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-ADHD_single), 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-ADHD_multi-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-ADHD_single 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-ADHD_multi-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-ADHD_multi-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).

Conclusion Polygenic predisposition to ADHD confers increased risk for all-cause mortality in the general population of adults aged 50 years old and onwards. Our results further suggest that to fully capture the genetic risk of ADHD, it is imperative to incorporate genetic information contained in traits with an overlapping molecular basis. Even though PGSs can be seen as unconfounded proxies for the life-time predisposition to ADHD, their low generalisability across populations is noteworthy. This is because the construction of PGSs is mainly dependent on the availability of summary statistics from the genome wide association studies, which are currently predominately based on European participants.