Large-scale genetic investigation reveals genetic liability to multiple complex traits influencing a higher risk of ADHD

Luis M. García-Marín,Scott H. Kollins,Adrián I. Campos,Miguel E. Rentería,Sarah E. Medland,Gabriel Cuéllar-Partida

doi:10.1038/s41598-021-01517-7

Abstract

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex psychiatric and neurodevelopmental disorder that develops during childhood and spans into adulthood. ADHD’s aetiology is complex, and evidence about its cause and risk factors is limited. We leveraged genetic data from genome-wide association studies (GWAS) and performed latent causal variable analyses using a hypothesis-free approach to infer causal associations between 1387 complex traits and ADHD. We identified 37 inferred potential causal associations with ADHD risk. Our results reveal that genetic variants associated with iron deficiency anemia (ICD10), obesity, type 2 diabetes, synovitis and tenosynovitis (ICD10), polyarthritis (ICD10), neck or shoulder pain, and substance use in adults display partial genetic causality on ADHD risk in children. Genetic variants associated with ADHD have a partial genetic causality increasing the risk for chronic obstructive pulmonary disease and carpal tunnel syndrome. Protective factors for ADHD risk included genetic variants associated with the likelihood of participating in socially supportive and interactive activities. Our results show that genetic liability to multiple complex traits influences a higher risk for ADHD, highlighting the potential role of cardiometabolic phenotypes and physical pain in ADHD’s aetiology. These findings have the potential to inform future clinical studies and development of interventions.

Highlights

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex neurodevelopmental and psychiatric disorder characterised by impulsivity, hyperactivity, and attention and concentration impairment[1,2]
Genetic variants associated with ADHD risk displayed positive genetic correlations and significant causal proportion on three complex traits (Fig. 1 and Table 1)
Our results suggest that genetic liability for ADHD increases risk of self-reported chronic obstructive pulmonary disease (COPD) (rG = 0.67, genetic causal proportion parameter (GCP) = 0.75, GCPpvalue = 4.90 × 10−07), having a blue badge disability allowance (rG = 0.64, GCP = 0.73, GCPpvalue = 3.58 × 10−04) and presenting carpal tunnel syndrome (rG = 0.37, GCP = 0.68, GCPpvalue = 1.66 × 10−03) as an adult

Summary

Introduction

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex neurodevelopmental and psychiatric disorder characterised by impulsivity, hyperactivity, and attention and concentration impairment[1,2]. We use the latent causal variable (LCV)[8] method, which is less susceptible to bias by horizontal pleiotropy and sample overlap than Mendelian randomisation[8], to conduct a large-scale genetic investigation of the causal architecture of ADHD. To this end, we conducted a hypothesis-free phenome-wide screening of traits causally associated with ADHD using the ADHD GWAS summary statistics from the Psychiatric Genomics Consortium (PGC) and an extensive collection of GWAS summary statistics for 1,387 other traits. Our results should be interpreted as a set of testable hypotheses for future epidemiological and interventional studies

Methods

Results

Conclusion