Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a highly disruptive childhood-onset disorder that often persists into adolescence and adulthood. Comorbidity with other problems, such as autism, dyslexia and conduct disorder (CD) is very common. Although little is known about the pathophysiology of ADHD, family, twin and adoption studies have shown that it is highly heritable. Whole genome linkage studies suggest there are no common susceptibility genes of moderate effect size. Most published research has been based on functional candidate gene studies. The most consistent evidence for association with ADHD relates to a dopamine D4 receptor (DRD4) gene variable number tandem repeat (VNTR), a dopamine D5 receptor (DRD5) gene microsatellite and a dopamine transporter (DAT1) gene VNTR. In addition, the catechol-O-methyltransferase (COMT) val158/108 met variant has been shown to increase risk for associated antisocial behavior. The first genome-wide association studies (GWAS) of ADHD have been completed and although larger studies are still required to detect common risk variants, novel risk pathways are being suggested for ADHD. Further research on the contribution of rare variants, larger genome-wide association and sequencing studies and ADHD phenotype refinement is now needed

Role of the Y chromosome in sex differences in ADHD and schizophrenia

ADHD and schizophrenia are neurodevelopmental disorders that are more prevalent in males and show sex differences in age of onset or severity. The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. The way the Y chromosome could increase risk to neuropsychiatric disorders is directly or indirectly by interacting with autosomal genes expressed in the brain. In addition, it could modify the disease phenotype. However, due to difficulties arising from the lack of recombination and widely accepted nomenclature, the Y chromosome has been largely excluded from genetic and genomic studies of neuropsychiatric disorders. To overcome this lack of knowledge, 9 Y chromosome markers were selected to represent the main Y chromosome haplogroups that are present in the U.K. and they were genotyped in a sample of 210 cases with ADHD, 313 cases with schizophrenia and 637 U.K. controls. Statistical analysis of Y chromosome haplogroups revealed that although there was no significantly increased representation of any haplogroup in cases with ADHD or schizophrenia compared to controls, there was evidence of a possible modifying effect on the phenotype of ADHD and schizophrenia. Y chromosome haplogroup 3 was associated with higher performance and full scale IQ within the sample of patients with ADHD. Haplogroup 1 was associated with better outcome and higher educational level within the sample of patients with schizophrenia. There was no association of Y chromosome haplogroups with IQ in a population sample of 3,749 individuals. Y chromosome haplogroups were also tested for interaction with tyrosine hydroxylase SNPs because animal studies suggest this is biologically plausible. Although there was no evidence of interaction, three tyrosine hydroxylase SNPs showed nominally significant association in the sample of male patients with schizophrenia. This study is one of the largest Y chromosome studies in the UK. It suggests that although Y chromosome variation does not appear to be associated with ADHD or schizophrenia, it may modify cognitive performance and clinical features

Genetic liability to rheumatoid arthritis on autism and autistic traits:polygenic risk score and mendelian randomization analyses

Higher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73–1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88–1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98–1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism

Assessment of age-at-onset criterion for adult attention-deficit hyperactivity disorder

To investigate the accuracy of the age-at-onset criterion in those who meet other DSM-5 ADHD criteria (N=138), using a prospective population cohort, we compared four different approaches to asking those at age 25 years when their symptoms started. Receiver Operating Characteristic curves showed variation between the approaches (χ((3)))=8.99, p=0.03); all four showed low discrimination against symptoms that had been assessed when they were children (area under the curve 0.57-0.68). Asking adults to recall specific symptoms may be preferable to recalling at what age symptoms started. However limitations to retrospective recall add to debate on the validity of ADHD age-at-onset assessment

Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness

Investigating attention-deficit hyperactivity disorder and autism spectrum disorder traits in the general population:What happens in adult life?

Background. ADHD and ASD are generally considered early-onset disorders so most research has therefore tended to focus on children. Differences between ADHD/ASD in adult life and childhood have been noted, but few population-based studies have examined them in adulthood. Furthermore, interpretation of findings is hampered by changes in measure and from parent- to self-report. Method. We examined continuous/trait measures of parent- and self-rated ADHD and ASD) in adulthood (age 25 years) in a UK prospective longitudinal sample ALPSAC (the Avon Longitudinal Study of Parents and Children), using many of the same measures that parents reported on in childhood (N=6,064). Our aim was to investigate these traits in this population for mean-level sex differences, overlaps with other cognitive, learning and communication problems and their associations with polygenic risk scores (PRS) for neuropsychiatric disorders (ADHD, ASD, schizophrenia, depression and anxiety). Results. ADHD and ASD traits in adulthood, as in childhood, showed associations with childhood cognitive, learning and communication problems and with adult communication/language measures, although less so for self- than parent-ratings. Males had higher ADHD and ASD trait levels, but this was not as marked as in childhood. In adulthood, ADHD (both parent and self -rated) and ASD (parent-rated) symptoms showed associations with ADHD PRS; self-reported ADHD also showed association with depression PRS and self-reported ASD did not show strong PRS associations. Conclusions. Our findings suggest that in young adults, ADHD and ASD symptoms have similar characteristics as they do in in childhood. Associations with other cognitive, learning and communication problems, and with ADHD PRS, were somewhat less pronounced for self-reported adult ADHD and ASD symptoms, sugges

ADHD and depression:investigating a causal explanation

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods. METHODS: First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18–25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data. RESULTS: Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05–1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12–1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02–1.13). CONCLUSIONS: Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression

Co-development of attention deficit hyperactivity disorder and autistic trait trajectories from childhood to early adulthood

Background: Attention deficit hyperactivity disorder (ADHD) and autism, defined as traits or disorders, commonly co-occur. Developmental trajectories of ADHD and autistic traits both show heterogeneity in onset and course, but little is known about how symptom trajectories co-develop into adulthood. Methods: Using data from a population cohort, the Avon Longitudinal Study of Parents and Children, we examined correlations between ADHD and autistic traits across development, using the Social Communication Disorders Checklist and ADHD subscale of the Strengths and Difficulties Questionnaire. We modelled joint developmental trajectories of parent-reported ADHD and autistic traits between 4 and 25 years, then characterised trajectory classes based on sociodemographic, perinatal, psychopathology, cognition and social functioning variables and tested for associations with neurodevelopmental/ psychiatric polygenic scores (PGS). Results: Three classes of trajectories were identified; a typically developing majority with low-stable ADHD-autistic traits (87%), a male-predominant subgroup with child/adolescent-declining traits (6%) and a subgroup with late-emerging traits (6%). ADHD-autistic trait correlations were greatest in young adulthood for the two nontypically developing classes. There were higher rates of emotional and conduct problems, low IQ, childhood seizures and poor social functioning in the declining and late-emerging classes compared to the low-stable class. Emotional, conduct and peer problems were more prevalent during childhood in the childhood/ adolescent-declining class compared to other classes, but were more prevalent in young adulthood in the late�emerging class. Neurodevelopmental/psychiatric PGS also differed: both nontypically developing classes showed elevated ADHD PGS compared to the low-stable group, and the late-emerging group additionally showed elevated schizophrenia PGS and decreased executive function PGS, whereas the declining group showed elevated broad depression PGS. Conclusions: Distinct patterns of ADHD-autism co-development are present across development in the general population, each with different characterising factors and genetic signatures as indexed by PG