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AbstractDifferences between early (within 30 days) and late (after 30 days) respondents in a survey study were analyzed in twins and siblings registered with the Netherlands Twin Register. We compared early and late respondents on personality traits, health, lifestyle, and demographic variables. The odds of being a late respondent were significantly higher for men (OR 1.14), alcohol use on a daily/weekly basis (OR 1.20), having a relationship (OR 1.40), higher score on experience seeking scale (OR 1.02), and criticizing the questionnaire as too long (OR 1.27). The odds of being a late respondent were significantly lower for nontwin subjects (OR 0.71), regular cycling (OR 0.83), and judging the questionnaire to be fun (OR 0.80). There were no significant interactions with sex. To examine to what extent early and late response is influenced by genetic factors, twin and sibling data of 5040 subjects were analyzed. The best model includes genetic factors (31%), shared environmental influences (36%), and unique environmental influences (43%) on variation in response time.

AbstractTwin studies that examine the effect of specific environmental risk factors on psychiatric disorders assume that there are no differences in prevalences of these risk factors between twins and singletons. Violation of this assumption signifies that the results from twin studies might not generalize to singletons. Another assumption, not only often underlying twin studies but also epidemiological research, is that life- events are not influenced by familial factors. We tested differences in prevalences of experienced life events in a Dutch sample of 2086 monozygotic (MZ) twins, 2090 dizygotic (DZ) twins and 1307 of their siblings. Self-reported data on life events (illness of self, illness of a significant other, spouse/romantic relationship, divorce/break-up of a relationship, death of a significant other, traffic accident, robbery, violent assault, sexual assault) were available from a survey- study. We further investigated whether familial resemblance was present for the exposure to these life events and, if so, whether this resemblance was due to genetic or common environmental factors. No differences were found in the prevalences of life events between MZ twins, DZ twins and their siblings. There was evidence for familial aggregation of all life events, except for traffic accidents in women. Results indicated genetic control on the presence of a spouse or involvement in a relationship. Familial resemblance of illness and death of a significant other was mainly due to common environment. For the other life events, it was not possible to distinguish between genetic and common environmental effects.

AbstractOur current society is characterized by an increased availability of industrially processed foods with high salt, fat and sugar content. How is it that some people prefer these unhealthy foods while others prefer more healthy foods? It is suggested that both genetic and environmental factors play a role. The aim of this study was to (1) identify food preference clusters in the largest twin-family study into food preference to date and (2) determine the relative contribution of genetic and environmental factors to individual differences in food preference in the Netherlands. Principal component analysis was performed to identify the preference clusters by using data on food liking/disliking from 16,541 adult multiples and their family members. To estimate the heritability of food preference, the data of 7833 twins were used in structural equation models. We identified seven food preference clusters (Meat, Fish, Fruits, Vegetables, Savory snacks, Sweet snacks and Spices) and one cluster with Drinks. Broad-sense heritability (additive [A] + dominant [D] genetic factors) for these clusters varied between .36 and .60. Dominant genetic effects were found for the clusters Fruit, Fish (males only) and Spices. Quantitative sex differences were found for Meat, Fish and Savory snacks and Drinks. To conclude, our study convincingly showed that genetic factors play a significant role in food preference. A next important step is to identify these genes because genetic vulnerability for food preference is expected to be linked to actual food consumption and different diet-related disorders.

This study aimed to explore if natural dizygotic (DZ) twinning is associated with earlier menopause and lower anti-Mullerian hormone (AMH) values. We investigated if advanced biological reproductive aging, which can be responsible for the multiple follicle growth in familial twinning, is similar to mechanisms that occur in normal ovarian aging, reflected by earlier menopause in mothers of DZ twins and lower levels of AMH. A total of 16 mothers of DZ twins enrolled with the Netherlands Twin Register (average age at first assessment: 35.9 ± 3.0 years) and 14 control mothers (35.1 ± 3 years) took part in a prospective study. Fifteen years after entry into the study, which included follicle-stimulating hormone (FSH) assessment, AMH was measured in stored serum samples and menopause status was evaluated. Average AMH levels were not significantly different between DZ twin mothers and controls (2.1 ± 2.4 μg/L vs. 1.9 ± 1.9 μg/L). Among the 16 mothers of twins, 7 had an elevated (FSH) value over 10 U/L at first assessment. Their AMH levels were lower than the nine twin mothers with normal FSH values: 0.6 ± 0.4 versus 3.4 ± 2.6 μg/L (p = .01). Of the mothers of twins, eight mothers had entered menopause at the second assessment compared with only one control mother (p = .07). Thus, slightly more DZ mothers were in menopause than the control mothers, although this difference was not significant. The subgroup of DZ twin mothers who had an increased FSH concentration 15 years ago had a limited ovarian reserve as reflected by lower AMH levels. These data indicate that advanced ovarian aging can be a feature in familial DZ twinning, particularly with elevated early follicular phase FSH.

BACKGROUND: Tobacco, alcohol, and cannabis use are prevalent behaviors that pose considerable health risks. Genetic vulnerability and characteristics of the neighborhood of residence form important risk factors for substance use. Possibly, these factors do not act in isolation. This study tested the interaction between neighborhood characteristics and genetic risk (gene-environment interaction, GxE) and the association between these classes of risk factors (gene-environment correlation, rGE) in substance use. METHODS: Two polygenic scores (PGS) each (based on different discovery datasets) were created for smoking initiation, cigarettes per day, and glasses of alcohol per week based on summary statistics of different genome-wide association studies (GWAS). For cannabis initiation one PGS was created. These PGS were used to predict their respective phenotype in a large population-based sample from the Netherlands Twin Register (N = 6,567). Neighborhood characteristics as retrieved from governmental registration systems were factor analyzed and resulting measures of socioeconomic status (SES) and metropolitanism were used as predictors. RESULTS: There were (small) main effects of neighborhood characteristics and PGS on substance use. One of the 14 tested GxE effects was significant, such that the PGS was more strongly associated with alcohol use in individuals with high SES. This was effect was only significant for one out of two PGS. There were weak indications of rGE, mainly with age and cohort covariates. CONCLUSION: We conclude that both genetic and neighborhood-level factors are predictors for substance use. More research is needed to establish the robustness of the findings on the interplay between these factors.

