The online version of this article (doi:10.1186/s13229-017-0131-2) contains supplementary material, which is available to authorized users.
Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk.
Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data.
In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait r g ≤ 1, p min = 3 × 10−4) as those between repeated measures of the same trait (within-trait r g ≤ 0.94, p min = 7 × 10−4). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (p-meta = 6.4 × 10−4).
Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R 2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder.
In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
Additional file 1: Additional note. Selection of SDQ-ADHD measures. Additional note. Meta-analysis of correlated test statistics from pathway analysis. Additional note. Additional references. Additional note. Web resources. Table S1. Descriptives of SDQ-ADHD and SCDC scores in ALSPAC. Table S2. Phenotypic correlations of SDQ-ADHD scores in ALSPAC. Table S3. Phenotypic correlations of SCDC scores in ALSPAC. Table S4. Univariate GREML of SDQ-ADHD scores in ALSPAC. Table S5. Univariate GREML of SCDC scores in ALSPAC. Table S6. Bivariate GREML of SDQ-ADHD scores in ALSPAC. Table S7. Bivariate GREML of SCDC scores in ALSPAC. Table S8. Bivariate GREML and Pearson correlations of SDQ-ADHD and SCDC scores in ALSPAC. Table S10. Association between ADHD polygenic scores and SDQ-ADHD scores in ALSPAC. Table S11. Association between ASD polygenic scores and SDQ-ADHD scores in ALSPAC. Table S12. Association between ADHD polygenic scores and SCDC scores in ALSPAC. (DOCX 92 kb)13229_2017_131_MOESM1_ESM.docx
Additional file 2: Table S9. Pathway-based dissection of additive genetic variance in SDQ-ADHD and SCDC scores according to 50 molecular signatures database hallmark gene set collections. (XLSX 20 kb)13229_2017_131_MOESM2_ESM.xlsx
Nijmeijer JS, Hoekstra PJ, Minderaa RB, Buitelaar JK, Altink ME, Buschgens CJM, et al. PDD symptoms in ADHD, an independent familial trait? J Abnorm Child Psychol. 2008;37:443–53. CrossRef
Reiersen AM, Constantino JN, Grimmer M, Martin NG, Todd RD. Evidence for shared genetic influences on self-reported ADHD and autistic symptoms in young adult Australian twins. Twin Res Hum Genet Off J Int Soc Twin Stud. 2008;11:579–85. CrossRef
Hartman CA, Geurts HM, Franke B, Buitelaar JK, Rommelse NNJ. Changing ASD-ADHD symptom co-occurrence across the lifespan with adolescence as crucial time window: illustrating the need to go beyond childhood. Neurosci Biobehav Rev. 2016; doi: 10.1016/j.neubiorev.2016.09.003.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association Publishing; 1994.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association Publishing; 2013. CrossRef
Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators, Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders. Morb Mortal Wkly Rep Surveill Summ Wash DC 2002. 2012;61:1–19.
Plomin R, Haworth CMA, Davis OSP. Common disorders are quantitative traits. Nat Rev Genet. 2010;10:872. CrossRef
Robinson EB, St Pourcain B, Anttila V, Kosmicki JA, Bulik-Sullivan B, Grove J, et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet. 2016;advance online publication: doi: 10.1038/ng.3529.
Ronald A, Edelson LR, Asherson P, Saudino KJ. Exploring the relationship between autistic-like traits and ADHD behaviors in early childhood: findings from a community twin study of 2-year-olds. J Abnorm Child Psychol. 2009;38:185–96. CrossRef
Bristol U of. Bristol University | Avon Longitudinal Study of Parents and Children | Access the resource [Internet]. [cited 2016 Jun 7]. Available from: http://www.bristol.ac.uk/alspac/researchers/access/
St Pourcain B, Robinson EB, Anttila V, Bulik-Sullivan B, Maller J, Golding J, et al. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties. Mol Psychiatry. 2017. doi: 10.1038/mp.2016.198.
Falconer PDS, Mackay PTFC. Introduction to quantitative genetics. 4th ed. Essex, England: Longman; 1995.
Lajeunesse MJ. Meta‐analysis and the comparative phylogenetic method. Am Nat. 2009;174:369–81. PubMed
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52. PubMed
Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol. 2013;4:133–42. CrossRef
Janssens MJJ. Co-heritability: its relation to correlated response, linkage, and pleiotropy in cases of polygenic inheritance. Euphytica. 1979;28:601–8. CrossRef
Wolke D, Waylen A, Samara M, Steer C, Goodman R, Ford T, et al. Selective drop-out in longitudinal studies and non-biased prediction of behaviour disorders. Br J Psychiatry J Ment Sci. 2009;195:249–56. CrossRef
Martin J, Tilling K, Hubbard L, Stergiakouli E, Thapar A, Smith GD, et al. Association of genetic risk for schizophrenia with nonparticipation over time in a population-based cohort study. Am J Epidemiol 2016; doi: 10.1093/aje/kww009.
- Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development
George Davey Smith
David H. Skuse
Susan M. Ring
David E. Evans
Simon E. Fisher
Beate St Pourcain
- BioMed Central