ABSTRACT
Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.
Methods: Children born in Denmark between 1995–2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10–18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward–treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5.
Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55–1.66) in males (HR = 1.59; 1.53–1.65) and females (HR = 1.65; 1.54–1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00–1.14), with a genetic correlation of 0.53 (0.21–0.85).
Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.
Continue Reading...
Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.
References (72)
- Sonuga-Barke EJ, Daley D, Thompson M, et al. Preschool ADHD: exploring uncertainties in diagnostic validity and utility, and treatment efficacy and safety. Expert Rev Neurother. 2003;3(4):465–476. PubMed CrossRef
- Dal Santo JA, Goodman RM, Glik D, et al. Childhood unintentional injuries: factors predicting injury risk among preschoolers. J Pediatr Psychol. 2004;29(4):273–283. PubMed CrossRef
- Bourguet CC, McArtor RE. Unintentional injuries: risk factors in preschool children. Am J Dis Child. 1989;143(5):556–559. PubMed CrossRef
- Ribeiro MGC, Paula ABR, Bezerra MAR, et al. Social determinants of health associated with childhood accidents at home: an integrative review. Rev Bras Enferm. 2019;72(1):265–276. PubMed CrossRef
- Seidman LJ, Biederman J, Monuteaux MC, et al. Impact of gender and age on executive functioning: do girls and boys with and without attention deficit hyperactivity disorder differ neuropsychologically in preteen and teenage years? Dev Neuropsychol. 2005;27(1):79–105. PubMed CrossRef
- Garzon DL. Contributing factors to preschool unintentional injury. J Pediatr Nurs. 2005;20(6):441–447. PubMed CrossRef
- Klein D. Some applications of delinquency theory to childhood accidents. Pediatrics. 1969;44(5):805–810. PubMed
- Matheny AP Jr. Injuries among toddlers: contributions from child, mother, and family. J Pediatr Psychol. 1986;11(2):163–176. PubMed CrossRef
- Langley J, McGee R, Silva P, et al. Child behavior and accidents. J Pediatr Psychol. 1983;8(2):181–189. PubMed CrossRef
- Speltz ML, Gonzales N, Sulzbacher S, et al. Assessment of injury risk in young children: a preliminary study of the Injury Behavior Checklist. J Pediatr Psychol. 1990;15(3):373–383. PubMed CrossRef
- Piazza-Waggoner C, Dotson C, Adams CD, et al. Preinjury behavioral and emotional problems among pediatric burn patients. J Burn Care Rehabil. 2005;26(4):371–378, discussion 369–370. PubMed CrossRef
- Dalsgaard S, Nielsen HS, Simonsen M. Consequences of ADHD medication use for children’s outcomes. J Health Econ. 2014;37:137–151. PubMed CrossRef
- Dalsgaard S, Leckman JF, Mortensen PB, et al. Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study. Lancet Psychiatry. 2015;2(8):702–709. PubMed CrossRef
- Lindemann C, Langner I, Banaschewski T, et al. The risk of hospitalizations with injury diagnoses in a matched cohort of children and adolescents with and without attention deficit/hyperactivity disorder in Germany: a database study. Front Pediatr. 2017;5:220. PubMed CrossRef
- Ruiz-Goikoetxea M, Cortese S, Aznarez-Sanado M, et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2018;84:63–71. PubMed CrossRef
- Adeyemo BO, Biederman J, Zafonte R, et al. Mild traumatic brain injury and ADHD: a systematic review of the literature and meta-analysis. J Atten Disord. 2014;18(7):576–584. PubMed CrossRef
- Chang HK, Hsu JW, Wu JC, et al. Traumatic brain injury in early childhood and risk of attention-deficit/hyperactivity disorder and autism spectrum disorder: a nationwide longitudinal study. J Clin Psychiatry. 2018;79(6):17m11857. PubMed CrossRef
- Stojanovski S, Felsky D, Viviano JD, et al. Polygenic risk and neural substrates of attention-deficit/hyperactivity disorder symptoms in youths with a history of mild traumatic brain injury. Biol Psychiatry. 2019;85(5):408–416. PubMed CrossRef
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition. American Psychiatric Publishing; 2013.
- Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562–575. PubMed CrossRef
- Stergiakouli E, Martin J, Hamshere ML, et al. Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) traits in children and clinical ADHD. J Am Acad Child Adolesc Psychiatry. 2015;54(4):322–327. PubMed CrossRef
- Riglin L, Collishaw S, Thapar AK, et al. Association of genetic risk variants with attention-deficit/hyperactivity disorder trajectories in the general population. JAMA Psychiatry. 2016;73(12):1285–1292. PubMed CrossRef
- Martin J, Hamshere ML, Stergiakouli E, et al. Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population. Biol Psychiatry. 2014;76(8):664–671. PubMed CrossRef
- Demontis D, Walters RK, Martin J, et al; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research Team. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019;51(1):63–75. PubMed CrossRef
- Lyngsøe BK, Munk-Olsen T, Vestergaard CH, et al. Maternal depression and childhood injury risk: a population-based cohort study in Denmark. Brain Behav. 2021;11(3):e02029. PubMed
- Ordoñana JR, Caspi A, Moffitt TE. Unintentional injuries in a twin study of preschool children: environmental, not genetic, risk factors. J Pediatr Psychol. 2008;33(2):185–194. PubMed CrossRef
- Salminen S, Vuoksimaa E, Rose RJ, et al. Age, sex, and genetic and environmental effects on unintentional injuries in young and adult twins. Twin Res Hum Genet. 2018;21(6):502–506. PubMed CrossRef
- Acar E, Dursun OB, Esin IS, et al. Unintentional injuries in preschool age children: is there a correlation with parenting style and parental attention deficit and hyperactivity symptoms. Medicine (Baltimore). 2015;94(32):e1378. PubMed CrossRef
- Pedersen CB, Gøtzsche H, Møller JØ, et al. The Danish Civil Registration System: a cohort of eight million persons. Dan Med Bull. 2006;53(4):441–449. PubMed
- Schmidt M, Schmidt SA, Sandegaard JL, et al. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–490. PubMed CrossRef
- Mors O, Perto GP, Mortensen PB. The Danish Psychiatric Central Research Register. Scand J Public Health. 2011;39(suppl):54–57. PubMed CrossRef
- World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization; 1992.
- Pedersen CB, Bybjerg-Grauholm J, Pedersen MG, et al. The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders. Mol Psychiatry. 2018;23(1):6–14. PubMed CrossRef
- Privé F, Luu K, Blum MGB, et al. Efficient toolkit implementing best practices for principal component analysis of population genetic data. Bioinformatics. 2020;36(16):4449–4457. PubMed CrossRef
- Loh PR, Bhatia G, Gusev A, et al; Schizophrenia Working Group of Psychiatric Genomics Consortium. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat Genet. 2015;47(12):1385–1392. PubMed CrossRef
- Debost JC, Larsen JT, Munk-Olsen T, et al. Childhood infections and schizophrenia: the impact of parental SES and mental illness, and childhood adversities. Brain Behav Immun. 2019;81:341–347. PubMed CrossRef
- Vilhjálmsson BJ, Yang J, Finucane HK, et al; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study. Modeling linkage disequilibrium increases accuracy of polygenic risk scores. Am J Hum Genet. 2015;97(4):576–592. PubMed CrossRef
- Loh PR, Tucker G, Bulik-Sullivan BK, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47(3):284–290. PubMed CrossRef
- Albiñana C, Grove J, McGrath JJ, et al. Leveraging both individual-level genetic data and GWAS summary statistics increases polygenic prediction. Am J Hum Genet. 2021;108(6):1001–1011. PubMed CrossRef
- Borgan O, Langholz B, Samuelsen SO, et al. Exposure stratified case-cohort designs. Lifetime Data Anal. 2000;6(1):39–58. PubMed CrossRef
- Lee SH, Goddard ME, Wray NR, et al. A better coefficient of determination for genetic profile analysis. Genet Epidemiol. 2012;36(3):214–224. PubMed CrossRef
- Stata Statistical Software: Release 14. StataCorp; 2016.
- R Development Core Team. R: A Language and Environment for Statistical Programming. R Foundation for Statistical Consulting; 2010.
