Genome-wide association study of inattention and hyperactivity-impulsivity measured as quantitative traits.

Genome-wide association studies (GWAS) of attention-deficit/hyperactivity disorder (ADHD) offer the benefit of a hypothesis-free approach to measuring the quantitative effect of genetic variants on affection status. Generally the findings of GWAS relying on ADHD status have been non-significant, but the one study using quantitative measures of symptoms found SLC9A9 and SLC6A1 were associated with inattention and hyperactivity-impulsivity. Accordingly, we performed a GWAS using quantitative measures of each ADHD subtype measured with the Strengths and Weaknesses of ADHD and Normal Behaviour (SWAN) scale in two community-based samples. This scale captures the full range of attention and kinetic behavior; from high levels of attention and appropriate activity to the inattention and hyperactivity-impulsivity associated with ADHD within two community-based samples. Our discovery sample comprised 1,851 participants (mean age = 22.8 years [4.8]; 50.6% female), while our replication sample comprised 155 participants (mean age = 26.3 years [3.1]; 68.4% females). Age, sex, age × sex, and age2 were included as covariates and the results from each sample were combined using meta-analysis, then analyzed with a gene-based test to estimate the combined effect of markers within genes. We compare our results with markers that have previously been found to have a strong association with ADHD symptoms. Neither the GWAS nor subsequent meta-analyses yielded genome-wide significant results; the strongest effect was observed at rs2110267 (4.62 × 10-7) for symptoms of hyperactivity-impulsivity. The strongest effect in the gene-based test was for GPR139 on symptoms of inattention (6.40 × 10-5). Replication of this study with larger samples will add to our understanding of the genetic etiology of ADHD.

Genetic and Environmental Influences on Inattention, Hyperactivity-Impulsivity, and Reading: Kindergarten to Grade 2.

Twin children from Australia, Scandinavia and the USA were assessed for inattention, hyperactivity-impulsivity and reading across the first three school years. Univariate behavior-genetic analyses indicated substantial heritability for all three variables in all years. Longitudinal analyses showed one genetic source operating across the time span and a second entering in the second school year for each variable, though possibly not reliable for inattention. Other analyses confirmed previous findings of pleiotropy (shared genes) between inattention and reading, and showed that this genetic overlap is in place from kindergarten onwards and is restricted to one of the genetic sources that affect reading and inattention. The results extend previous conclusions about the developmental trajectories of inattention, hyperactivity-impulsivity, and reading and their relationships. Limitations of this studyare discussed, as are educational implications.

The genetic epidemiology of substance use disorder: A review.

BACKGROUND: Substance use disorder (SUD) remains a significant public health issue. A greater understanding of how genes and environment interact to regulate phenotypes comprising SUD will facilitate directed treatments and prevention. METHODS: The literature studying the neurobiological correlates of SUD with a focus on the genetic and environmental influences underlying these mechanisms was reviewed. Results from twin/family, human genetic association, gene-environment interaction, epigenetic literature, phenome-wide association studies are summarized for alcohol, nicotine, cannabinoids, cocaine, and opioids. RESULTS: There are substantial genetic influences on SUD that are expected to influence multiple neurotransmission pathways, and these influences are particularly important within the dopaminergic system. Genetic influences involved in other aspects of SUD etiology including drug processing and metabolism are also identified. Studies of gene-environment interaction emphasize the importance of environmental context in SUD. Epigenetic studies indicate drug-specific changes in gene expression as well as differences in gene expression related to the use of multiple substances. Further, gene expression is expected to differ by stage of SUD such as substance initiation versus chronic substance use. While a substantial literature has developed for alcohol and nicotine use disorders, there is comparatively less information for other commonly abused substances. CONCLUSIONS: A better understanding of genetically-mediated mechanisms involved in the neurobiology of SUD provides increased opportunity to develop behavioral and biologically based treatment and prevention of SUD.

Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention.

Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity.

Variation in Latent Classes of Adult Attention-Deficit Hyperactivity Disorder by Sex and Environmental Adversity.

OBJECTIVE: The findings of genetic, imaging and neuropsychological studies of attention-deficit hyperactivity disorder (ADHD) are mixed. To understand why this might be the case we use both dimensional and categorical symptom measurement to provide alternate and detailed perspectives of symptom expression. METHOD: Interviewers collected ADHD, conduct problems (CP) and sociodemographic data from 3793 twins and their siblings aged 22 to 49 (M = 32.6). We estimate linear weighting of symptoms across ADHD and CP items. Latent class analyses and regression describe associations between measured variables, environmental risk factors and subsequent disadvantage. Additionally, the clinical relevance of each class was estimated. RESULTS: Five classes were found for women and men; few symptoms, hyperactive-impulsive, CP, inattentive, combined symptoms with CP. Women within the inattentive class reported more symptoms and reduced emotional health when compared to men and to women within other latent classes. Women and men with combined ADHD symptoms reported comorbid conduct problems but those with either inattention or hyperactivity-impulsivity only did not. CONCLUSION: The dual perspective of dimensional and categorical measurement of ADHD provides important detail about symptom variation across sex and with environmental covariates.

Head Motion and Inattention/Hyperactivity Share Common Genetic Influences: Implications for fMRI Studies of ADHD.

Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity.

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts.

OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.

Attention deficit hyperactivity disorder in Australian adults: prevalence, persistence, conduct problems and disadvantage.

BACKGROUND: The Prevalence and persistence of ADHD have not been described in young Australian adults and few studies have examined how conduct problems (CP) are associated with ADHD for this age group. We estimate lifetime and adult prevalence and persistence rates for three categories of ADHD for 3795 Australian adults, and indicate how career, health and childhood risk factors differ for people with ADHD symptoms and ADHD symptoms plus CP. METHODOLOGY: Trained interviewers collected participant experience of ADHD, CP, education, employment, childhood experience, relationship and health variables. Three diagnostic definitions of ADHD used were (i) full DSM-IV criteria; (ii) excluding the age 7 onset criterion (no age criterion); (iii) participant experienced difficulties due to ADHD symptoms (problem symptoms). RESULTS: Prevalence rates in adulthood were 1.1%, 2.3% and 2.7% for each categorization respectively. Persistence of ADHD from childhood averaged across gender was 55.3% for full criteria, 50.3% with no age criterion and 40.2% for problem symptoms. ADHD symptoms were associated with parental conflict, poor health, being sexually assaulted during childhood, lower education, income loss and higher unemployment. The lifetime prevalence of conduct problems for adults with ADHD was 57.8% and 6.9% for adults without ADHD. The greatest disadvantage was experienced by participants with ADHD plus CP. CONCLUSION: The persistence of ADHD into adulthood was greatest for participants meeting full diagnostic criteria and inattention was associated with the greatest loss of income and disadvantage. The disadvantage associated with conduct problems differed in severity and was relevant for a high proportion of adults with ADHD. Women but not men with ADHD reported more childhood adversity, possibly indicating varied etiology and treatment needs. The impact and treatment needs of adults with ADHD and CP and the report of sexual assault during childhood by women and men with ADHD also deserve further study.