085497
24.  The Role of Constraint in the Development of Nicotine, Marijuana, and Alcohol Dependence in Young Adulthood 
Behavior genetics  2013;44(1):14-24.
The personality-related construct of behavioral disinhibition is hypothesized to confer a generalized risk for alcohol and drug dependence. On average, rates of substance use and scores on measures of disinhibition peak in adolescence and decline as people mature into adulthood. The present study investigated this developmental change by evaluating the relationship between disinhibition and substance use disorders using a longitudinal study of 2,608 twins assessed at ages 17, 24, and 29. These ages include the period of highest risk for substance use disorders (ages 17-24) as well as when substance dependence symptoms typically decline (ages 24-29). Disinhibition was measured with the Multidimensional Personality Questionnaire higher-order scale of Constraint, as well as its constituent facet scales of Harm Avoidance, Control, and Traditionalism. Constraint’s relationship with substance dependence was statistically significant but small and largely genetic, with the genetic relationship declining from adolescence into adulthood. However, this result appeared to be almost entirely driven by Traditionalism, a propensity to hold traditional moral and social values, and not an obvious component of behavioral disinhibition. The results suggest that personality measures of Control and Harm Avoidance play only a small role in the development of substance dependence during late adolescence, and previous findings linking personality measures of disinhibition and substance use may be driven significantly by social and moral values than deficits in impulse control.
doi:10.1007/s10519-013-9629-3
PMCID: PMC3951055  PMID: 24343204
25.  SIMPLE SEQUENCE REPEATS IN THE NATIONAL LONGITUDINAL STUDY OF ADOLESCENT HEALTH: AN ETHNICALLY DIVERSE RESOURCE FOR GENETIC ANALYSIS OF HEALTH AND BEHAVIOR 
Behavior genetics  2014;44(5):487-497.
Simple sequence repeats (SSRs) are one of the earliest available forms of genetic variation available for analysis and have been utilized in studies of neurological, behavioral, and health phenotypes. Although findings from these studies have been suggestive, their interpretation has been complicated by a variety of factors including, among others, limited power due to small sample sizes. The current report details the availability, diversity, and allele and genotype frequencies of six commonly examined SSRs in the ethnically diverse, population-based National Longitudinal Study of Adolescent Health (Add Health). A total of 106,743 genotypes were generated across 15,140 participants that included four microsatellites and two di-nucleotide repeats in three dopamine genes (DAT1, DRD4, DRD5), the serotonin transporter (5HTT), and monoamine oxidase A (MAOA). Allele and genotype frequencies showed a complex pattern and differed significantly between populations. For both di-nucleotide repeats we observed a greater allelic diversity than previously reported. The availability of these six SSRs in a large, ethnically diverse sample with extensive environmental measures assessed longitudinally offers a unique resource for researchers interested in health and behavior.
doi:10.1007/s10519-014-9662-x
PMCID: PMC4244076  PMID: 24890516
DRD4; DAT1; 5HTTLPR; MAOA; DRD5; Add Health

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