Introduction

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both neurodevelopmental conditions that manifest at an early age. Individuals with ADHD exhibit symptoms such as inattention, hyperactivity, impulsivity, risk-taking behavior and poor judgment compared with healthy individuals, which can lead to an increased susceptibility to injury, stress or traumatic events (Adler et al., 2004). ASD, on the other hand, is a severe disorder that affects approximately one in 59 children. It is characterized by deficits in social interaction, verbal and nonverbal communication and restricted and repetitive patterns of behavior, interests or activities (Baio et al., 2018).

Individuals with ASD often struggle to cope with novel or environmental stressors (Anesiadou et al., 2021). The symptoms and functional deficits of both ADHD and ASD typically persist throughout an individual’s lifespan. These two disorders also have a high comorbidity rate and share some common symptoms, such as executive function deficits, lower social skills and attention deficits (Ghirardi et al., 2018). Additionally, ADHD and ASD share both overlapping and distinct genetic underpinnings (Baranova et al., 2022; Cao et al., 2022; Rao et al., 2022). A genetic correlation between ADHD and ASD has been identified (rg = 0.37) (Cao et al., 2022). As individuals with ADHD and ASD age, they are also more likely to develop other psychiatric comorbidities (Baranova et al., 2022; Rao et al., 2022). Furthermore, individuals with these developmental disorders may be three times more likely to experience traumatic events (Reiter et al., 2007).

Post-traumatic stress disorder (PTSD) is characterized by a cluster of symptoms (intrusion symptoms, avoidance, negative alterations in cognitive function and mood and hypervigilance) that impair the individual’s function after exposure to traumatic events of catastrophic intensity or an extraordinary threat (Al Jowf et al., 2022). Globally, approximately 2.9–10% of people suffer from PTSD, making it a significant public health concern (Qassem et al., 2021).

Extensive research suggests that the stress systems of ASD, ADHD and PTSD are abnormal, including dysregulation in the diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis sluggishness in response to stressors (Angeli et al., 2018; Anesiadou et al., 2021; Corbett et al., 2021). Observational studies have found a bidirectional association between ADHD and PTSD (Spencer et al., 2016). For instance, ADHD in combat soldiers increases the risk of developing PTSD (Adler et al., 2004; Biederman et al., 2014; Howlett et al., 2018), and individuals with PTSD often exhibit ADHD symptoms during childhood (Gurvits et al., 2000). Moreover, individuals with ASD are more likely to experience traumatic events, which subsequently serve as risk factors for developing PTSD (Haruvi-Lamdan et al., 2018). Research has shown that individuals with ASD are more susceptible to displaying symptoms of or being diagnosed with full-blown PTSD (Brenner et al., 2018; Rumball et al., 2020). One study found that 72% of autistic adults experienced interpersonal trauma, with 44% meeting the diagnostic criteria for PTSD (Reuben et al., 2021).

ADHD, ASD and PTSD are complex disorders influenced by multiple factors, including genetics and environmental factors (Maihofer et al., 2022; Genovese and Butler, 2023). Family, twin, adoption and genome-wide association studies (GWAS) have demonstrated that all three psychiatric disorders have high heritability rates, with higher concordance rates among siblings of probands, and involve a multitude of genes (Gilman et al., 2011; Risch et al., 2014; Faraone and Larsson, 2019). Studies have primarily focused on neurotransmitter pathways when examining the genetics of ADHD (Sudre et al., 2023). Several genes, such as KIAA0040, MYO1G, CRISPLD1 and ADAMTS9, have been found to be differentially expressed in the brains of individuals with ADHD and have also been implicated in other mental disorders (Sudre et al., 2023). In ASD, approximately 50% of cases involve chromosome deletions or duplications (Genovese and Butler, 2023). A large-scale sequencing study identified 102 risk genes relating to ASD, including KCNQ3, DEAF1, SCN1A and SLC6A1. (Satterstrom et al., 2020). Twin studies estimated that genetic factors contributed to 30–40% of the variance in PTSD (Banerjee et al., 2017), while a meta-analysis of a genome-wide association study found the heritability range to be between 5 and 20% (Nievergelt et al., 2019).

