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No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies

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Title: No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies
Authors: Dinkelbach, Lars, Peters, Triinu, Grasemann, Corinna, Hebebrand, Johannes, Hinney, Anke, Hirtz, Raphael
Source: Eur Child Adolesc Psychiatry
Publisher Information: Cold Spring Harbor Laboratory, 2023.
Publication Year: 2023
Subject Terms: ADHD, Female [MeSH], Mendelian randomization, Adult [MeSH], Humans [MeSH], Testosterone/blood [MeSH], Middle Aged [MeSH], Sex effects, Attention Deficit Disorder with Hyperactivity/genetics [MeSH], Polymorphism, Single Nucleotide/genetics [MeSH], Genome-Wide Association Study [MeSH], United Kingdom/epidemiology [MeSH], Male [MeSH], Original Contribution, Testosterone, Mendelian Randomization Analysis [MeSH], Sex Factors [MeSH], Male, Adult, 0301 basic medicine, 0303 health sciences, Medizin, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, United Kingdom, 03 medical and health sciences, Sex Factors, Attention Deficit Disorder with Hyperactivity, Humans, Female, Genome-Wide Association Study
Description: The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk were found, neither in males (inverse-variance weighted (IVW): beta=0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta=0.24, 95%-CI [0.09, 0.39). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.
Document Type: Article
Other literature type
ISSN: 1435-165X
1018-8827
DOI: 10.1101/2023.09.09.23295037
DOI: 10.1007/s00787-024-02421-x
Access URL: https://pubmed.ncbi.nlm.nih.gov/38536491
https://repository.publisso.de/resource/frl:6497221
Rights: CC BY
Accession Number: edsair.doi.dedup.....481160f5214293a3c1d37e9920b8d568
Database: OpenAIRE
Description
Abstract:The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk were found, neither in males (inverse-variance weighted (IVW): beta=0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta=0.24, 95%-CI [0.09, 0.39). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.
ISSN:1435165X
10188827
DOI:10.1101/2023.09.09.23295037