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Background: The association between life events and anxious depression might be due to causality or to gene-environment correlation. We examined unidirectional and reciprocal causality and a gene-environment correlation model, in which genes that influence the vulnerability for anxious depression also increase the risk of exposure to life events. The effect of genes that influence environmental exposure might be mediated through personality and we therefore also examined the association between life events and personality (neuroticism and extraversion). Method: Information on life events, anxious depression, neuroticism and extraversion was collected in 5782 monozygotic (MZ) and dizygotic (DZ) twins who participated in a longitudinal survey study of the Netherlands Twin Register. To examine causality, data were analysed longitudinally. To examine gene-environment correlation, the co-twin control method was used. Results: Anxious depression and, to a lesser extent, neuroticism scores increased after exposure to life events. Anxious depression and neuroticism also predicted the experience of life events. Prospectively, extraversion was not associated with life events. Anxious depression, neuroticism and extraversion scores did not differ between the non-exposed subjects of MZ and DZ twin pairs and unrelated subjects discordant for life events. Conclusions: Our findings suggest that reciprocal causation explains the relationship between life events and anxious depression and between life events and neuroticism. Extraversion is not related to life events. No evidence was found for gene-environment correlation, i.e. the genes that influence anxious depression, neuroticism or extraversion do not overlap with the genes that increase the risk of exposure to life events. Copyright © 2008 Cambridge University Press.

Previous genetic investigations of variation in normal sleep have focused on measures that describe sleep over longer periods of time. We undertook a study with the aim of evaluating whether heritability can be found in single-night sleep traits. A classical twin study design of monozygotic and dizygotic twins, enriched with siblings of twins was employed. The study included adult twin pairs and their siblings (N = 813 subjects from 342 families). A subsample of 66 individuals participated twice. For a single night, bedtime, awakening time and subjective sleep quality were assessed using a diary. The diary also assessed smoking, alcohol and coffee consumption, and the subjective evaluation of stress. Resemblance between family members was used to estimate the heritability of bedtime, awakening time, sleep problems and sleep quality as a function of sex. Most sleep measures showed familial clustering, but results differed for men and women. Heritability for bedtime and sleep problems was seen in women; and for awakening time in men. We conclude that heritability can be demonstrated for bedtime and subjective evaluation of even a single night of sleep. The contribution of the genetic make-up is sex specific. In women variance in awakening time is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible. In contrast, for males, variance in the evening bedtime is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible.

Background: The association between life events and anxious depression might be due to causality or to gene-environment correlation. We examined unidirectional and reciprocal causality and a gene-environment correlation model, in which genes that influence the vulnerability for anxious depression also increase the risk of exposure to life events. The effect of genes that influence environmental exposure might be mediated through personality and we therefore also examined the association between life events and personality (neuroticism and extraversion). Method: Information on life events, anxious depression, neuroticism and extraversion was collected in 5782 monozygotic (MZ) and dizygotic (DZ) twins who participated in a longitudinal survey study of the Netherlands Twin Register. To examine causality, data were analysed longitudinally. To examine gene-environment correlation, the co-twin control method was used. Results: Anxious depression and, to a lesser extent, neuroticism scores increased after exposure to life events. Anxious depression and neuroticism also predicted the experience of life events. Prospectively, extraversion was not associated with life events. Anxious depression, neuroticism and extraversion scores did not differ between the non-exposed subjects of MZ and DZ twin pairs and unrelated subjects discordant for life events. Conclusions: Our findings suggest that reciprocal causation explains the relationship between life events and anxious depression and between life events and neuroticism. Extraversion is not related to life events. No evidence was found for gene-environment correlation, i.e. the genes that influence anxious depression, neuroticism or extraversion do not overlap with the genes that increase the risk of exposure to life events. Copyright © 2008 Cambridge University Press.

Previous genetic investigations of variation in normal sleep have focused on measures that describe sleep over longer periods of time. We undertook a study with the aim of evaluating whether heritability can be found in single-night sleep traits. A classical twin study design of monozygotic and dizygotic twins, enriched with siblings of twins was employed. The study included adult twin pairs and their siblings (N = 813 subjects from 342 families). A subsample of 66 individuals participated twice. For a single night, bedtime, awakening time and subjective sleep quality were assessed using a diary. The diary also assessed smoking, alcohol and coffee consumption, and the subjective evaluation of stress. Resemblance between family members was used to estimate the heritability of bedtime, awakening time, sleep problems and sleep quality as a function of sex. Most sleep measures showed familial clustering, but results differed for men and women. Heritability for bedtime and sleep problems was seen in women; and for awakening time in men. We conclude that heritability can be demonstrated for bedtime and subjective evaluation of even a single night of sleep. The contribution of the genetic make-up is sex specific. In women variance in awakening time is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible. In contrast, for males, variance in the evening bedtime is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible.

