Genetics Genetics has captured the imagination of the public, the interest of the media and a large place in the sciences. Since complex the discovery of the structure of DNA by Watson and Crick, the double helix has epitomized the main dogma of media genetics: everything from the tiniest details of the human body to the most complex of behaviours is encoded in the DNA genes. This belief has been strengthened by the tremendous success that has been achieved in cloning more than 1000 genes are that cause simple Mendelian disorders. However, for complex disorders, particularly psychiatric conditions, the search for genes has been frustrating and Crick, has not yielded definitive results, although claims of gene discoveries are made regularly. In this article, we discuss the possible from causes for these difficulties, along with some directions that may help in reducing these problems. We also consider the implications health. of psychiatric genetic research for individual and public health.

A A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early general Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through cognitive a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples SNPs of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample effect (N=1310) approached significance (P= .06) in the direction of the original finding, but results from the other samples (N=205-758) were mixed.a A meta-analysis of the results - allowing for effect size heterogeneity between samples - yielded a non-significant correlation (r=- .01, P= .57),targeted indicating that this SNP set was not associated with general cognitive ability in the populations studied.European Journal of Human Genetics doi:10.1038/ejhg.2008.100. advance online publication, 21 May 2008; doi:10.1038/ejhg.2008.100.

Recent studies studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent the cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary capacities. microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This size has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human independent cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing hominid the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only human in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well.human The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal measures trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive most abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several characterizing measures of IQ. Five independent samples were used, totaling 2,393 subjects, including both family-based and population-based datasets. Our overall findings our do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ.loci As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight adaptive the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Abstract Human Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels [FokI] are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as levels contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 A (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants similar with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian samples from found Australia (N = 3906) and the Netherlands (N = 1689) for polymorphisms in VDR. The Australian samples were twin families a with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family in data to perform both within and between family tests of association. We found no significant associations for any of the the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same to direction and of similar magnitude (additive effect .3cm) to the effect observed in the published adult meta-analysis. An effect of (rs10735810 this size explains ~ .1% of the phenotypic variance in height - this implies that many, probably hundreds, of such variants not are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166)We of VDR in explaining variation in height.

It It is well established that major depressive disorder (MDD) is partly heritable. We present a genome-wide linkage study aiming to find of regions on the genome that influence the vulnerability for MDD. Our sample consists of 110 Australian and 23 Dutch pedigrees genome-wide with two or more siblings affected with MDD (total N = 278). Linkage analysis was carried out in MERLIN. Three 110 regions showed suggestive linkage signals. The highest LOD-score of 2.1 was found on chromosome 17 at 52.6 cM along with the LOD scores of 1.9 and 1.7 on chromosome 8 at 2.7 cM and chromosome 2 at 90.6 cM, respectively. The Dutch result on chromosome 8 seems most promising as two previous studies also found linkage in this region, once suggestive and analysis once significant. The linkage peak on chromosome 17 harbors the serotonin transporter gene. In the Australian and Dutch sample, the Inc. serotonin transporter length polymorphism did not show evidence for association, thus other genes in this region or other polymorphisms in and the serotonin transporter gene might be associated with MDD. Further replication is needed to establish the relevance of our linkage aiming finding on chromosome 2.(c) 2008 Wiley-Liss, Inc.

CONTEXT:People People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying thousand this personality dimension can give insights into the etiology of these important psychiatric disorders. OBJECTIVES: To undertake a comprehensive genome-wide can linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between compare countries for replication and across time within countries for consistency. DESIGN: Genome-wide linkage scan. SETTING: Twin individuals and their family Linkage members from Australia and the Netherlands. PARTICIPANTS: Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up across to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite thousand markers. METHODS: Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were association conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results. RESULTS: Three chromosomal regions evidence exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM)(Dutch study sample), 14q etiology 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance Five after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 to (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other neuroticism studies of neuroticism or related traits and/or in studies of anxiety in mice. CONCLUSIONS: Our results demonstrate the value of results the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage Additional regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can SETTING: inform prioritization of results from genome-wide association studies.

