Genetic Influences on the Covariance and Genetic Correlations in a Bivariate Twin Model: An Application to Well-Being.

The distinction between genetic influences on the covariance (or bivariate heritability) and genetic correlations in bivariate twin models is often not well-understood or only one is reported while the results show distinctive information about the relation between traits. We applied bivariate twin models in a large sample of adolescent twins, to disentangle the association between well-being (WB) and four complex traits (optimism, anxious-depressed symptoms (AD), aggressive behaviour (AGG), and educational achievement (EA)). Optimism and AD showed respectively a strong positive and negative phenotypic correlation with WB, the negative correlation of WB and AGG is lower and the correlation with EA is nearly zero. All four traits showed a large genetic contribution to the covariance with well-being. The genetic correlations of well-being with optimism and AD are strong and smaller for AGG and EA. We used the results of the models to explain what information is retrieved based on the bivariate heritability versus the genetic correlations and the (clinical) implications.

Genetically Informed Regression Analysis: Application to Aggression Prediction by Inattention and Hyperactivity in Children and Adults.

We present a procedure to simultaneously fit a genetic covariance structure model and a regression model to multivariate data from mono- and dizygotic twin pairs to test for the prediction of a dependent trait by multiple correlated predictors. We applied the model to aggressive behavior as an outcome trait and investigated the prediction of aggression from inattention (InA) and hyperactivity (HA) in two age groups. Predictions were examined in twins with an average age of 10 years (11,345 pairs), and in adult twins with an average age of 30 years (7433 pairs). All phenotypes were assessed by the same, but age-appropriate, instruments in children and adults. Because of the different genetic architecture of aggression, InA and HA, a model was fitted to these data that specified additive and non-additive genetic factors (A and D) plus common and unique environmental (C and E) influences. Given appropriate identifying constraints, this ADCE model is identified in trivariate data. We obtained different results for the prediction of aggression in children, where HA was the more important predictor, and in adults, where InA was the more important predictor. In children, about 36% of the total aggression variance was explained by the genetic and environmental components of HA and InA. Most of this was explained by the genetic components of HA and InA, i.e., 29.7%, with 22.6% due to the genetic component of HA. In adults, about 21% of the aggression variance was explained. Most was this was again explained by the genetic components of InA and HA (16.2%), with 8.6% due to the genetic component of InA.

Early-life antibiotic use and risk of asthma and eczema: results of a discordant twin study.

RATIONALE: Early-life antibiotic use has been associated with the development of atopic diseases, but the aetiology remains unclear. To elucidate the aetiology, we used a discordant twin design to control for genetic and environmental confounding. METHODS: We conducted a retrospective cohort study in twins aged 3-10 years from the Netherlands Twin Register (NTR, n=35 365) and a replication study in twins aged 9 years from the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7916). Antibiotic use was recorded at age 0-2 years. Doctor-diagnosed asthma and eczema were reported by parents when children were aged 3-12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs. RESULTS: Early-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34, 95% CI 1.28-1.41; CATSS OR 1.45, 95% CI 1.34-1.56) and eczema (NTR OR 1.08, 95% CI 1.03-1.13; CATSS OR 1.07, 95% CI 1.01-1.14) in unmatched analyses. Co-twin analyses in monozygotic and dizygotic twin pairs showed similar results for asthma (NTR OR 1.54, 95% CI 1.20-1.98; CATSS OR 2.00, 95% CI 1.28-3.13), but opposing results for eczema in the NTR (OR 0.99, 95% CI 0.80-1.25) and the CATSS (OR 1.67, 95% CI 1.12-2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS OR 1.45, 95% CI 1.34-1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS OR 1.02, 95% CI 0.88-1.17). CONCLUSION: Children exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors.

Aggressive behaviour in childhood and adolescence: the role of smoking during pregnancy, evidence from four twin cohorts in the EU-ACTION consortium.

BACKGROUND: Maternal smoking during pregnancy (MSDP) has been linked to offspring's externalizing problems. It has been argued that socio-demographic factors (e.g. maternal age and education), co-occurring environmental risk factors, or pleiotropic genetic effects may account for the association between MSDP and later outcomes. This study provides a comprehensive investigation of the association between MSDP and a single harmonized component of externalizing: aggressive behaviour, measured throughout childhood and adolescence. METHODS: Data came from four prospective twin cohorts - Twins Early Development Study, Netherlands Twin Register, Childhood and Adolescent Twin Study of Sweden, and FinnTwin12 study - who collaborate in the EU-ACTION consortium. Data from 30 708 unrelated individuals were analysed. Based on item level data, a harmonized measure of aggression was created at ages 9-10; 12; 14-15 and 16-18. RESULTS: MSDP predicted aggression in childhood and adolescence. A meta-analysis across the four samples found the independent effect of MSDP to be 0.4% (r = 0.066), this remained consistent when analyses were performed separately by sex. All other perinatal factors combined explained 1.1% of the variance in aggression across all ages and samples (r = 0.112). Paternal smoking and aggressive parenting strategies did not account for the MSDP-aggression association, consistent with the hypothesis of a small direct link between MSDP and aggression. CONCLUSIONS: Perinatal factors, including MSDP, account for a small portion of the variance in aggression in childhood and adolescence. Later experiences may play a greater role in shaping adolescents' aggressive behaviour.

