Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition.

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.

Sex differences on the Dutch WISC-R were examined in Dutch children (350 boys, 387 girls, age 11-13 years) and Belgian children (370 boys, 391 girls, age 9.5-13 years). Multi-group covariance and means structure analysis was used to establish whether the WISC-R was measurement invariant across sex, and whether sex differences on the level of the subtests were indicative of sex differences in general intelligence (g). In both samples, girls outperformed boys on the subtest Coding, while boys outperformed girls on the subtests Information and Arithmetic. The sex differences in the means of these three subtests could not be accounted for by the first-order factors Verbal, Performance, and Memory. Measurement invariance with respect to sex was however established for the remaining 9 subtest. Based on these subtests, no significant sex differences were observed in the means of the first-order factors, or the second-order g-factor. In conclusion, the cognitive differences between boys and girls concern subtest-specific abilities, and these sizeable differences are not attributable to differences in first-order factors, or the second-order factor g. (c) 2007 Elsevier Inc. All rights reserved.

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.

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.

Epistatic effect of genes from the dopamine and serotonin systems on the temperament traits of Novelty Seeking and Harm Avoidance

Several groups have reported association between large CAG/CTG repeats in the genome and BP disorder using the Repeat Expansion Detection (RED) method. Molecular interpretation studies demonstrated that around 90% of the large CAG/CTG repeats detected by RED can by explained by repeat size at either the CTG18.1 or ERDA-1 locus. In this study we report the findings on a large European BP case-control sample analysed for these two frequently expanded repeats. The frequency of expanded alleles (>40 repeats) at the CTG18.1 locus was significantly higher in the subgroup of patients with a more severe phenotype BPI and a positive first degree family history than in a group of matched controls (9% vs 5%). No difference in ERDA-1 expansion frequency was seen between BP cases and matched controls. We conclude that the ERDA-1 locus is not related to the BP phenotype while expanded alleles at the CTG18.1 locus cannot be excluded as a vulnerability factor for BP disorder.

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. (C) 2001 Society of Biological Psychiatry.

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 significance 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 subject. Biol Psychiatry 2001;49:405-409 (C) 2001 Society of Biological Psychiatry.

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.

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 (WISCR). 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.

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, χ 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 (χ 2 ?=?7.34, df 1, P ?=?0.006) and BP (χ 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.

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