Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability.

Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-B and lymphocyte mAChRs as potential markers of exposure to these neurotoxicants. The blood neurotoxicity biomarkers were compared with prenatal and current exposures and with neuropsychological test results. Both biomarkers showed homogeneous distributions within this cohort (mAChR, range 0.04-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol mg(-1) protein h(-1)). No correlation was found between the two biomarkers and either blood neurotoxicant concentrations or clinical findings. MAO-B and mAChR sensitivity may not be sufficiently high to assess early, subclinical responses to low/moderate methylmercury and/or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents.

Individual differences in intelligence (cognitive abilities) are a prominent aspect of human psychology, and play a substantial role in influencing important life outcomes. Their phenotypic structure-as described by the science of psychometrics-is well understood and well replicated. Approximately half of the variance in a broad range of cognitive abilities is accounted by a general cognitive factor (g), small proportions of cognitive variance are caused by separable broad domains of mental function, and the substantial remainder is caused by variance that is unique to highly specific cognitive skills. The heritability of g is substantial. It increases from a low value in early childhood of about 30%, to well over 50% in adulthood, which continues into old age. Despite this, there is still almost no replicated evidence concerning the individual genes, which have variants that contribute to intelligence differences. Here, we describe the human intelligence phenotype, summarise the evidence for its heritability, provide an overview of and comment on molecular genetic studies, and comment on future progress in the field.

A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample (N=1310) approached significance (P=0.06) in the direction of the original finding, but results from the other samples (N=205-758) were mixed. A meta-analysis of the results - allowing for effect size heterogeneity between samples - yielded a non-significant correlation (r=-0.01, P=0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.European Journal of Human Genetics advance online publication, 21 May 2008; doi:10.1038/ejhg.2008.100.

The COMT Val(108/158)Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val(108/158)Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account.European Journal of Human Genetics advance online publication, 2 April 2008; doi:10.1038/ejhg.2008.57.

CONTEXT: Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems. OBJECTIVE: To test the utility of using a multivariate externalizing phenotype in (1) linkage analyses and (2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders. DESIGN: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene (CHRM2). SETTING: Six centers across the United States. Other PARTICIPANTS: Approximately 2300 individuals from 262 families. MAIN OUTCOME MEASURES: Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables. RESULTS: Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype. CONCLUSIONS: Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.

Abstract This article discusses findings of two recent studies conducted in collaboration with the East Flanders Prospective Twin Survey in the field of cognitive ability. The first study examined the effect of chorion type on heritability estimates of intelligence in children. The second study investigated the causes of association between child psychopathology and lower cognitive ability. Findings of these studies are discussed in the light of the current view on cognitive ability (or 'g') and recommendations for future research are made.

ABSTRACT: BACKGROUND: The CHRM2 gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation. METHODS: We previously reported an association between polymorphisms in the 5'UTR regions of the CHRM2 gene and intelligence. However, no functional variants within this area have currently been identified. In order to identify the relevant functional variant(s), we conducted a denser coverage of SNPs, using two independent Dutch cohorts, consisting of a children's sample (N = 371 ss; mean age 12.4) and an adult sample (N= 391 ss; mean age 37.6). For all individuals standardized intelligence measures were available. Subsequently, we investigated genotype-dependent CHRM2 gene expression levels in the brain, to explore putative enhancer/inhibition activity exerted by variants within the muscarinic acetylcholinergic receptor. RESULTS: Using a test of within-family association two of the previously reported variants - rs2061174, and rs324650 - were again strongly associated with intelligence (P< 0.01). A new SNP (rs2350780) showed a trend towards significance. SNP rs324650, is located within a short interspersed repeat (SINE). Although the function of short interspersed repeats remains contentious, recent research revealed potential functionality of SINE repeats in a gene-regulatory context. Gene-expression levels in post-mortem brain material, however were not dependent on rs324650 genotype. CONCLUSION: Using a denser coverage of SNPs in the CHRM2 gene, we confirmed the 5'UTR regions to be most interesting in the context of intelligence, and ruled out other regions of this gene. Although no correlation between genomic variants and gene expression was found, it would be interesting to examine allele-specific effects on CHRM2 transcripts expression in much more detail, for example in relation to transcripts specific halve-life and their relation to LTP and memory.

