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

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.

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

Abstract Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian samples from Australia (N = 3906) and the Netherlands (N = 1689) for polymorphisms in VDR. The Australian samples were twin families with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height - this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.

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

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

There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations of -0.44 and -0.33 with respective Performance and Verbal IQ; heritabilities were 57%(IT), 83%(PIQ) and 77%(VIQ). Directional causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than genes which are unique to specific traits.

The 6p21-p22 chromosomal region has been identified as a developmental dyslexia locus both in linkage and association studies, the latter generating evidence for the doublecortin domain containing 2 (DCDC2) as a candidate gene at this locus (and also for KIAA0319). Here, we report an association between DCDC2 and reading and spelling ability in 522 families of adolescent twins unselected for reading impairment. Family-based association was conducted on 21 single nucleotide polymorphisms (SNPs) in DCDC2 using quantitative measures of lexical processing (irregular-word reading), phonological decoding (non-word reading) and spelling-based measures of dyslexia derived from the Components of Reading Examination test. Significant support for association was found for rs1419228 with regular-word reading and spelling (P=0.002) as well as irregular-word reading (P=0.004), whereas rs1091047 was significantly associated (P=0.003) with irregular-word reading (a measure of lexical storage). Four additional SNPs (rs9467075, rs9467076, rs7765678 and rs6922023) were nominally associated with reading and spelling. This study provides support for DCDC2 as a risk gene for reading disorder, and suggests that this risk factor acts on normally varying reading skill in the general population.European Journal of Human Genetics advance online publication, 13 January 2010; doi:10.1038/ejhg.2009.237.

Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p = 8.9 x 10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p = 1.2 x 10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p = 5.3 x 10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values = 0.001, 9.9 x 10(-5), and 7 x 10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.

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

This paper argues that understanding developmental disorders requires developing theories and models that explicitly represent the role of general intelligence in the cognitive phenotype of the disorder. In the case of autism it is argued that the low-IQ scores of people with autism are not likely to be due to a deficit in the cognitive process that is arguably the major 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 reading disorder (ability = disability and a modular deficit model) are likely to be influenced by the effect of general intelligence on reading performance in ways that will remain unclear without an explicit model of how general intelligence influences reading.

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

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

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

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

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

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

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

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