The aetiology of ADHD is complex, and there is limited evidence about its cause and risk factors; therefore, the aim of this study was to conduct a large-scale genetic investigation of the causal architecture of ADHD, using a method that is less susceptible to bias than traditional methods (O’Connor & Price, 2018).
ADHD genome-wide association studies (GWAS) summary statistics from the Psychiatric Genomics Consortium and an extensive collection of GWAS summary statistics of 1387 other traits were utilised to analyse the causal association between these traits and ADHD, using the latent causal variable (LCV) method (O’Connor & Price, 2018).
A total of 578 significant genetic correlations between ADHD risk and other complex traits were identified, of which 37 showed robust evidence of partial genetic causality with ADHD (genetic causal proportion >0.60; false discovery rate <5%). Of those 37 traits:
- Self-reported chronic obstructive pulmonary disease, blue-badge disability allowance and carpal tunnel syndrome as an adult were traits influenced by genetic liability for ADHD and showed a positive correlation with ADHD.
- Genetic liability for cardiometabolic diseases (including iron deficiency anaemia, peripheral artery disease, self-reported type 2 diabetes and obesity); musculoskeletal-related traits (including synovitis and tenosynovitis, neck or shoulder pain for >3 months and fibroblastic disorders); and eye diseases (including entropion and trichiasis of the eyelid) were found to be associated with an increased risk of ADHD as a child.
- Genetic variants associated with frequent use of various medications as an adult were identified to contribute to a higher risk of ADHD as a child; these medications included those typically prescribed for treating hypertension, seizures and epilepsy, and gastro-oesophageal reflux disease.
- High-density lipoprotein, being a schoolteacher or a teaching professional, and doing unpaid or voluntary work as an adult showed a negative correlation and significant genetic causal proportion with a high risk of ADHD as a child.
It was noted that the generalisability of the results across ethnicities may be limited, and that potential causal genetic effects with other traits not analysed in this study may exist. Furthermore, GWAS used in this study may have proxied other complex traits, complicating the interpretability of the results. For example, medication-use GWAS were used as proxies for the phenotypes that these medications are commonly prescribed for. Furthermore, the identification of potential causal genetic effects may have been limited for some phenotypes, especially for those with small sample sizes. The authors also acknowledged that in certain cases, the LCV method may produce false or biased findings.
The authors concluded that the results of this study show that genetic liability to multiple complex traits influences a higher risk for ADHD. It was suggested that these results highlight the potential role of cardiometabolic phenotypes and physical pain in the aetiology of ADHD.
Read more about complex traits and the risk of ADHD here
Disclaimer: The views expressed here are the views of the author(s) and not those of Takeda.
García-Marín LM, Campos AI, Cuéllar-Partida G, et al. Large-scale genetic investigation reveals genetic liability to multiple complex traits influencing a higher risk of ADHD. Sci Rep 2021; 11: 22628.
O’Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet 2018; 50: 1728-1734.