Neurodevelopmental disorders (NDDs) are a serious and complex health concern, starting from childhood1. NDDs affect around 15% of children and adolescents worldwide and lead to impaired cognition, communication, adaptive behavior, and psychomotor skills2. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) categorizes the following seven disorders under NDDs: intellectual disabilities, communication disorders, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), specific learning disorders, motor disorders and other neurodevelopmental disorders3.NDDs often have lifelong trajectories: they can manifest as early as before the child reaches 12 months of age4 and can be identified and diagnosed before children enter primary education5,3. While some NDDs (e.g. ASD and ADHD) may persist throughout adolescence and adulthood6,7, others are more likely to alleviate as children get older (e.g., tic disorder8 and communication disorders9); nevertheless, all NDDs can lead to social and behavioural difficulties and reduced, or even a lack of, independence over the lifespan6,7.
A systematic understanding of the aetiology of NDDs remains incomplete. A disproportionate number of studies, reviews, and syntheses of extant literature have focused on ASD and ADHD. However, other neurodevelopmental conditions, despite showing similar prevalence rates and severity as ASD and ADHD, are less well understood and studied10. The focus on ASD and ADHD has resulted in several studies that have systematically synthesized the literature on the aetiology of these two NDDs, pointing to their substantial heritability– the extent to which observed individual differences are accounted for by underlying genetic differences.
A meta-analysis of 7 twin studies of clinically diagnosed ASD in childhood and adolescent samples (aged 2 to 23 years) yielded a grand heritability estimate of 0.74 (95% CIs = 0.70, 0.87)11. Similarly sizeable heritability estimates also emerged from a meta-analysis of 26 studies of ADHD in childhood and adolescence, which yielded a pooled estimate for additive genetic effects –independent effects of genetic variants– of 0.26 (95% CIs = 0.20, 0.32) and a pooled estimate for dominant genetic effects – interactive effects between genetic variants at one more loci– of 0.44 (95% CIs = 0.38, 0.51)12. A subsequent systematic review of 37 twin studies of ADHD, including studies that had adopted either categorical or dimensional measures, yielded a mean h2 of 0.7413. Heritability estimates were found to differ across the two major components of ADHD, with genetic factors playing a more substantial role in the aetiology of hyperactivity (h2 = 0.71, 95% CIs = 0.63, 0.75; based on 9 studies), if compared inattention (h2 = 0.56, 95% CIs = 0.48, 0.63; based on 13 studies)14.
In line with what observed for all complex traits, heritability estimates for ASD and ADHD obtained from DNA data are lower than those obtained from twin and family designs15, likely due, at least in part, to the additive models used to calculate heritability from single nucleotide polymorphism (SNP)16. SNP heritability can be calculated using large samples of individual-level genotype data17 or summary statistics from genome-wide association studies (GWAS)18, hypothesis-free studies aimed at discovering associations between genetic variation across the genome and individual differences in traits and disorders. The two largest studies to date that have estimated the SNP heritability of ASD and ADHD have applied linkage disequilibrium score (LDSC) regression to GWAS summary statistics18 and report estimates of 0.12 (SE = 0.01) for ASD19 and 0.22 (SE = 0.01) for ADHD20.
It is now well-established that NDDs often co-occur with one another, a phenomenon known as homotypic co-occurrence, and this points to a shared underlying liability between conditions21,22. Even in this instance, most genetic investigations have focused on examining the genetic correlations (i.e., the degree to which the same genetic variants contribute to the observed covariation between pairs of traits or disorders23) between ASD and ADHD, which were found to be strongly phenotypically correlated (0.54)24. Knowledge on the co-occurrence between ASD and ADHD has been synthesized by a meta-analysis of 11 twin studies that yielded a grand genetic correlation estimate of 0.59 (95% CIs = 0.49, 0.69)25. Aetiological sources of co-occurrence between the several remaining NDD categories have not been meta-analysed, nor has been the proportion of genetic variants shared between NDDs (SNP-based genetic correlation). The SNP-based genetic overlap between ASD and ADHD, based on summary-level data obtained from the largest GWAS meta-analyses to date has been estimated at 0.35 (SE = 0.01)26 in adult samples.
Individual studies point to a moderate to strong shared liability between ASD/ADHD and other NDDs. ASD and specific learning disorders were found to co-occur in 34% of children and their genetic correlation has been estimated at 0.70 (95% CIs = 0.63, 0.73)27. ADHD and specific learning disorders were found to co-occur in 16% of cases27 and their genetic correlation to range between 0.25 (95% CIs= -1, 1)27 to 0.60 (95% CIs = 0.52, 0.68)28. Genetic overlap has also been investigated between ASD/ADHD and motor disorders, with greater rates of co-occurrence for ADHD (50%)29 if compared to ASD (34%)30. For ADHD the genetic correlations ranged between 0.42 (95% CIs = 0.36, 0.48)31 with developmental coordination disorder to 0.99 (95% CIs = 0.81, 1) with tic disorder27. Genetic correlations were found to be strong between ASD and developmental coordination disorder (0.71, 95% CIs = 0.51, 0.91) and between ASD with tic disorder (0.60, 95% CIs = 0.42, 0.78)27. ASD was found to co-occur to a lesser extent with communication disorders, as indexed by weak phenotypic (a mean of -0.15 across language measures)32 and weak to moderate genetic correlations (ranging between − 0. 18, 95% CIs= -0.32-0.0432 to 0.33, 95% CIs = 0.31, 0.35)33.
