Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study

Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated

Polymorphism in the Tyrosine Hydroxylase (TH) Gene Is Associated with Activity-Impulsivity in German Shepherd Dogs

We investigated the association between repeat polymorphism in intron 4 of the tyrosine hydroxylase (TH) gene and two personality traits, activity-impulsivity and inattention, in German Shepherd Dogs. The behaviour of 104 dogs was characterized by two instruments: (1) the previously validated Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS) filled in by the dog owners and (2) the newly developed Activity-impulsivity Behavioural Scale (AIBS) containing four subtests, scored by the experimenters. Internal consistency, inter-observer reliability, test-retest reliability and convergent validity were demonstrated for AIBS

Genetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults

Context: In contrast to the large number of studies in children, there is little information on the contribution of genetic factors to Attention Deficit Hyperactivity Disorder (ADHD) in adults. Objective: To estimate the heritability of ADHD in adults as assessed by the ADHD index scored from the CAARS (Conners’ Adult ADHD Rating Scales). Design: Phenotype data from over 12,000 adults (twins, siblings and parents) registered with the Netherlands Twin Register were analyzed using genetic structural equation modeling. Main outcome measures: Heritability estimates for ADHD from the twin-family study. Results: Heritability of ADHD in adults is estimated around 30 % in men and women. There is some evidence for assortative mating. All familial transmission is explained by genetic inheritance, there is no support for the hypothesis that cultural transmission from parents to offspring is important. Conclusion: Heritability for ADHD features in adults is present, but is substantially lower than it is in children

DRD4 Polymorphism Moderates the Effect of Alcohol Consumption on Social Bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse

Choline transporter gene variation is associated with attention-deficit hyperactivity disorder

The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder

The relation between ADHD symptoms and fine motor control: a genetic study

Previous research has shown that fine motor control (MC) performance, measured with a computerized task, was less accurate in children with ADHD and in their unaffected siblings, compared to healthy children. This might indicate a shared genetic etiology between MC and ADHD; it was therefore suggested that MC could serve as endophenotype for ADHD. We examined the association between ADHD symptoms (AS) and MC in a genetically informative design that can distinguish between a genetic and a nongenetic familial etiology for the association. Participants were 12-year-old twins and their siblings (N = 409). AS were rated on a continuous scale with the Strengths and Weaknesses of ADHD and Normal behavior scale (SWAN). MC accuracy and stability was measured with the computerized pursuit task of the Amsterdam Neuropsychological Tasks (ANT). Analyses were performed with Structural Equation Modelling. AS were weakly associated with MC accuracy of the left and right hand (r =-.10/-.10). No association with MC stability was found (r =-.01/-.03). AS were highly heritable (75%), while MC accuracy of the right hand and MC stability showed no genetic influences. For MC accuracy of the left hand, variance was explained by genetic (10%), common environmental (23%), and unique environmental variances. The association between MC accuracy of the left hand and AS was explained by a shared genetic influence but the genetic correlation was low (r =-.14). The phenotypic and genetic associations between AS and computerized MC were weak, suggesting that fine MC is not a proper endophenotype for ADHD. © 2010 Psychology Press

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

MtNramp1 mediates iron import in rhizobia-infected Medicago truncatula cells.

Symbiotic nitrogen fixation is a process that requires relatively high quantities of iron provided by the host legume. Using synchrotron-based X-ray fluorescence, we have determined that this iron is released from the vasculature into the apoplast of zone II of M. truncatula nodules. This overlaps with the distribution of MtNramp1, a plasma membrane iron importer. The importance of MtNramp1 in iron transport for nitrogen fixation is indicated by the 60% reduction of nitrogenase activity observed in knock-down lines, most likely due to deficient incorporation of this essential metal cofactor at the necessary levels

Influence of Candidate Genes on Attention Problems in Children: A Longitudinal Study

Attention problems form one of the core characteristics of Attention-Deficit Hyperactive Disorder (ADHD), a multifactorial neurodevelopmental disorder. From twin research it is clear that genes play a considerable role in the etiology and in the stability of ADHD in childhood. Association studies have focused on genes involved in the dopaminergic and serotoninergic systems, but with inconclusive results. This study investigated the effect of 26 Single Nucleotide Polymorphisms (SNPs) in genes encoding for serotonin receptors 2A (HTR2A), Catechol-O-Methyltransferase (COMT), Tryptophane Hydroxylase type 2 (TPH2), and Brain Derived Neurotrophic Factor (BDNF). Attention problems (AP) were assessed by parental report at ages 3, 7, 10, and 12 years in more than 16,000 twin pairs. There were 1148 genotyped children with AP data. We developed a longitudinal framework to test the genetic association effect. Based on all phenotypic data, a longitudinal model was formulated with one latent factor loading on all AP measures over time. The broad heritability for the AP latent factor was 82%, and the latent factor explained around 55% of the total phenotypic variance. The association of SNPs with AP was then modeled at the level of this factor. None of the SNPs showed a significant association with AP. The lowest p-value was found for the rs6265 SNP in the BDNF gene (p = 0.035). Overall, our results suggest no evidence for a role of these genes in childhood AP