An Extended Twin-Pedigree Study of Neuroticism in the Netherlands Twin Register.

For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of 253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568-1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.

Heritability of compulsive Internet use in adolescents.

Over the past decades, Internet use has grown substantially, and it now serves people as a supportive tool that is used regularly and-in large parts of the world-inevitably. Some people develop problematic Internet use, which may lead to addictive behavior and it is becoming important to explore the risk factors for compulsive Internet use. Data were analyzed on compulsive Internet use [with the Compulsive Internet Use Scale (CIUS)] from 5247 monozygotic (MZ) and dizygotic (DZ) adolescent twins registered with the Netherlands Twin Register. The participants form a sample that is informative for genetic analyses, allowing the investigation of the causes of individual differences in compulsive Internet use. The internal consistency of the instrument was high and the 1.6-year test-retest correlation in a subsample (n = 902) was 0.55. CIUS scores increased slightly with age. Remarkably, gender did not explain variation in CIUS scores, as mean scores on the CIUS were the same in boys and girls. However, the time spent on specific Internet activities differed: boys spent more time on gaming, whereas girls spent more time on social network sites and chatting. The heritability estimates were the same for boys and girls: 48 percent of the individual differences in CIUS score were influenced by genetic factors. The remaining variance (52 percent) was due to environmental influences that were not shared between family members. Because a life without Internet is almost impossible nowadays, it is important to further explore the determinants of compulsive Internet use, including genetic risk factors.

Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

The Influence of Chorion Type on Health Measures at Birth and Dental Development in Australian and Dutch Twins: A Comparative Study.

Chorion type may significantly influence the prenatal environment of twins. This study explored the associations between chorion type and gestational age, birth weight, birth length, and the timing of emergence of the first primary tooth in two populations of twins, Australian and Dutch. Additionally, we investigated the relationship between chorion type and birth weight discordance (BWD) in order to determine whether a significant relationship existed between discordance in birth weight and discordance in the timing of emergence of the first primary tooth. The two study samples consisted of 409 Australian twin pairs and 301 Dutch twin pairs, all of European ancestry. Data were collected through a combination of questionnaires and recording charts administered to the parents and through linkage with biological databases. In the Australian sample, monozygotic monochorionic (MZMC) twins experienced the shortest mean gestation time (35 weeks), the lowest mean birth length (46 cm) and the lowest mean birth weight (2.3 kg) compared with other twin groups. For the same variables in the Dutch sample, these trends with MZMC twinning were not observed. Chorion type did not significantly affect the mean timing of emergence of the first primary tooth in either sample. Monochorionicity was found to be significantly associated with BWD in both samples, but there was a significant association between BWD in MZMC twin pairs and timing of emergence of the first primary tooth only in the Australian sample. Results from this study support previous findings that the timing of emergence of the first primary tooth is influenced strongly by genetic factors and is well protected from environmental disturbances.

GE covariance through phenotype to environment transmission: an assessment in longitudinal twin data and application to childhood anxiety.

We considered identification of phenotype (at occasion t) to environment (at occasion t + 1) transmission in longitudinal model comprising genetic, common and unique environmental simplex models (autoregressions). This type of transmission, which gives rise to genotype-environment covariance, is considered to be important in developmental psychology. Having established identifying constraints, we addressed the issue of statistical power to detect such transmission given a limited set of parameter values. The power is very poor in the ACE simplex, but is good in the AE model. We investigated misspecification, and found that fitting the standard ACE simplex to covariance matrices generated by an AE simplex with phenotype to E transmission produces the particular result of a rank 1 C (common environment) covariance matrix with positive transmission, and a rank 1 D (dominance) matrix given negative transmission. We applied the models to mother ratings of anxiety in female twins (aged 3, 7, 10, and 12 years), and obtained support for the positive effect of one twin's phenotype on the other twin's environment.

Exploring the association between well-being and psychopathology in adolescents.

