ADHD is a highly heritable disorder known to be associated with a significantly higher risk of death compared with people without ADHD (Dalsgaard et al, 2015). However, research around the risk of mortality in adults with ADHD is scarce, and it is unknown whether a high polygenic predisposition to ADHD may increase mortality risk among older adults. Hence, this study investigated the extent to which the polygenic predisposition to ADHD is associated with all-cause mortality in the general adult population.
This UK-based study utilised data from the English Longitudinal Study of Ageing (ELSA*), of a nationally representative sample of adults aged ≥50 years who were followed-up for an average period of 11.2 years, or until death occurred. No participant had previously received a clinical diagnosis of ADHD. Blood samples were used to extract genetic data, and a polygenic score (PGS) for ADHD (PGS-ADHDsingle) was calculated using summary statistics from several large genome-wide association studies (GWAS) of ADHD. A multi-trait analysis of GWAS was used to calculate a PGS for ADHD based on genetic data from additional traits (chronic obstructive pulmonary disease and younger at age giving birth) that have an overlapping genetic make-up with ADHD (PGS-ADHDmulti-trait). Data were analysed independently for men and women, given that ADHD affects life expectancy differently between the two sexes (Dalsgaard et al, 2015).
A total of 7133 adults (46.2% male) were included in the sample, with a mean (standard deviation [SD]) age at baseline of 64.7 (9.5) years. By the end of the 11-year follow-up, 1778 (24.9%) participants had died, with an average (SD) length of survival of 134.3 (37.5) months. Compared with people who were still alive at the end of follow-up, a higher proportion of responders who died during the follow-up period were smokers (15.0% vs 19.8%; p<0.001) and not married (27.0% vs. 44.5%; p<0.001).
The PGS-ADHDsingle was associated with a greater risk for all-cause mortality in the whole sample (hazard ratio [HR] 1.06; 95% confidence interval [CI] 1.02–1.12; p=0.010). This association was also significant in men (HR 1.07; 95% CI 1.00–1.14; p=0.043), and there was an increase in risk of all-cause mortality in men of 12% for each SD increase when analyses were limited to adults aged 50–75 years at baseline (HR 1.12; 95% CI 1.03‒1.22; p=0.006). In women, the association between PGS-ADHDsingle and risk for all-cause mortality was insignificant for all ages (HR 1.06; 95% CI 0.99–1.13; p=0.121) and for participants aged 50–75 years at baseline (HR 1.05; 95% CI 0.96–1.16; p=0.284).
However, multi-trait analysis showed a significant association between PGS-ADHDmulti-trait and increased risk for all-cause mortality for both women (HR 1.11; 95% CI 1.04–1.19; p=0.003) and men (HR 1.10; 95% CI 1.03–1.18; p=0.003). In the whole sample, the risk of all-cause mortality increased by approximately 11% for each SD increase in PGS-ADHDmulti-trait (HR 1.11; 95% CI 1.06–1.16; p<0.001). When analyses were limited to adults aged 50–75 years, each SD increase in PGS-ADHDmulti-trait was associated with an increase in the risk for all-cause mortality of 14% in men (HR 1.14; 95% CI 1.05–1.25; p=0.002) and 13% in women (HR 1.13; 95% CI 1.03–1.24; p=0.014).
The authors noted that because a continuous measure of polygenic predisposition to ADHD was used to identify people at an increased risk for ADHD rather than relying on a clinical diagnosis, the results of this study were unlikely to be affected by sex bias, which can lead to delays in referral and diagnosis of females with ADHD. However, they acknowledged that the absence of ADHD cases in ELSA may imply underdiagnosis of the condition. Furthermore, the correlation between PGS and all-cause mortality may have been underestimated, as a higher proportion of adults with high ADHD manifestation might have died prior to enrolment in ELSA. A potential gene–environmental correlation, as well as other traits correlated with ADHD, and confounding factors such as smoking and educational attainment, may have influenced the reported associations with all-cause mortality. In addition, because PGS were calculated based on summary statistics from GWAS, the generalisability of the results was potentially limited by the high proportion of European participants in GWAS, and PGS may be restricted by the inherent limitations of GWAS.
The authors concluded that polygenic predisposition to ADHD is associated with increased risk of all-cause mortality in the general population of adults aged ≥50 years, and emphasised the importance of including genetic information for traits correlated with ADHD when evaluating the genetic risk of ADHD.
*ELSA recruited participants from Health Survey for England, which was designed to monitor the health of the general population, and collected socio-economic, psychological, cognitive, health, biological and genetic data of English residents aged ≥50 years between 2002 and 2011, with regular follow-ups every 2 years (Steptoe et al, 2013)
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Ajnakina O, Shamsutdinova D, Wimberley T, et al. High polygenic predisposition for ADHD and greater risk of all-cause mortality: a large population-based longitudinal study. BMC Med 2022; 20: 62.
Dalsgaard S, Østergaard SD, Leckman JF, et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190-2196.
Steptoe A, Breeze E, Banks J, et al. Cohort profile: the English Longitudinal Study of Ageing. Int J Epidemiol 2013; 42: 1640-1648.