A prospective twin study of birth weight discordance and child problem behavior.

BACKGROUND: We investigated whether low birth weight constitutes a causal risk factor for child problem behavior, using a variation of the co-twin control method. METHODS: In a representative sample of 745 twin pairs (monozygotic: 324 pairs), birth weight was recorded at birth and child problem behavior at mean age 10 years was measured with the Child Behaviour Checklist (CBCL). RESULTS: Lower birth weight was a continuous risk factor for later child problem behavior (adjusted regression coefficient over units of 500 g: beta = -.15, p =.046), and greater levels of within-pair CBCL discordance did not result in a reduced effect size. Greater within-pair birth weight discordance was associated with greater within-pair CBCL score discordance (beta =.35, p <.001). This latter effect was similar in monozygotic (beta =.34, p =.005) and dizygotic twins (beta =.37, p =.003). CONCLUSIONS: The fact that (1) the effect size of the association between low birth weight and child problem behavior was not reduced in pairs with greater levels of CBCL discordance, and (2) similar effect sizes were found in monozygotic and dizygotic twins for the within-pair association between birth weight discordance and CBCL score discordance, suggests that the observed relationship between low birth weight and child problem behavior is not due to a shared environmental or genetic variable that influences both characteristics. Lower birth weight is a causal risk factor for child problem behavior, the effects of which may well extend into adulthood.

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

No evidence for the involvement of CAG/CTG repeats from within 18q21.33-q23 in bipolar disorder.

We previously identified 18q21.33-q23 as a candidate region in one BP family and constructed a yeast artificial chromosome (YAC) contig map. Here, we mapped eight known CAG/CTG repeats relative to 18q21.33-q23. We also isolated four CAG/CTG repeats from within the region using CAG/CTG YAC fragmentation, one of which is located in the 5' untranslated region of the CAP2 gene coding for a brain-expressed serine proteinase inhibitor. The triplet repeats located in the 18q21.33-q23 BP candidate region showed no expanded alleles in the linked BP family nor in a BP case-control sample. Moreover, only the CAP2 triplet repeat was polymorphic but no genetic association with BP disorder was observed.

5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait.

The purpose [corrected] of this study was to investigate the relationship between bipolar disorder and the harm avoidance personality trait (HA), and the genetic contribution of the polymorphic DNA variation T102C in exon 1 of 5-HTR2a (chromosome 13q14-21) in bipolar disorder and HA personality trait. Forty bipolar patients and 89 normal subjects completed the TPQ questionnaire and were genotyped for 5-HT2a. Bipolar patients scored higher than normal subjects on the HA dimension. However, no contribution of the 5-HTR2a polymorphism on the bipolar disorder or on the HA personality trait emerged. Despite the limited sample size, these results exclude a major effect of the 5-HTR2a polymorphism on bipolar disorder and HA personality trait but not a minor effect.

Intrauterine environment and cognitive development in young twins.

Intrauterine factors important for cognitive development, such as birth weight, chorionicity and umbilical cord characteristics were investigated. A total of 663 twin pairs completed the Wechsler Intelligence Scale for Children-Revised and scores were available for Performance, Verbal and Total Intelligence Quotient (IQ). The intrauterine factors examined were birth weight, placental weight and morphology, cord knots, cord length and cord insertion. IQ scores for the varying levels of the intrauterine markers adjusting for gender and gestational age were calculated. The heritability of IQ and the association between IQ and intrauterine environment were examined. Twins with lower birth weight and cord knots had lower IQ scores. The aetiology of IQ is largely distinct from that of birth weight and cord knots, and non-shared environment may influence the observed relationships.

Genetics of personality: are we making progress?

For centuries, scientists are intrigued by the differences in personality between individuals. As early as in the ancient Greek civilization, people tried to formulate theories to systematize this diversity. With the increased interest in behavior genetics, personality was also considered a challenging phenotype. From the early start, studies suggested a heritable component in personality. After the successes of molecular genetic studies in unraveling the genetic basis of (mostly) monogenic diseases, the focus shifted towards complex traits, including psychiatric disorders. It was observed in several studies that personality measures differed between patients with psychiatric disorders and healthy controls. Therefore, normal personality was considered a viable endophenotype in the search for genes involved in psychiatric disorders such as affective disorders, ADHD and substance dependence. Genes that were to be found in studies on personality could be candidate genes for particular psychiatric disorders. In the course of time, however the study of genes for personality turned out to be at least as hard as the search for genes involved in other complex disorders. In this review, past studies, present problems and future directions concerning the study of personality genetics are discussed.

Validation of a telephone zygosity questionnaire in twins of known zygosity.

