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Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders.
We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls.
We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex.
We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders.
Behavioral problems in young children can be assessed by asking their parents or teachers to rate their behaviors. Genetic analyses of parental ratings show relatively large heritabilities for emotional and behavioral problems in young children, but data from teachers for this age group are scarce. Sources of variation in the Teacher's Report Form (TRF) problem scales were examined. The TRF was completed for 211 Dutch 5-year-old twin pairs and 4 single twins. Twins rated by different teachers had higher means and variances than twins rated by the same teacher, in addition twin correlations were lower in this group. In both groups monozygotic (MZ) correlations were generally higher than dizygotic (DZ) correlations. A model for twin resemblance was tested that allowed for these effects. For 5 problem scales (Withdrawn, Social Problems, Aggressive Behavior, Rule Breaking Behavior and Attention Problems) a model with genetic and unique environmental sources of variation fitted best to the data. For 3 problem scales (Anxious/Depressed, Thought Problems and Somatic Complaints) there were familial influences but it was not possible to distinguish between common environmental influences or genetic influences. Heritability was 63% for Attention problems, around 45% for Withdrawn, Social Problems, Aggressive Behavior and Rule Breaking Behavior, and around 30% for Anxious/Depressed, Thought Problems and Somatic Complaints.
The Netherlands Twin Register (NTR) was established around 1987 at the Vrije Universiteit in Amsterdam, the Netherlands. The current article summarizes the longitudinal genetic analyses of maternal and paternal ratings of twins' behavior as a function of the sex of the children for the traits of aggression (AGG), attention problems (AP), anxious/depression (ANX), internalizing behavior (INT) and externalizing behavior (EXT). We found that genetic influences are the most important factor in explaining individual differences in these traits. For most phenotypes, influences of genetic factors fluctuate throughout development, with the exception of AP, for which genetic influences remain of similar magnitude. Changes in genetic influences parallel those in shared environmental influences, while nonshared environmental influences remain relatively constant. Around 10% to 20% of the variance is accounted for by parent-specific shared environment, which includes rater bias. For all phenotypes, stability throughout childhood is accounted for by genetic and shared environmental factors, while nonshared environmental influences are mainly age/measurement specific. About 15% of the phenotypic stability is accounted for by rater-specific shared environmental influences, which include rater bias. In conclusion, between ages 3 and 12 genetic factors are the most important cause of individual differences in emotional and behavioral problems.
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.
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