In recent years, Mendelian randomization (MR) analysis has been frequently employed to explore causal relationships between various diseases (Baranova et al., 2023a,2023b,2023c; Cao et al., 2023). However, limited data exists regarding the genetic associations between ADHD/ASD and PTSD. Given the shared characteristics mentioned above, we sought to test the hypothesis that ADHD and ASD are associated with PTSD. Therefore, this study aimed to investigate the genetic relationships between these disorders using MR analysis.

Methods Data sources and study design

This study utilized publicly available GWAS summary results of ADHD, ASD and PTSD in individuals of European descent. The ADHD dataset included 38 691 cases and 275 986 controls (Demontis et al., 2023). The ASD dataset included 18 381 cases and 27 969 controls (Grove et al., 2019). The GWAS summary results for PTSD included 23 212 cases and 151 447 controls (Nievergelt et al., 2019). The study compared single-nucleotide polymorphisms (SNPs) alleles across the ADHD, ASD and PTSD datasets and implemented quality control measures, such as removing SNPs with a minor allele frequency >0.42 and harmonizing allele and effect directions across datasets.

Genetic correlation analysis

Genetic correlations between ADHD/ASD and PTSD were calculated using linkage disequilibrium score regression. The linkage disequilibrium structure for European populations was estimated using the 1000 Genome Project phase 3 data.

Mendelian randomization analysis

The primary analyses utilized the inverse-variance weighted (IVW) method. Sensitivity analyses were also performed using the weighted median and MR-Egger methods, which were implemented in TwoSampleMR (Hemani et al., 2018). The weighted median and MR-Egger methods were used to evaluate the pleiotropy and heterogeneous instrumental variants. The MR-Egger regression intercept term was used to test for pleiotropy (Bowden et al., 2015). If the MR-Egger intercept of the linear regression model is close to 0 (P > 0.05), it suggests no pleiotropy in the instrumental variants, supporting the validity of the exclusion hypothesis; conversely, if it deviates significantly from 0, it suggests the presence of genetic pleiotropy and invalidates the exclusion hypothesis. The significance threshold for identifying associations between ADHD/ASD and PTSD was set at an false discovery rate < 0.05 using the IVW method. In each MR analysis, instrumental variants were selected as SNPs with genome-wide significance (P < 5 × 10−8) and were further pruned using a clumping r2 cutoff of 0.01. If fewer than 10 instrumental variants surpassed the threshold, a P value threshold of 1 × 10−5 was used.

Results Genetic correlation analysis

The genetic correlation analysis revealed highly positive correlations of PTSD with ADHD (rg = 0.70; P = 1.04 × 10−20), and ASD (rg = 0.34; P = 1.13 × 10−4).

Mendelian randomization analysis

The number of SNPs used as instrumental variants is listed in Table 1. The primary MR analysis using the IVW method indicated the causal effects of ADHD and ASD on PTSD.