Promotion of mental well-being and prevention of emotional and behavioral problems are suggested to go hand in hand. The present study examined the association between subjective well-being (SWB) and psychopathology and investigated the etiology of this association in a large population-based cohort study of adolescent twins (n = 9,136) and their non-twin siblings (n = 1,474) aged 12-20 years. Phenotypic, genetic, and environmental correlations between SWB and psychopathology were obtained from multivariate genetic modeling conditional on sex. An SWB factor score was used based on measures of subjective happiness, satisfaction with life, and quality of life. Psychopathology was obtained from all syndrome and broad-band scales of the Dutch version of the ASEBA Youth Self Report. Males reported significantly higher levels of SWB than females. Females reported significantly more internalizing problems while males report significantly higher levels of externalizing behavior. In both sexes, significant negative associations were found between SWB and psychopathology, with the strongest associations seen for SWB and the YSR syndrome scale anxious/depression behavior. The observed associations were primarily explained by genetic correlations while non-shared environmental influences were mainly domain specific. The genetic liability to lower levels of SWB are indicative of a genetic liability to higher levels of psychopathology, suggesting that it might be feasible to screen for emotional and behavioral problems before clear signs are present by screening on indices of subjective well-being.

Direct and Indirect Genetic Effects on Aggression.

Background: Family members resemble each other in their propensity for aggression. In twin studies, approximately 50% of the variance in aggression can be explained by genetic influences. However, if there are genotype-environment correlation mechanisms, such as environmental manifestations of parental and sibling genotypes, genetic influences may partly reflect environmental influences. In this study, we investigated the importance of indirect polygenic score (PGS) effects on aggression. Methods: We modeled the effect of PGSs based on 3 genome-wide association studies: early-life aggression, educational attainment, and attention-deficit/hyperactivity disorder (ADHD). The associations with aggression were tested in a within- and between-family design (37,796 measures from 7740 individuals, ages 3-86 years [mean = 14.20 years, SE = 12.03], from 3107 families, 55% female) and in a transmitted/nontransmitted PGS design (42,649 measures from 6653 individuals, ages 3-61 years [mean = 11.81 years, SE = 8.68], from 3024 families, 55% female). All participants are enrolled in the Netherlands Twin Register. Results: We found no evidence for contributions of indirect PGS effects on aggression in either a within- and between-family design or a transmitted/nontransmitted PGS design. Results indicate significant direct effects on aggression for the PGSs based on early-life aggression, educational attainment, and ADHD, although explained variance was low (within- and between-family: early-life aggression R2 = 0.3%, early-life ADHD R2 = 0.6%, educational attainment R2 = 0.7%; transmitted/nontransmitted PGSs: early-life aggression R2 = 0.2%, early-life ADHD R2 = 0.9%, educational attainment R2 = 0.5%). Conclusions: PGSs included in the current study had a direct (but no indirect) effect on aggression, consistent with results of previous twin and family studies. Further research involving other PGSs for aggression and related phenotypes is needed to determine whether this conclusion generalizes to overall genetic influences on aggression.

Brain SCALE: brain structure and cognition: an adolescent longitudinal twin study into the genetic etiology of individual differences.

From childhood into adolescence, the child's brain undergoes considerable changes in both structure and function. Twin studies are of great value to explore to what extent genetic and environmental factors explain individual differences in brain development and cognition. In The Netherlands, we initiated a longitudinal study in which twins, their siblings and their parents are assessed at three year intervals. The participants were recruited from The Netherlands Twin Register (NTR) and at baseline consisted of 112 families, with 9-year-old twins and an older sibling. Three years later, 89 families returned for follow-up assessment. Data collection included psychometric IQ tests, a comprehensive neuropsychological testing protocol, and parental and self-ratings of behavioral and emotional problems. Physical maturation was measured through assessment of Tanner stages. Hormonal levels (cortisol, luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogens) were assessed in urine and saliva. Brain scans were acquired using 1.5 Tesla Magnetic Resonance Imaging (MRI), which provided volumetric measures and measures of cortical thickness. Buccal swabs were collected for DNA isolation for future candidate gene and genome-wide analysis studies. This article gives an overview of the study and the main findings. Participants will return for a third assessment when the twins are around 16 years old. Longitudinal twin-sibling studies that map brain development and cognitive function at well-defined ages aid in the understanding of genetic influences on normative brain development.

Effects of gestational age and birth weight on brain volumes in healthy 9 year-old children.