The synaptosomal associated protein of 25 kDa (SNAP-25) gene, located on chromosome 20 p12-12p11.2 encodes a presynaptic terminal protein. SNAP-25 is differentially expressed in the brain, and primarily present in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recently, a family-based genetic association was reported between variation in intelligence quotient (IQ) phenotypes and two intronic variants on the SNAP-25 gene. The present study is a follow-up association study in two Dutch cohorts of 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). It examines the complete genomic region of the SNAP-25 gene to narrow down the location of causative genetic variant underlying the association. Two new variants in intron 1 (rs363043 and rs353016), close to the two previous reported variants (rs363039 and rs363050) showed association with variation in IQ phenotypes across both cohorts. All four single nucleotide polymorphisms were located in intron 1, within a region of about 13.8 kbp, and are known to affect transcription factor-binding sites. Contrary to what is expected in monogenic traits, subtle changes are postulated to influence the phenotypic outcome of complex (common) traits. As a result, functional polymorphisms in (non)coding regulatory sequences may affect spatial and temporal regulation of gene expression underlying normal cognitive variation.

The synaptosomal associated protein of 25 kDa (SNAP-25) gene, located on chromosome 20 p12-12p11.2 encodes a presynaptic terminal protein. SNAP-25 is differentially expressed in the brain, and primarily present in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recently, a family-based genetic association was reported between variation in intelligence quotient (IQ) phenotypes and two intronic variants on the SNAP-25 gene. The present study is a follow-up association study in two Dutch cohorts of 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). It examines the complete genomic region of the SNAP-25 gene to narrow down the location of causative genetic variant underlying the association. Two new variants in intron 1 (rs363043 and rs353016), close to the two previous reported variants (rs363039 and rs363050) showed association with variation in IQ phenotypes across both cohorts. All four single nucleotide polymorphisms were located in intron 1, within a region of about 13.8 kbp, and are known to affect transcription factor-binding sites. Contrary to what is expected in monogenic traits, subtle changes are postulated to influence the phenotypic outcome of complex (common) traits. As a result, functional polymorphisms in (non)coding regulatory sequences may affect spatial and temporal regulation of gene expression underlying normal cognitive variation.

The synaptosomal-associated protein of 25 kDa (SNAP-25) gene plays an integral role in synaptic transmission, and is differentially expressed in the mammalian brain in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recent studies have suggested a possible involvement of SNAP-25 in learning and memory, both of which are key components of human intelligence. In addition, the SNAP-25 gene lies in a linkage area implicated previously in human intelligence. In two independent family-based Dutch samples of 391 (mean age 12.4 years) and 276 (mean age 37.3 years) subjects, respectively, we genotyped 12 single-nucleotide polymorphisms (SNPs) in the SNAP-25 gene on 20p12-20p11.2. From all individuals, standardized intelligence measures were available. Using a family-based association test, a strong association was found between three SNPs in the SNAP-25 gene and intelligence, two of which showed association in both independent samples. The strongest, replicated association was found between SNP rs363050 and performance IQ (PIQ), where the A allele was associated with an increase of 2.84 PIQ points (P=0.0002). Variance in this SNP accounts for 3.4 % of the phenotypic variance in PIQ.Molecular Psychiatry advance online publication, 27 June 2006; doi:10.1038/sj.mp.4001868.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.Molecular Psychiatry advance online publication, 9 December 2008; doi:10.1038/mp.2008.125.