Table 1 - Causal relationship of ADHD and ASD with PTSD Exposure Outcome Method b (se) OR (95%CI) N_IV P_IV Q_P I 2 Egger_intercept P_pleiotropy P FDR ADHD PTSD IVW 0.135 (0.040) 1.14 (1.06–1.24) 26 5.00E-08 0.058 0.324 NA NA 7.88E-04 3.15E-03 ADHD PTSD WM 0.079 (0.055) 1.08 (0.97–1.20) 26 5.00E-08 NA NA NA NA 0.151 NA ADHD PTSD MR-Egger −0.049 (0.123) 0.95 (0.75–1.21) 26 5.00E-08 0.094 0.254 0.004 0.128 0.695 NA ASD PTSD IVW 0.043 (0.017) 1.04 (1.01–1.08) 60 1.00E-05 0.016 0.302 NA NA 0.014 0.028 ASD PTSD WM 0.046 (0.022) 1.05 (1.00–1.09) 60 1.00E-05 NA NA NA NA 0.038 NA ASD PTSD MR-Egger 0.048 (0.049) 1.05 (0.95–1.16) 60 1.00E-05 0.013 0.301 0 0.914 0.337 NA PTSD ADHD IVW 0.077 (0.048) 1.08 (0.98–1.19) 29 1.00E-05 3.88E-03 0.461 NA NA 0.11 0.147 PTSD ADHD WM 0.012 (0.054) 1.01 (0.91–1.13) 29 1.00E-05 NA NA NA NA 0.832 NA PTSD ADHD MR-Egger 0.035 (0.112) 1.04 (0.83–1.29) 29 1.00E-05 2.93E-03 0.458 0.001 0.686 0.755 NA PTSD ASD IVW 0.009 (0.064) 1.01 (0.89–1.15) 36 1.00E-05 0.492 −0.015 NA NA 0.884 0.884 PTSD ASD WM −0.005 (0.093) 1.00 (0.83–1.20) 36 1.00E-05 NA NA NA NA 0.961 NA PTSD ASD MR-Egger −0.037 (0.155) 0.96 (0.71–1.31) 36 1.00E-05 0.449 −0.018 0.001 0.746 0.815 NA

ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CI, confidence interval; IVW, inverse variance weighted; FDR, false discovery rate; N_IV: number of instrumental variables; OR, odds ratio; PTSD, posttraumatic stress disorder; Q_P: Cochran’s P value of heterogeneity analysis; WM, weighted median.

Analysis showed that ADHD was associated with an increased risk of PTSD [odds ratio (OR) = 1.14; 95% confidence interval (CI), 1.06–1.24; P = 7.88 × 10−4) (Table 1). Sensitivity analyses using the weighted median showed similar estimates (OR = 1.08; CI, 0.97–1.20; P = 0.151). However, the MR-Egger model yielded an opposite direction (OR = 0.95; CI, 0.75–1.21; P = 0.695). Due to the higher power of the IVW method, the results from IVW were considered final. Scatter plots depicting the association between ADHD and PTSD for the instrumental variants were presented in Fig. 1, with colored lines representing different regression analyses. Cochran’s Q statistic indicated no evidence of pleiotropy (Q = 37; P = 0.058) across instrument effects.

Fig. 1:

Scatter plots of MR analyses using three models to investigate causal relationships between ADHD, ASD and PTSD. The trait on the x-axis denotes exposure, the trait on the y-axis denotes outcomes, and each cross point represents an instrumental variant. ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; MR, Mendelian randomization; PTSD, posttraumatic stress disorder.

Analysis showed that ASD was associated with an increased risk of PTSD (OR = 1.04; CI, 1.01–1.08; P = 0.014) (Table 1 and Fig. 1). Sensitivity analyses using the weighted median showed similar estimates (OR = 1.05; CI, 1.00–1.09; P = 0.038), as did the MR-Egger models (OR = 1.05; CI, 0.95–1.16; P = 0.337). Cochran’s Q statistic suggested the presence of pleiotropy (Q = 84.47; P = 0.016) across instrument effects.

In the reverse MR analysis, genetic liability to PTSD did not have a causal effect on ADHD (OR = 1.08; CI, 0.98–1.19) or ASD (OR = 1.01; CI, 0.89–1.15) (Table 1 and Fig. 1).

Discussion

An MR study revealed genetic correlations between ADHD and PTSD phenotypes (rg = 0.43–0.52), with ADHD being causally linked with an increased risk of PTSD (β = 0.367; CI, 0.186–0.552) (Wendt et al., 2023). Our analysis, using the latest and largest GWAS data on ADHD, showed a high correlation between ADHD and PTSD (rg = 0.70) at the genetic level. ADHD conferred a causal effect on the development of PTSD (OR = 1.14).