We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P < 0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression. © 2007 Springer Science+Business Media, LLC.

We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P < 0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression. © 2007 Springer Science+Business Media, LLC.

A transmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures.

Maximum likelihood estimation techniques are widely used in twin and family studies, but soon reach computational boundaries when applied to highly complex models (e.g., models including gene-by-environment interaction and gene-environment correlation, item response theory measurement models, repeated measures, longitudinal structures, extended pedigrees). Markov Chain Monte Carlo (MCMC) algorithms are very well suited to fit complex models with hierarchically structured data. This article introduces the key concepts of Bayesian inference and MCMC parameter estimation and provides a number of scripts describing relatively simple models to be estimated by the freely obtainable BUGS software. In addition, inference using BUGS is illustrated using a data set on follicle-stimulating hormone and luteinizing hormone levels with repeated measures. The examples provided can serve as stepping stones for more complicated models, tailored to the specific needs of the individual researcher.

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2. © 2006 Springer Science+Business Media, Inc.

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2. © 2006 Springer Science+Business Media, Inc.

Maximum likelihood estimation techniques are widely used in twin and family studies, but soon reach computational boundaries when applied to highly complex models (e.g., models including gene-by-environment interaction and gene-environment correlation, item response theory measurement models, repeated measures, longitudinal structures, extended pedigrees). Markov Chain Monte Carlo (MCMC) algorithms are very well suited to fit complex models with hierarchically structured data. This article introduces the key concepts of Bayesian inference and MCMC parameter estimation and provides a number of scripts describing relatively simple models to be estimated by the freely obtainable BUGS software. In addition, inference using BUGS is illustrated using a data set on follicle-stimulating hormone and luteinizing hormone levels with repeated measures. The examples provided can serve as stepping stones for more complicated models, tailored to the specific needs of the individual researcher.

A transmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures.

The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.

The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.

Obesity is a rapidly growing threat to public health, driven by the increased occurrence of high caloric diets and sedentary lifestyles. Within this environment, genetic influences may largely determine inter-individual differences in obesity-related traits. To map genes involved in weight regulation, we performed a genome-wide linkage scan for body mass index (BMI), a reliable measure of total body fat, in 192 Dutch families including 315 twins and 210 siblings with data on BMI. Using variance components linkage analysis, regions with LOD-scores greater than 2 were observed on 6p25.1 (LOD-score, 2.13) and 7p21.1 (LOD-score, 2.40). LOD-scores higher than 1 were found on chromosomes 3, 13, 15 and 21. Of note, evidence for the putative quantitative trait locus for BMI on 7p was obtained previously from such diverse populations as Mexican-Americans, Asians and Nigerians, suggesting that the underlying genes may effect weight regulation in diverse environments. An obvious positional candidate in the 7p linkage region is the gene encoding neuropeptide Y (NPY) that controls satiety and food intake.

Height is a highly heritable, complex trait. At present, the genes responsible for the variation in height have not yet been identified. This paper summarizes the results of previous linkage studies and presents results of an additional linkage analysis. Using data from the Netherlands Twin Register, a sib-pair-based linkage analysis for adult height was conducted. For 513 sib-pairs from 174 families complete genome scans and adult height were available. The strongest evidence for linkage was found for a region on chromosome 6, near markers D6S1053 and D6S1031 (LOD = 2.32). This replicated previous findings in other data sets. LOD scores ranging from 1.53 to 2.04 were found for regions on chromosomes 1, 5, 8, 10, and 18. The region on chromosome 18 (LOD = 1.83) also corresponded with the results of previous studies. Several chromosomal regions are now implied in the variance in height, but further study is needed to draw definite conclusions with regard to the significance of these regions for adult height. © 2004 Nature Publishing Group All rights reserved.

