Sleep during a regular week night: a twin-sibling study.

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.

Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.

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.

Implementation of a combined association-linkage model for quantitative traits in linear mixed model procedures of statistical packages.

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.

Combined linkage and association analyses of the 124-bp allele of marker D2S2944 with anxiety, depression, neuroticism and major depression.

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.

Familial clustering of major depression and anxiety disorders in Australian and Dutch twins and siblings.

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 Fagerström Test for Nicotine Dependence in a Dutch sample of daily smokers and ex-smokers.

We explored the performance of the Fagerström Test for Nicotine Dependence (FTND) in a sample of 1378 daily smokers and 1058 ex-smokers who participated in a survey study of the Netherlands Twin Register. FTND scores were higher for smokers than for ex-smokers. Nicotine dependence level was not associated with age. FTND score was highly correlated with the maximum number of cigarettes smoked (even after excluding the item 'number of cigarettes per day' from FTND), but the FTND score showed a low correlation with age of first cigarette and total number of years smoked. In a subsample of smokers (n = 143) and ex-smokers (n = 181) the test-retest correlations for the FTND were high. In general, the performance of the FTND in ex-smokers was comparable with that in smokers. These findings suggest the FTND to be a valuable tool for studies of nicotine dependence in large epidemiological samples.

QTLs for height: results of a full genome scan in Dutch sibling pairs.

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.

Further evidence for a QTL influencing body mass index on chromosome 7p from a genome-wide scan in Dutch families.

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.

Theory and practice in quantitative genetics.

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.

Netherlands Twin Register: a focus on longitudinal research.

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.