Another category of disorders that onset and progress through childhood and adolescence are Disruptive, Impulse Control and Conduct Disorders (DICCs), which the DSM-5 describes as disorders that share the underlying features of impulsive behavior, aggressiveness, and pathological rule breaking3. The DSM-5 identifies eight main DICC categories: Oppositional Defiant Disorder, Intermittent Explosive Disorder, Conduct Disorder, Antisocial Personality Disorder, Pyromania, Kleptomania, Other Specified DICC Disorder, and Unspecified DICC Disorders3 (Fig. 1). The developmental nature of DICCs makes them an ideal primary target for the investigation of how NDDs co-occur with other disorders (i.e., heterotypic co-occurrence) during childhood and adolescence. However, the distinction between NDDs and DICCs in the published literature is often unclear, particularly for disorders that include clinical features that overlap with both NDD and DICC categories, such as ADHD. This lack of a clear-cut distinction is exemplified by the different classifications of ADHD across the iterations of the DSM, which transitioned from being included under the Attention-deficit and Disruptive Behaviour Disorders category (DSM-III-R)34, to Disorders Usually Diagnosed in Infancy, Childhood, and Adolescence (DSM-IV)35, to its current classification under the Neurodevelopmental Disorders category (DSM-5)3.
The most investigated example of symptom overlap between NDDs and DICCs involve ADHD and conduct disorder36,37, and ADHD and oppositional defiant disorder38. Studies reporting on the behavioural and cognitive profiles of ADHD and these disorders highlight how both disorders are characterised by disturbances in emotion regulation, attention problems, cognitive inflexibility, executive functioning, and impaired inhibition37,39,40. A shared symptomatology has also been observed between ASD and antisocial behaviour/personality disorder (that we refer to as conduct disorder in the current work due to antisocial personality disorder referring to adult diagnosis)3,41,42, with both disorders characterized by impairments in social reciprocity, expressing emotions and affective empathy43,44. Symptom resemblance that characterizes these disorder pairs is reflected in the phenotypic correlations between ADHD and conduct disorder (0.40)38 and between ADHD and oppositional defiant disorder (0.55)38, but not ASD and conduct disorder traits, for which the phenotypic correlation is modest (0.22 between social impairments and callous-unemotional traits and 0.21 between communication impairments and callous-unemotional traits)45.
Individual studies on the association between NDDs and DICCs are characterized by a great deal of heterogeneity and inconsistencies across co-occurring conditions. For example, one study found that, in a sample of 7-year-olds, genetic effects on ASD and callous-unemotional traits, one of the manifestations of conduct disorder in childhood and of antisocial personality disorder in adulthood, were largely independent, as indicated by small to moderate genetic correlations (0.23 (95% CIs = 0.16, 0.31) between the communication impairments domain of ASD and callous-unemotional traits, and 0.31 (95% CIs = 0.26, 0.36) between the social interaction impairments domain of ASD and callous-unemotional traits)45. Another study reported moderate genetic overlap of 0.43 (95% CIs = 0.34, 0.52) between ASD and psychopathic tendencies in 9-year-olds of 0.99 (95% CIs = 0.92, 1)43.
With three core aims (Fig. 1), the current meta-analysis bridges major gaps in our knowledge of the aetiology of NDDs and of their co-occurrence with other developmental conditions. First, we meta-analysed studies on the relative contribution of genetic and environmental influences to all NDDs categories described in the DSM-5. Second, we meta-analysed estimates for the genetic and environmental comorbidities between different NDDs (homotypic co-occurrences). Third, given the historical associations between NDDs and DICCs, and their developmental onset and progression, we examined the aetiology of the co-occurrence between NDDs and DICCs (heterotypic co-occurrences).
In addition to addressing each disorder individually, we take a transdiagnostic approach by combining data across NDDs, their manifestations, and including categorical (i.e., presence or absence of a disorder) and quantitative (i.e., continuously measured symptoms) measures. Taking a transdiagnostic approach provides us with a holistic picture of the extent to which genetic and environmental factors contribute to NDDs, to their co-occurrence, and to their co-occurrence with other common developmental conditions. This will result in a clearer appreciation of the size, strength, pervasiveness, and developmental progression of the associations between different developmental disorders.
Clarifying the genetic and environmental aetiology of all NDDs and their homotypic and heterotypic co-occurrences will advance our knowledge of how developmental disorders cluster together, which could in turn inform educational and clinical practice46. Accurate and efficient evaluations and diagnoses, and related adjustments in the care and education of children with NDDs, will in turn have a positive impact on the children and their development, their families, and their educators47.