The aim of this study was to validate a zygosity questionnaire that can be administered over the telephone. Mothers of same-sexed twins of known zygosity and chronicity between 2 and 31 years of age were interviewed on a nine-item questionnaire. From the answers one unweighted and four weighted indices were computed. As single questions, the mother's opinion and the "two peas in a pod" question differentiated best between monozygotic and dizygotic twins. One independent well-trained observer assessed the zygosity based on the questionnaire and made the correct diagnosis in 96% of the cases. A weighted index of eight similarity questions yielded an accuracy of 98%. This study shows that the zygosity of same-sexed twins more than 2 years old and without gross physical malformation can reliably be determined by a telephone questionnaire with a high accuracy.

Power of selective genotyping in genetic association analyses of quantitative traits.

A power calculation is described in which the power of selective genotyping in genetic association studies of quantitative traits is evaluated. The method of selective genotyping implies the selection of the extremely high and low scoring individuals from the continuous distribution of a quantitative trait. The selected individuals are genotyped and association is tested. In the power calculation the following parameters are varied: total sample size of the phenotyped group (1000, 1500, 2000); selection of extremely high and low scoring individuals (2.5%, 5%, 10%); allele frequency of the risk increasing allele (0.10 to 0.90); mode of inheritance and proportion of variance explained by the quantitative trait locus (QTL) (omega 2 = 0.01, 0.05, 0.10). We conclude that the method of selective genotyping is a powerful method to detect association for a quantitative trait.

Heritability estimates of intelligence in twins: effect of chorion type.

This study investigates the basic assumption of homogeneity of monozygotic (MZ) twins: are there differences according to the timing of the zygotic splitting, early in dichorionic (DC) and later in monochorionic (MC) pairs? We assessed the IQ of 451 same-sexed twin pairs of known zygosity and chorion type with the Wechsler Intelligence Scale for Children-Revised (WISC-R). The variances of within-pair differences were compared for monochorionic (MC), dichorionic monozygotic (DC-MZ) and dizygotic same-sexed (DZ) twins and structural equation modeling was applied. High heritability estimates were found for almost all subscales and IQ-scores. A significant effect of chorion type was found: the MC twins resembled each other more than the DC-MZ twins on the subscales Arithmetic and Vocabulary. The effect accounts for respectively 14% and 10% of the total variance.

Associations between nonshared environment and child problem behaviour.

BACKGROUND: Twin studies suggest that environmental effects on the development of child psychopathology largely involve nonshared environmental processes. However, the influence of the nonshared environment may have been overestimated, as the relationship between environment and behaviour may be genetically mediated. A direct measure of the nonshared environment (using the Sibling Inventory of Differential Experience - SIDE) was investigated in relation to child psychopathology, and tested for possible genetic mediation. METHOD: Parent-rated versions of the Child Behaviour Checklist (CBCL) and the SIDE were collected in 760 twin pairs aged 6-17 years. Multilevel regression analysis was used to assess the influence of SIDE scores on CBCL total problem scores, internalising symptoms, externalising symptoms and depressive symptom scores. Genetic mediation was assessed by examining interaction with zygosity in the association between SIDE scores and differences in CBCL scores (absence of interaction indicating no genetic mediation). RESULTS: The results revealed significant associations between SIDE dimensions on the one hand, and degree of internalising, externalising, depression and total symptom scores on the other. However, the effects were non-linear, and especially apparent for the extremes of differential environmental experience within twin pairs. Overall, there was no strong evidence for genetic mediation of associations between nonshared environment and symptoms. CONCLUSIONS: Direct, genetically unconfounded but skewed relationships may exist between nonshared environment on the one hand and behavioural differences on the other, although longitudinal data are necessary to determine the direction of effects.

A novel CpG-associated brain-expressed candidate gene for chromosome 18q-linked bipolar disorder.

We previously identified 18q21-q22 as a candidate region for bipolar (BP) disorder and constructed a yeast artificial chromosome (YAC) contig map. Here we identified three potential CpG islands using CCG/CGG YAC fragmentation. Analysis of available genomic sequences using bioinformatic tools identified an exon of 3639 bp downstream of a CpG island of 1.2 kb containing a putative transcription initiation site. The exon contained an open reading frame coding for 1212 amino acids with significant homology to the SART-2 protein; weaker homology was found with a series of sulphotransferases. Alignment of cDNA sequences of corresponding ESTs and RT-PCR sequencing predicted a transcript of 9.5 kb which was confirmed by Northern blot analysis. The transcript was expressed in different brain areas as well as in multiple other peripheral tissues. We performed an extensive mutation analysis in 113 BP patients. A total of nine single nucleotide polymorphisms (SNPs) were identified. Five SNPs predicted an amino acid change, of which two were present in BP patients but not in 163 control individuals.

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.