- Mortensen PB. Response to “Ethical concerns regarding Danish genetic research.” Mol Psychiatry. 2019;24(11):1574–1575. PubMed CrossRef
- Nørgaard-Pedersen B, Hougaard DM. Storage policies and use of the Danish Newborn Screening Biobank. J Inherit Metab Dis. 2007;30(4):530–536. PubMed CrossRef
- Nikolas MA, Elmore AL, Franzen L, et al. Risky bicycling behavior among youth with and without attention-deficit hyperactivity disorder. J Child Psychol Psychiatry. 2016;57(2):141–148. PubMed CrossRef
- Chang Z, Lichtenstein P, D’Onofrio BM, et al. Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study. JAMA Psychiatry. 2014;71(3):319–325. PubMed CrossRef
- Dalsgaard S, Østergaard SD, Leckman JF, et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet. 2015;385(9983):2190–2196. PubMed CrossRef
- Sun S, Kuja-Halkola R, Faraone SV, et al. Association of psychiatric comorbidity with the risk of premature death among children and adults with attention-deficit/hyperactivity disorder. JAMA Psychiatry. 2019;76(11):1141–1149. PubMed CrossRef
- Anttila V, Bulik-Sullivan B, Finucane HK, et al; Brainstorm Consortium. Analysis of shared heritability in common disorders of the brain. Science. 2018;360(6395):eaap8757. PubMed
- Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179(7):1469–1482.e11. PubMed CrossRef
- Nevriana A, Pierce M, Dalman C, et al. Association between maternal and paternal mental illness and risk of injuries in children and adolescents: nationwide register based cohort study in Sweden. BMJ. 2020;369:m853. PubMed CrossRef
- McCoy BM, Rickert ME, Class QA, et al. Mediators of the association between parental severe mental illness and offspring neurodevelopmental problems. Ann Epidemiol. 2014;24(9):629–634.e1. PubMed CrossRef
- Sideri S, Marcenes W, Stansfeld SA, et al. Family environment and traumatic dental injuries in adolescents. Dent Traumatol. 2018;34(6):438–444. PubMed CrossRef
- Keilow M, Wu C, Obel C. Cumulative social disadvantage and risk of attention deficit hyperactivity disorder: results from a nationwide cohort study. SSM Popul Health. 2020;10:100548. PubMed CrossRef
- Østergaard SD, Dalsgaard S, Faraone SV, et al. Teenage parenthood and birth rates for individuals with and without attention-deficit/hyperactivity disorder: a nationwide cohort study. J Am Acad Child Adolesc Psychiatry. 2017;56(7):578–584.e3. PubMed CrossRef
- Harold GT, Leve LD, Barrett D, et al. Biological and rearing mother influences on child ADHD symptoms: revisiting the developmental interface between nature and nurture. J Child Psychol Psychiatry. 2013;54(10):1038–1046. PubMed CrossRef
- Stern A, Agnew-Blais J, Danese A, et al. Associations between abuse/neglect and ADHD from childhood to young adulthood: a prospective nationally-representative twin study. Child Abuse Negl. 2018;81:274–285. PubMed CrossRef
- Østergaard SD, Trabjerg BB, Als TD, et al. Polygenic risk score, psychosocial environment and the risk of attention-deficit/hyperactivity disorder. Transl Psychiatry. 2020;10(1):335. PubMed CrossRef
- Greenwood M, Woods HM. The Incidence of Industrial Accidents Upon Individuals, With Special Reference to Multiple Accidents. Her Majesty’s Stationery Office. Industrial Fatigue Research Board; 1919.
- Farmer E, Chambers EG. A Psychological Study of Individual Differences in Accident Rates. H. M. Stationery Office; 1926.
- Marbe K. Praktische Psychologie der Unfälle und Betriebsschäden. Oldenbourg; 1926.
- Newbold EM. A Contribution to the Study of the Human Factor in the Causation of Accidents. H.M.S.O.; 1926.
- Bakwin RM, Bakwin H. Accident proneness. J Pediatr. 1948;32(6):749–752. PubMed CrossRef
- Dalsgaard-Nielsen T, Dirksen H. Head injury and accident-proneness (somato-psychic causes of such injuries). Acta Psychiatr Neurol Scand. 1954;29(1):28–30. PubMed CrossRef
- Partington MW. The importance of accident-proneness in the aetiology of head injuries in childhood. Arch Dis Child. 1960;35(181):215–223. PubMed CrossRef
- Dunbar F. Psychosomatic Diagnosis. Paul B. Hoeber, Inc.; 1943:172–247.
- Froggatt P, Smiley JA. The concept of accident proneness: a review. Br J Ind Med. 1964;21(1):1–12. PubMed CrossRef
- McKenna FP. Accident proneness: a conceptual analysis. Accid Anal Prev. 1983;15(1):65–71. CrossRef
- Sundhedsstyrrelsen [Danish Health Authority], National Klinisk Retningslinje for Udredning og Behandling af ADHD Hos Børn og Unge [National Clinical Guideline for Assessment and Treatment of ADHD in Children and Adolescents]. 2018; v3.1. December 2018. https://www.sst.dk/-/media/Udgivelser/2018/National-Klinisk-Retningslinje-Udredning-og-behandling-af-ADHD-hos-boern-og-unge
- Mohr-Jensen C, Vinkel Koch S, Briciet Lauritsen M, et al. The validity and reliability of the diagnosis of hyperkinetic disorders in the Danish Psychiatric Central Research Registry. Eur Psychiatry. 2016;35:16–24. PubMed CrossRef
- Weissbrod O, Flint J, Rosset S. Estimating SNP-based heritability and genetic correlation in case-control studies directly and with summary statistics. Am J Hum Genet. 2018;103(1):89–99. PubMed CrossRef
Members enjoy free PDF downloads on all articles.
Save
Cite
Already a member? Login
Advertisement
GAM ID: sidebar-top