Individuals with ADHD are more susceptible to experiencing trauma, such as physical injuries and abuse (Koenen et al., 2007). Cross-sectional studies have also found a high prevalence of ADHD among individuals with PTSD (Spencer et al., 2016). Longitudinal studies have indicated that children with ADHD have a higher risk of developing PTSD in the next 10 years (Biederman et al., 2014). In addition, US Army soldiers with preexisting ADHD deployed to Afghanistan were associated with a doubled risk of postdeployment PTSD (Howlett et al., 2018). Both ADHD and PTSD exhibit structural and functional abnormalities in brain regions and endocrine factors (Martínez et al., 2016). Preliminary studies suggested that both disorders shared common polymorphisms in the dopamine transporter gene and cannabinoid gene (Lu et al., 2008; Onaivi, 2009; Spencer et al., 2013). The genetic overlap of the two disorders aligns with their shared symptoms, including attention and concentration difficulties, attention shift, impulsive behavior, irritability and executive function impairments (Biederman et al., 2013; Martínez et al., 2016). Dysfunctions in the HPA axis and inflammatory biomarkers have been observed in both ADHD and PTSD, characterized by lower cortisol levels and disrupted cortisol rhythms (Al Jowf et al., 2021; Chang et al., 2021). Lower cortisol levels have been correlated with hyperactivity in ADHD and hyperarousal/flashback in PTSD (Kaneko et al., 1993). Another MR study found low morning plasma cortisol levels associated with ADHD (Jue et al., 2023). Psychostimulants used for ADHD treatment may also be effective for PTSD (Barreto et al., 2022). The mechanism of psychostimulants’ effectiveness could involve decreased dopamine activity and increased catecholamine release in certain brain regions (Houlihan, 2011).

In our study, we also found a correlation between ASD and PTSD (rg = 0.34) at the genetic level, with ASD conferring a causal effect on PTSD (OR = 1.04).

Individuals with ASD are more vulnerable to maltreatment, abuse, bullying, serious physical injuries and extended psychiatric hospitalization, increasing their risk of developing post-traumatic symptoms (Sterzing et al., 2012; Lobregt-van Buuren et al., 2021). Studies have demonstrated that disease-related disasters and quarantine for ASD can increase the risk of PTSD (Sprang and Silman, 2013; Cénat et al., 2021). During the COVID-19 pandemic, individuals with ASD exhibited increased sleep difficulties, aberrant behaviors, irritability, tantrums, anxiety and lethargy (Arazi et al., 2022; Hall et al., 2023). Childhood sexual abuse has been found to impact brain function in adults with ASD, as evidenced by altered event-related potential components and P300 amplitudes (Okazaki et al., 2020). Research on gene expression in cord blood has shown that maternal psychological distress and adverse childhood experiences increase the risk of neurodevelopmental disorders (Breen et al., 2018). In ASD, a compromised HPA axis leads to insufficient stress response, resulting in delayed cortisol secretion and low cortisol levels, similar to the dysregulation observed in PTSD (Makris et al., 2021). These findings suggest impaired stress systems in ASD and provide a potential explanation for the increased risk of PTSD.

Limitations

There are several limitations to this study. First, the data used are primarily from individuals of European descent, limiting the generalizability of the results to other populations. International collaborations are needed to validate these findings across diverse populations. Second, although we identified causal relationships between ADHD/ASD and PTSD, the exact mechanisms by which genes influence the pathology of these disorders remain unclear. Further research is needed to elucidate these mechanisms. Finally, ADHD, ASD and PTSD are influenced by a complex interplay of genetic and environmental factors. Understanding how other factors contribute to the development of these disorders is crucial.

Conclusion

Our study contributes to understanding the genetic relationships between ADHD/ASD and PTSD. We found that ADHD and ASD may increase the risk of developing PTSD, but not vice versa.

Acknowledgements

We thank all investigators and participants for contributing their genetics. We also thank members of the consortia, who generously shared the GWAS data.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

F.Z. conceived the project, supervised the study and analyzed the data. F.Z., W.Y., H.C., Y.S. and A.B. wrote the manuscript. All authors read and approved the final manuscript.

Conflicts of interest

There are no conflicts of interest.

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