OBJECTIVE: To assess the effects of gestational age and birth weight on brain volumes in a population-based sample of normal developing children at the age of 9 years. STUDY DESIGN: A total of 192 children from twin births were included in the analyses. Data on gestational age and birth weight were reported shortly after birth. Total brain, cerebellum, cerebrum, gray and white matter, and lateral ventricle volumes were assessed with structural magnetic resonance imaging. The Wechsler Intelligence Scale for Children-III was administered to assess general cognitive abilities. Structural equation modeling was used to analyze the effects of gestational age and birth weight on brain volumes. RESULTS: Shorter gestational age was associated with a relatively smaller cerebellar volume (P = .002). This effect was independent of IQ scores. Lower birth weight was associated with lower IQ score (P = .03). Birth weight was not associated with brain volumes. CONCLUSION: The effect of gestational age on cerebellar volume is not limited to children with very premature birth or very low birth weight, but is also present in children born >32 weeks of gestation and with birth weight >1500 g.

Heritability and genome-wide linkage scan of subjective happiness.

Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted.

Genetic and environmental influences on the stability of withdrawn behavior in children: a longitudinal, multi-informant twin study.

We examined the contribution of genetic and environmental influences on the stability of withdrawn behavior (WB) in childhood using a longitudinal multiple rater twin design. Maternal and paternal ratings on the withdrawn subscale of the Child Behavior Checklist (CBCL) were obtained from 14,889 families when the twins were 3, 7, 10 and 12 years old. A longitudinal psychometric model was fitted to the data and the fit of transmission and common factor models were evaluated for each variance component. WB showed considerable stability throughout childhood, with correlation coefficients ranging from about .30 for the 9-year time interval to .65 for shorter time intervals. Individual differences in WB as observed by the mother and the father were found to be largely influenced by genetic effects at all four time points, in both boys (50-66%) and girls (38-64%). Shared environmental influences explained a small to modest proportion (0-24%) of the variance at all ages and were slightly more pronounced in girls. Non-shared environmental influences were of moderate importance to the variance and slightly increased with age, from 22-28% at age 3 to 35-41% at age 12 years. The stability of WB was largely explained by genetic effects, accounting for 74% of stability in boys and 65% in girls. Shared environmental effects explained 7% (boys) and 17% (girls) of the behavioral stability. Most shared environmental effects were common to both raters, suggesting little influence of rater bias in the assessment of WB. The shared environmental effects common to both raters were best described by a common factor model, indicating that these effects are stable and persistent throughout childhood. Non-shared environmental effects accounted for the remaining covariance over time.

Familial twinning and fertility in Dutch mothers of twins.

We studied twinning and fertility indices in mothers with spontaneous monozygotic (MZ) and dizygotic (DZ) twins and in mothers who conceived their twins after the use of assisted reproduction techniques (ART). Participants in this study consisted of 8,222 and 5,505 women with spontaneous DZ and MZ offspring and 4,164 and 250 women with ART DZ and MZ twin pairs, respectively. Women were compared with respect to the number of sibs and offspring, the presence of other relatives with twins and the time it took to conceive the twins. We also compared familial twinning between a younger and an older age group. Women with spontaneous DZ twins more often reported female relatives with twins than those with spontaneous MZ twins. The proportion of DZ versus MZ twin offspring in relatives was also larger in women with spontaneous DZ offspring than in women with MZ offspring. The first group of women reported a shorter time to conceive. Women with ART twins had fewer sibs and offspring and less often reported relatives with twins. We did not observe that DZ twinning was more familial in women who had their twins before age 36 years compared to older women. Familial DZ twinning is clearly present in mothers of spontaneous DZ twins. The mechanisms underlying spontaneous and non-spontaneous DZ twinning are different and fertility treatment should be taken into account in any study of twinning. Twinning is not more familial in women who have their twins at a younger age.

An exploration of gene-environment interaction and asthma in a large sample of 5-year-old Dutch twins.

A consistent finding from twin studies is that the environment shared by family members does not contribute to the variation in susceptibility to asthma. At the same time, it is known that environmental risk factors that are shared by family members are associated with the liability for asthma. We hypothesize that the absence of a main effect of shared environmental factors in twin studies can be explained by gene-environment interaction, that is, that the effect of an environmental factor shared by family members depends on the genotype of the individual. We explore this hypothesis by modeling the resemblance in asthma liability in twin pairs as a function of various environmental risk factors and test for gene-environment interaction. Asthma data were obtained by parental report for nearly 12,000 5-year-old twin pairs. A series of environmental risk factors was examined: birth cohort, gestational age, time spent in incubator, breastfeeding, maternal educational level, maternal smoking during pregnancy, current smoking of parents, having older siblings, and amount of child care outside home. Results revealed that being a boy, born in the 1990s, premature birth, longer incubator time, and child care outside home increased the risk for asthma. With the exception of premature birth, however, none of these factors modified the genetic effects on asthma. In very premature children shared environmental influences were important. In children born after a gestation of 32 weeks or more only genetic factors were important to explain familial resemblance for asthma.

