Mendelian randomization analysis for attention deficit/hyperactivity disorder: studying a broad range of exposures and outcomes

Abstract

Mendelian randomization; Attention deficit and hyperactivity disorder

Aleatorització mendeliana; Trastorn per dèficit d'atenció i hiperactivitat

Aleatorización mendeliana; Trastorno por déficit de atención e hiperactividad

Background Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder caused by a combination of genetic and environmental factors and is often thought as an entry point into a negative life trajectory, including risk for comorbid disorders, poor educational achievement or low income. In the present study, we aimed to clarify the causal relationship between ADHD and a comprehensive range of related traits. Methods We used genome-wide association study (GWAS) summary statistics for ADHD (n = 53 293) and 124 traits related to anthropometry, cognitive function and intelligence, early life exposures, education and employment, lifestyle and environment, longevity, neurological, and psychiatric and mental health or personality and psychosocial factors available in the MR-Base database (16 067 ≤n ≤766 345). To investigate their causal relationship with ADHD, we used two-sample Mendelian randomization (MR) with a range of sensitivity analyses, and validated MR findings using causal analysis using summary effect estimates (CAUSE), aiming to avoid potential false-positive results. Results Our findings strengthen previous evidence of a causal effect of ADHD liability on smoking and major depression, and are consistent with a causal effect on odds of decreased average total household income [odds ratio (OR) = 0.966, 95% credible interval (CrI) = (0.954, 0.979)] and increased lifetime number of sexual partners [OR = 1.023, 95% CrI = (1.013, 1.033)]. We also found evidence for a causal effect on ADHD for liability of arm predicted mass and weight [OR = 1.452, 95% CrI = (1.307, 1.614) and OR = 1.430, 95% CrI = (1.326, 1.539), respectively] and time spent watching television [OR = 1.862, 95% CrI = (1.545, 2.246)], and evidence for a bidirectional effect for age of first sexual intercourse [beta = −0.058, 95% CrI = (−0.072, −0.044) and OR = 0.413, 95% CrI = (0.372, 0.457), respectively], odds of decreased age completed full-time education [OR = 0.972, 95% CrI = (0.962, 0.981) and OR = 0.435, 95% CrI = (0.356, 0.533), respectively] and years of schooling [beta = -0.036, 95% CrI = (−0.048, −0.024) and OR = 0.458, 95% CrI = (0.411, 0.511), respectively]. Conclusions Our results may contribute to explain part of the widespread co-occurring traits and comorbid disorders across the lifespan of individuals with ADHD and may open new opportunities for developing preventive strategies for ADHD and for negative ADHD trajectories.

This work was supported by European Union H2020 Programme (H2020/2014–2020) under grant agreements no. 667302 (CoCA), no. 728018 (Eat2beNICE), no. 848228 (DISCOvERIE) and no. 2020604 (TIMESPAN); by the Instituto de Salud Carlos III (PI18/01788, PI19/00721, P19/01224, PI20/00041, FI18/00285 to L.V.R., CD15/00199 to C.S.M, CP09/00119 and CPII15/00023 to M.R.); by the Pla estratègic de recerca i innovació en salut (PERIS), Generalitat de Cata-lunya (METAL-Cat; SLT006/17/287); by the Agència de Gestiód'Ajuts Universitaris i de Recerca AGAUR, Generalitat de Catalunya (2017SGR1461, 2016FI_B00899 to P.R.); Ministry of Science, Innovation and Universities (IJC2018-035346-I to M.S.A); by the European Regional Development Fund (ERDF); and by ‘la Marató de TV3’ (092330/31) and by the ECNP Network ‘ADHD across the Lifespan' [https://www.ecnp.eu/researchinnovation/ECNP-networks/List-ECNP-Networks/]. This paper reflects only the authors' views, and the European Union is not liable for any use that may be made of the information contained therein.