Childhood environment, social environment and behavior, leisure time activities and life events have been hypothesized to contribute to individual differences in cognitive abilities and physical and emotional well-being. These factors are often labeled 'environmental', suggesting they shape but not reflect individual differences in behavior. The aim of this study is to test the hypothesis that these factors are not randomly distributed across the population but reflect heritable individual differences. Self-report data on Childhood Environment, Social Environment and Behavior, Leisure Time Activities and Life Events were obtained from 560 adult twins and siblings (mean age 47.11 years). Results clearly show considerable genetic influences on these factors with mean broad heritability of 0.49 (0.00-0.87). This suggests that what we think of as measures of 'environment' are better described as external factors that might be partly under genetic control. Understanding causes of individual differences in external factors may aid in clarifying the intricate nature between genetic and environmental influences on complex traits.

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype-environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.Molecular Psychiatry advance online publication, 2 June 2009; doi:10.1038/mp.2009.55.

Several linkage studies on anxiety have been carried out in samples ascertained through probands with panic disorder. The results indicated that using a broad anxiety phenotype instead of a DSM-IV anxiety disorder diagnosis might enhance the chance of finding a linkage signal. In the current study, a genome-wide linkage analysis was performed on anxiety measured with a self-report questionnaire whose scores are highly correlated with DSM-IV anxiety disorders. The self-report questionnaire was included in five surveys of a longitudinal study of the Netherlands Twin Register. Genotype and phenotype data were available for 1602 twins and siblings. To estimate identity by descent , additional genotype data for 564 parents and 22 siblings were used. Linkage analyses were carried out using MERLIN-regress on the average anxiety scores across time. A linkage signal (logarithm of odds score 3.4, empirical P-value 0.07) was obtained at chromosome 14 for marker D14S65 at 105 cM (90% confidence interval, 99-115 cM bounded by markers D14S1434 and D14S985). This finding replicates a linkage finding for a broad anxiety phenotype in a clinically based sample, indicating that the region might harbor a quantitative trait locus associated with the whole spectrum of general anxiety, that is from the normal to the clinical range. Moreover, genome-wide linkage and association studies on emotionality in mice obtained significant results in a syntenic region on mouse chromosome 12. Two homolog genes lie in this region -Dlk1 (delta-like 1 homolog, Drosophila) and Rtl1 (retrotransposon-like 1). Future association studies of these genes are warranted.Molecular Psychiatry advance online publication, 14 August 2007; doi:10.1038/sj.mp.4002061.

Previous studies have reported that individual variation in N1 amplitude is related to attentional problems and alcoholism. Using data from 651 twins and siblings from 292 families we examined whether variation in N1 amplitude and latency can be explained by genetic factors. In half of the subjects the age centered around 26 (young adult cohort), in the other half the age centered around 49 (middle-aged adult cohort). Two visual N1 components were identified by a spatial PCA - an early anterior component peaking from 88 to 168 ms after stimulus presentation and a posterior one peaking from 132 to 220 ms. Significant heritability was found for anterior N1 amplitude (22%) and posterior amplitude (50%), and for anterior latency (45%) and posterior latency (43%). We conclude that visual N1 amplitude and latency may serve as endophenotypes to detect genetic variation in susceptibility to psychiatric disorders.

BACKGROUND Proper functioning of the male reproductive axis depends on complex feedback systems between several hormones. In this study, the genetic contribution of various endocrine components of the hypothalamic-pituitary-testicular axis is evaluated and previously observed differences in FSH and inhibin B levels between mono-(MZ) and dizygotic (DZ) twins are re-investigated. METHODS Inhibin B, FSH, LH, sex hormone-binding globulin (SHBG) and testosterone levels were assayed in 128 adult males (20 MZ twin pairs, 7 single MZ twins, 10 DZ twin pairs, 27 single DZ twins and 34 siblings of twins, constituting 10 sibling pairs), aged 15.6-68.7 years. Hormone levels were compared across zygosity groups and heritability estimates were obtained using maximum likelihood variance component analysis. RESULTS Heritability estimates ranged from 56%(testosterone) to 81%(inhibin B and SHBG). For LH and FSH, the heritability was estimated at 68% and 80% respectively. No mean differences in hormone levels were observed across groups. CONCLUSIONS All measured hormones are highly heritable. A difference in the FSH-inhibin B feedback system between DZ twin males and MZ twin males could not be confirmed.