Asthma and mode of birth delivery: a study in 5-year-old Dutch twins.

Several studies report caesarean section (CS) to be a risk factor for childhood asthma. We used data from a large cohort of 5-year-old twins to examine the relationship between mode of birth delivery and asthma. The extent to which an infant is exposed to maternal vaginal flora may protect against the risk of developing asthma. Therefore, we expect a lower rate of asthma in twins born by vaginal delivery (VD) than those born by CS, and a lower rate of asthma in first-born twins compared to second-born twins by VD. Information on mode of delivery was obtained at the time of birth in a survey completed by the mother shortly after delivery. Information on history of asthma diagnosis by a physician was obtained by parental report when the twins were 5 years old. Complete data were available for 6330 first-born and 5438 second-born twins from birth cohorts 1991-2000. Full term first-born twins born by CS had a significantly higher risk of asthma compared to those born by VD, odds ratio=1.59 (95% CI=1.23-2.06). No significant differences were observed between CS and VD first-born twins when gestational age was less than 37 weeks, and no significant differences were observed between CS and VD second-born twins at any gestational age. No differences in asthma prevalence were found between first- and second-born twins both born by VD. CS may increase the risk of asthma to full term infants, however, the underlying mechanism is unclear.

Heritability of self-reported asthma and allergy: a study in adult Dutch twins, siblings and parents.

The present study assessed the prevalence of asthma and allergy, and estimated the importance of genetic and environmental influences on asthma and allergy liability and their association. Longitudinal data on self-reported, doctor-diagnosed asthma and allergy were collected in over 14,000 individuals registered with the Netherlands Twin Register. Structural equation modeling was used for univariate and bivariate genetic analyses on data from twins, their siblings, and parents. Results showed no sex, age, and minimal birth cohort effects for asthma prevalence (11.8%). For allergy, prevalence was higher in women (19.8%) than in men (13.9%). Allergy prevalence at ages 22, 23, and 24 years increased from the 1970 to the 1980 birth cohort. The prevalence of allergy, but not of asthma, was higher in nontwin siblings than in twins. No assortative mating was observed. High (broad-sense) heritabilities were found for asthma (75%) and allergy (66%), with evidence for nonadditive genetic effects in asthma. The association between asthma and allergy (correlation=.65) was largely due to common genes (70%). No sex differences in genetic architecture were found. In conclusion, the prevalence of allergy but not of asthma increased in recent years. Individual differences in the liability to asthma, allergy and their co-occurrence are for a large part accounted for by differences in genetic background. Nonadditive gene action is important, which may have consequences for gene hunting strategies.

Dopaminergic Genetic Variants and Voluntary Externally Paced Exercise Behavior.

PURPOSE: Most candidate gene studies on the neurobiology of voluntary exercise behavior have focused on the dopaminergic signaling pathway and its role in the mesolimbic reward system. We hypothesized that dopaminergic candidate genes may influence exercise behavior through additional effects on executive functioning and that these effects are only detected when the types of exercise activity are taken into account. METHODS: Data on voluntary exercise behavior and at least one single-nucleotide polymorphism/variable number of tandem repeat (VNTR) were available for 12,929 participants of the Netherlands Twin Registry. Exercise activity was classified as externally paced if a high level of executive function skill was required. The total volume of voluntary exercise (minutes per week) as well as the volume specifically spent on externally paced activities were tested for association with nine functional dopaminergic polymorphisms (DRD1: rs265981, DRD2/ANKK1: rs1800497, DRD3: rs6280, DRD4: VNTR 48 bp, DRD5: VNTR 130-166 bp, DBH: rs2519152, DAT1: VNTR 40 bp, COMT: rs4680, MAOA: VNTR 30 bp), a polygenic score (PGS) based on nine alleles leading to lower dopamine responsiveness, and a PGS based on three alleles associated with both higher reward sensitivity and better executive functioning (DRD2/ANKK1: "G" allele, COMT: Met allele, DAT1: 440-bp allele). RESULTS: No association with total exercise volume or externally paced exercise volume was found for individual alleles or the nine-allele PGS. The volume of externally paced exercise behavior was significantly associated with the reward and executive function congruent PGS. This association was driven by the DAT1 440-bp and COMT Met allele, which acted as increaser alleles for externally paced exercise behavior. CONCLUSIONS: Taking into account the types of exercise activity may increase the success of identifying genetic variants and unraveling the neurobiology of voluntary exercise behavior.