Sequence-based association studies are at a critical inflexion point with the increasing availability of exome-sequencing data. A popular test of association is the sequence kernel association test (SKAT). Weights are embedded within SKAT to reflect the hypothesized contribution of the variants to the trait variance. Because the true weights are generally unknown, and so are subject to misspecification, we examined the efficiency of a data-driven weighting scheme. We propose the use of a set of theoretically defensible weighting schemes, of which, we assume, the one that gives the largest test statistic is likely to capture best the allele frequency–functional effect relationship. We show that the use of alternative weights obviates the need to impose arbitrary frequency thresholds. As both the score test and the likelihood ratio test (LRT) may be used in this context, and may differ in power, we characterize the behavior of both tests. The two tests have equal power, if the weights in the set included weights resembling the correct ones. However, if the weights are badly specified, the LRT shows superior power (due to its robustness to misspecification). With this data-driven weighting procedure the LRT detected significant signal in genes located in regions already confirmed as associated with schizophrenia — thePRRC2A(p= 1.020e-06) and theVARS2(p= 2.383e-06) — in the Swedish schizophrenia case-control cohort of 11,040 individuals with exome-sequencing data. The score test is currently preferred for its computational efficiency and power. Indeed, assuming correct specification, in some circumstances, the score test is the most powerful test. However, LRT has the advantageous properties of being generally more robust and more powerful under weight misspecification. This is an important result given that, arguably, misspecified models are likely to be the rule rather than the exception in weighting-based approaches.

Birth weight in triplets is, on average, lower than in singletons and twins, and more children are classified as having very low or extremely low birth weight. Still, there is limited research on factors that affect triplet birth weight, and samples under study are often small. Chorionicity and zygosity influence triplet birth weight, but it is unknown whether the effect of zygosity can be entirely ascribed to the effect of chorionicity or whether zygosity has an additional effect on triplet birth weight. This question was investigated in 346 triplets (from 116 trios) registered with the Netherlands Twin Register for whom data on chorionicity were available. 'Triplet' refers to one child and the set of three triplets is referred to as 'trio'. Trios and triplets were classified based on zygosity and chorionicity. With regression analysis, the effects of zygosity and chorionicity on triplet birth weight were examined, while controlling for gestational age, sex, and maternal smoking during pregnancy. In addition, within the dizygotic trios a within-family comparison was made between the birth weight of the triplets that were part of a monozygotic pair (with some pairs sharing a chorion), and the birth weight of the dizygotic triplet. Based on the classification on individual level, monozygotic, monochorionic triplets had a lower mean birth weight than dizygotic, dichorionic triplets. Most remarkably, in dizygotic trios, monozygotic pairs only had a lower mean birth weight than their dizygotic sibling triplet when the pair shared a chorion. We conclude that having shared a chorion, rather than being monozygotic, increases the risk of a low birth weight.

AbstractIn this article we describe the design and implementation of a database for extended twin families. The database does not focus on probands or on index twins, as this approach becomes problematic when larger multigenerational families are included, when more than one set of multiples is present within a family, or when families turn out to be part of a larger pedigree. Instead, we present an alternative approach that uses a highly flexible notion of persons and relations. The relations among the subjects in the database have a one-to-many structure, are user-definable and extendible and support arbitrarily complicated pedigrees. Some additional characteristics of the database are highlighted, such as the storage of historical data, predefined expressions for advanced queries, output facilities for individuals and relations among individuals and an easy-to-use multi-step wizard for contacting participants. This solution presents a flexible approach to accommodate pedigrees of arbitrary size, multiple biological and nonbiological relationships among participants and dynamic changes in these relations that occur over time, which can be implemented for any type of multigenerational family study.

AbstractIn the late 1980s The Netherlands Twin Register (NTR) was established by recruiting young twins and multiples at birth and by approaching adolescent and young adult twins through city councils. The Adult NTR (ANTR) includes twins, their parents, siblings, spouses and their adult offspring. The number of participants in the ANTR who take part in survey and / or laboratory studies is over 22,000 subjects. A special group of participants consists of sisters who are mothers of twins. In the Young NTR (YNTR), data on more than 50,000 young twins have been collected. Currently we are extending the YNTR by including siblings of twins. Participants in YNTR and ANTR have been phenotyped every 2 to 3 years in longitudinal survey studies, since 1986 and 1991 for the YNTR and ANTR, respectively. The resulting large population-based datasets are used for genetic epidemiological studies and also, for example, to advance phenotyping through the development of new syndrome scales based on existing items from other inventories. New research developments further include brain imaging studies in selected and unselected groups, clinical assessment of psychopathology through interviews, and cross-referencing the NTR database to other national databases. A large biobank enterprise is ongoing in the ANTR in which blood and urine samples are collected for genotyping, expression analysis, and meta-bolomics studies. In this paper we give an update on the YNTR and ANTR phenotyping and on the ongoing ANTR biobank studies.

Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10, 000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10-8) for ND (rs964170 in ARHGAPlOon chromosome 4, p = 4.43 x 10"8) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10-9), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10-9) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10-8)). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepre-sentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be requirec before the detailed causes of comorbidity between AC and ND are understood.

Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.