There There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds IQ. the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual global discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high well-replicated IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The poor Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations time of - .44 and - .33 with respective Performance and Verbal IQ; heritabilities were 57%(IT), 83%(PIQ) and 77%(VIQ). Directional is causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT traits. and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than causation genes which are unique to specific traits.

Blood cells cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key white regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative regulatory trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic whole-genome and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the third Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices.new We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The 6015 first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts cell (best SNP rs7023923, p = 8.9 x 10(-14)). The second locus was located on chromosome 6p21 and associated with mean hematopoietic cell erythrocyte volume (rs12661667, p = 1.2 x 10(-9), .7% variance explained) in a region that spanned five genes, including blood-related CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was and also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p = 5.3 x identification 10(-9), .6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values = .001, 9.9 x x 10(-5), and 7 x 10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of 10(-9), the mechanisms regulating hemopoietic cell fate.

We We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791,(combined combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV,to combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P =SNPs 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.

For For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects.visualized Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful initiation network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors in (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and (e.g., cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior.

This This paper argues that understanding developmental disorders requires developing theories and models that explicitly represent the role of general intelligence in deficit the cognitive phenotype of the disorder. In the case of autism it is argued that the low-IQ scores of people models with autism are not likely to be due to a deficit in the cognitive process that is arguably the major disorder. cause of mental retardation - namely, speed of processing - but rather low IQ reflects the pervasive and cascading effects = of the deficit in the information-processing module that causes autism. In the case of dyslexia, two radically different models of case reading disorder (ability = disability and a modular deficit model) are likely to be influenced by the effect of general people intelligence on reading performance in ways that will remain unclear without an explicit model of how general intelligence influences reading.reading.

OBJECTIVE:Autism Autism is a complex genetic disorder with a highly heterogeneous phenotype defined by repetitive behaviors, language deficits, and problems with Resource reciprocal social interactions. The authors present the first genome-wide scan for a social endophenotype in autism using the Social Responsiveness and Scale, which provides a quantitative measure of autistic-like behavior, primarily focused on social relatedness. METHOD: A nonparametric quantitative genome scan provides was performed using the Social Responsiveness Scale in a cohort of about 100 families with two or more autistic probands The from the Autism Genetic Resource Exchange to identify autism loci. To determine which additional loci were detected, linkage analysis with behavior, the same autism cohort using the qualitative diagnosis of autism was performed. To assess whether there were likely to be Scale sex-specific genetic risk factors, the cohort was stratified by the sex of affected individuals. RESULTS: The quantitative Social Responsiveness Scale factors. genome scan identified two loci on chromosomes 11 and 17, with the highest score on chromosome 11 (z=3.22). In contrast,Diagnostic no linkage signals reached significance in the Autism Diagnostic Interview-Revised qualitative scan. The Social Responsiveness Scale scan with only male social affecteds identified the same signals on chromosomes 11 and 17, as well as three other regions on chromosomes 4, 8,Genetic and 10. CONCLUSIONS: This study demonstrates the utility of the Social Responsiveness Scale quantitative endophenotype to detect autism-related genetic loci autism-related using quantitative behavioral information that may more closely relate to underlying genetic factors.

Human Human intelligence is a trait that is known to be significantly influenced by genetic factors and recent linkage data provide positional to evidence to suggest that a region on chromosome 6p, previously associated with schizophrenia, may be linked to variation in intelligence.to The gene for dysbindin-1 (DTNBP1) is located at 6p and has also been implicated in schizophrenia, a neuropsychiatric disorder characterized provide by cognitive dysfunction. We report an association between DTNBP1 genotype and general cognitive ability (g) in 2 independent cohorts, including (g) 213 patients with schizophrenia or schizoaffective disorder and 126 healthy volunteers. These data suggest that DTNBP1 genetic variation influences human evidence intelligence.

