High polygenic predisposition for ADHD and a greater risk of all-cause mortality: a large population-based longitudinal study

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Background: Attention deficit hyperactivity disorder (ADHD) is a highly heritable, neurodevelopmental disorder known to associate with more than double the risk of death compared with people without ADHD. Because most research on ADHD has focused on children and adolescents, among whom death rates are relatively low, the impact of a high polygenic predisposition to ADHD on accelerating mortality risk in older adults is unknown. Thus, the aim of the study was to investigate if a high polygenetic predisposition to ADHD exacerbates the risk of all-cause mortality in older adults from the general population in the UK. Methods: Utilising data from the English Longitudinal Study of Ageing, which is an ongoing multidisciplinary study of the English population aged ≥ 50 years, polygenetic scores for ADHD were calculated using summary statistics for (1) ADHD (PGS-ADHDsingle) and (2) chronic obstructive pulmonary disease and younger age of giving first birth, which were shown to have a strong genetic correlation with ADHD using the multi-trait analysis of genome-wide association summary statistics; this polygenic score was referred to as PGS-ADHDmulti-trait. All-cause mortality was ascertained from the National Health Service central register that captures all deaths occurring in the UK. Results: The sample comprised 7133 participants with a mean age of 64.7 years (SD = 9.5, range = 50–101); of these, 1778 (24.9%) died during a period of 11.2 years. PGS-ADHDsingle was associated with a greater risk of all-cause mortality (hazard ratio [HR] = 1.06, 95% CI = 1.02–1.12, p = 0.010); further analyses showed this relationship was significant in men (HR = 1.07, 95% CI = 1.00–1.14, p = 0.043). Risk of all-cause mortality increased by an approximate 11% for one standard deviation increase in PGS-ADHDmulti-trait (HR = 1.11, 95% CI = 1.06–1.16, p < 0.001). When the model was run separately for men and women, the association between PGS-ADHDmulti-trait and an increased risk of all-cause mortality was significant in men (HR = 1.10, 95% CI = 1.03–1.18, p = 0.003) and women (HR = 1.11, 95% CI = 1.04–1.19, p = 0.003). Conclusions: A high polygenetic predisposition to ADHD is a risk factor for all-cause mortality in older adults. This risk is better captured when incorporating genetic information from correlated traits.

TidsskriftBMC Medicine
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
The English Longitudinal Study of Ageing is funded by the National Institute on Aging (grant RO1AG7644) and a consortium of UK government departments coordinated by the National Institute for Health Research (NIHR). OA is further funded by an NIHR Post-Doctoral Fellowship (PDF-2018-11-ST2-020). SD research is supported by grants from The Lundbeck Foundation (iPSYCH grant no R248-2017-2003), the European Commission (Horizon 2020, grant no 667302), Helsefonden (grant no 19-8-0260) and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847879.

Publisher Copyright:
© 2022, The Author(s).

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