The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD = 3.05) and chromosome 14 (LOD = 1.66) for SI and on chromosome 3 (LOD = 1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD = 1.92) and for NC (LOD = 2.29) which may partly explain the overlapping etiological factors for SI and NC. © 2004 Nature Publishing Group All rights reserved.

The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD = 3.05) and chromosome 14 (LOD = 1.66) for SI and on chromosome 3 (LOD = 1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD = 1.92) and for NC (LOD = 2.29) which may partly explain the overlapping etiological factors for SI and NC. © 2004 Nature Publishing Group All rights reserved.

Height is a highly heritable, complex trait. At present, the genes responsible for the variation in height have not yet been identified. This paper summarizes the results of previous linkage studies and presents results of an additional linkage analysis. Using data from the Netherlands Twin Register, a sib-pair-based linkage analysis for adult height was conducted. For 513 sib-pairs from 174 families complete genome scans and adult height were available. The strongest evidence for linkage was found for a region on chromosome 6, near markers D6S1053 and D6S1031 (LOD = 2.32). This replicated previous findings in other data sets. LOD scores ranging from 1.53 to 2.04 were found for regions on chromosomes 1, 5, 8, 10, and 18. The region on chromosome 18 (LOD = 1.83) also corresponded with the results of previous studies. Several chromosomal regions are now implied in the variance in height, but further study is needed to draw definite conclusions with regard to the significance of these regions for adult height. © 2004 Nature Publishing Group All rights reserved.

Obesity is a rapidly growing threat to public health, driven by the increased occurrence of high caloric diets and sedentary lifestyles. Within this environment, genetic influences may largely determine inter-individual differences in obesity-related traits. To map genes involved in weight regulation, we performed a genome-wide linkage scan for body mass index (BMI), a reliable measure of total body fat, in 192 Dutch families including 315 twins and 210 siblings with data on BMI. Using variance components linkage analysis, regions with LOD-scores greater than 2 were observed on 6p25.1 (LOD-score, 2.13) and 7p21.1 (LOD-score, 2.40). LOD-scores higher than 1 were found on chromosomes 3, 13, 15 and 21. Of note, evidence for the putative quantitative trait locus for BMI on 7p was obtained previously from such diverse populations as Mexican-Americans, Asians and Nigerians, suggesting that the underlying genes may effect weight regulation in diverse environments. An obvious positional candidate in the 7p linkage region is the gene encoding neuropeptide Y (NPY) that controls satiety and food intake.

With the rapid advances in molecular biology, the near completion of the human genome, the development of appropriate statistical genetic methods and the availability of the necessary computing power, the identification of quantitative trait loci has now become a realistic prospect for quantitative geneticists. We briefly describe the theoretical biometrical foundations underlying quantitative genetics. These theoretical underpinnings are translated into mathematical equations that allow the assessment of the contribution of observed (using DNA samples) and unobserved (using known genetic relationships) genetic variation to population variance in quantitative traits. Several statistical models for quantitative genetic analyses are described, such as models for the classical twin design, multivariate and longitudinal genetic analyses, extended twin analyses, and linkage and association analyses. For each, we show how the theoretical biometrical model can be translated into algebraic equations that may be used to generate scripts for statistical genetic software packages, such as Mx, Lisrel, SOLAR, or MERLIN. For using the former program a web-library (available from http://www.psy.vu.nl/mxbib) has been developed of freely available scripts that can be used to conduct all genetic analyses described in this paper.

With the rapid advances in molecular biology, the near completion of the human genome, the development of appropriate statistical genetic methods and the availability of the necessary computing power, the identification of quantitative trait loci has now become a realistic prospect for quantitative geneticists. We briefly describe the theoretical biometrical foundations underlying quantitative genetics. These theoretical underpinnings are translated into mathematical equations that allow the assessment of the contribution of observed (using DNA samples) and unobserved (using known genetic relationships) genetic variation to population variance in quantitative traits. Several statistical models for quantitative genetic analyses are described, such as models for the classical twin design, multivariate and longitudinal genetic analyses, extended twin analyses, and linkage and association analyses. For each, we show how the theoretical biometrical model can be translated into algebraic equations that may be used to generate scripts for statistical genetic software packages, such as Mx, Lisrel, SOLAR, or MERLIN. For using the former program a web-library (available from http://www.psy.vu.nl/mxbib) has been developed of freely available scripts that can be used to conduct all genetic analyses described in this paper.

In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.

In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.