Telomeres Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and genomewide dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and and is heritable. We performed a quantitative-trait linkage analysis using an ~10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths individuals measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean chromosome batch-adjusted TRF was 36%(95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49%(95% CI 40%-58%).age, Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 is (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere humans. variation in humans.

Context:Context: Age at menarche (AAM) is an important anthropological variable, which has major implication for a woman's health later in life.genotyped Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown. Objective: To a identify the quantitative trait loci (QTL) underlying the variation in AAM. Methods: We performed a large-scale genomewide linkage scan in are 2,461 Caucasian women from 402 pedigrees. All the subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart and across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction.identify Results: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD = 3.70), the other two suggestive large-scale linkage was on 22q11 (LOD = 2.68) and 11q23 (LOD = 1.98), respectively. We also detected significant epistatic interaction between AAM. genomic regions of 22q13 and 3q13. Conclusions: The identification of QTL and epistatic interaction in a large female sample, laid regions a foundation for further independent replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming later at eventually finding the causal genetic variants and hidden mechanisms concerning the variation in AAM.

Over 30 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many hyperresponsiveness linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven in asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for Australian significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P =.00001 and genomewide P =to .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also proband. linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including marker 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising these from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing Dpter and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked have to 20q13 (empirical genomewide P =.042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we bronchial extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 and is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects were several of these traits.

This This study used genome-wide linkage analysis to detect Quantitative Trait Loci (QTLs) implicated in variation in general academic achievement as measured region by the Queensland Core Skills Test (QCST)(Queensland Studies Authority, 2004). Data from 210 families were analysed. While no empirically in derived significant or suggestive peaks for general academic achievement were indicated a peak on chromosome 2 was observed in a 2004). region where Posthuma et al.(2005) reported significant linkage for Performance IQ (PIQ) and suggestive linkage for Full Scale IQ a (FSIQ), and Luciano et al.(this issue) observed significant linkage for PIQ and word reading. A peak on chromosome 18 families was also observed approximately 20 cM removed from a region recently implicated in reading achievement. In addition, on chromosomes 2 academic and 18 peaks for a number of specific academic skills, two of which were suggestive, coincided with the general academic abilities. achievement peaks. The findings suggest that variation in general academic achievement is influenced by genes on chromosome 2 which have 18 broad influence on a variety of cognitive abilities.

Intelligence,Intelligence, as measured by standardized psychological tests, has been shown to be highly heritable, though identifying specific genes influencing general intelligence analyses has proven difficult. We conducted genome-wide linkage analyses to identify chromosomal regions containing genes influencing intelligence, as measured by WAIS highly full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ). Non-parametric multipoint linkage analyses were conducted with Merlin-regress software, using linkage a sample of 1111 genotyped and phenotyped individuals from 201 families, ascertained as part of the Collaborative Study on the suggestive Genetics of Alcoholism (COGA). The strongest evidence of linkage was obtained for FSIQ on chromosome 6 (LOD=3.28, 12 cM) near chromosomal the marker D6S1006. This region was also implicated with suggestive linkage in a recently published genome screen of IQ in (FSIQ), Australian and Dutch twin pairs, and it has been implicated in linkage studies of developmental dyslexia. Our findings provide further intelligence. support that chromosome 6p contains gene(s) affecting intelligence.

In In the post Genome era, the aim of behavior genetics has shifted from estimating the relative contributions of genes and environmental on factors to (co-)variation in human complex traits, to localization of genes and identification of functional genetic variants. This special issue shifted reflects this transition and presents fifteen papers that report on genome-wide linkage scans for complex traits in humans and on human methodological tools and innovations. Six papers focus on cognition and report overlapping linkage peaks on chromosomes 6p and 14p. Papers and on addictive behavior, i.e. smoking and alcohol dependence and its endophenotypes, find moderate LOD scores on chromosomes 6p, 5q, 4p to and 7q, respectively. Three papers concentrate on emotionality, depression and loneliness and examine chromosomes 2q and 12q. The papers in special this issue represent a summary of the first large scale linkage enterprises of human behavioral traits.