Frontal asymmetry of EEG alpha power (FA) may index the risk for anxiety and depression. Evidence linking FA to the underlying biological mechanisms is scarce. This is unfortunate because FA has potential as a biological marker to support gene finding in anxiety and depression. We examined the heritability of FA in 732 twins and their singleton siblings, and established the genetic and environmental contribution to the relation between FA and the risk for anxiety and depression. Multivariate models showed that FA is heritable only in young adults (males 32% and females 37%) but not in middle-aged adults. A significant relation between FA and the risk for anxiety and depression was only found in young adult females. This relation was explained by shared genes influencing both EEG and disease risk. Future studies on asymmetry of left and right frontal brain activation should carefully consider the effects of sex and age.

Mitochondria are central to optimal functioning of the nervous system and disruption of mitochondrial function is known to lead to cognitive impairment. However, there has been little focus on whether common mitochondrial DNA polymorphisms contribute to normal variation in cognitive phenotypes. In this study, we use methodology for carrying out whole mitochondrial association studies in family cohorts to test whether 69 common mitochondrial variants and 10 common European haplogroups are associated with a number of measures of cognition, including information processing, word recognition and general cognitive ability, in a sample of Australian adolescent twins and their singleton/non-twin siblings. With data from 1,385 individuals from 665 families, this is by far the largest mitochondrial association study of cognition undertaken to date. We find that there is no significant evidence that either common European mitochondrial SNPs or haplogroups are associated with variation in cognitive performance. In spite of the associations not reaching significance, several of the most highly associated SNPs are in mitochondrial genes that have previously been identified as potentially playing a role in cognitive performance in mice. These genes warrant further investigation in both functional and association studies with larger cohorts.

Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability.

ABSTRACT: BACKGROUND: The CHRM2 gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation. METHODS: We previously reported an association between polymorphisms in the 5'UTR regions of the CHRM2 gene and intelligence. However, no functional variants within this area have currently been identified. In order to identify the relevant functional variant(s), we conducted a denser coverage of SNPs, using two independent Dutch cohorts, consisting of a children's sample (N = 371 ss; mean age 12.4) and an adult sample (N= 391 ss; mean age 37.6). For all individuals standardized intelligence measures were available. Subsequently, we investigated genotype-dependent CHRM2 gene expression levels in the brain, to explore putative enhancer/inhibition activity exerted by variants within the muscarinic acetylcholinergic receptor. RESULTS: Using a test of within-family association two of the previously reported variants - rs2061174, and rs324650 - were again strongly associated with intelligence (P< 0.01). A new SNP (rs2350780) showed a trend towards significance. SNP rs324650, is located within a short interspersed repeat (SINE). Although the function of short interspersed repeats remains contentious, recent research revealed potential functionality of SINE repeats in a gene-regulatory context. Gene-expression levels in post-mortem brain material, however were not dependent on rs324650 genotype. CONCLUSION: Using a denser coverage of SNPs in the CHRM2 gene, we confirmed the 5'UTR regions to be most interesting in the context of intelligence, and ruled out other regions of this gene. Although no correlation between genomic variants and gene expression was found, it would be interesting to examine allele-specific effects on CHRM2 transcripts expression in much more detail, for example in relation to transcripts specific halve-life and their relation to LTP and memory.

ABSTRACT: BACKGROUND: The dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls. METHODS: From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF). RESULTS: Mean VIQ, PIQ, and FSIQ scores differed significantly (p<0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls. CONCLUSIONS: Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning.