August 19, 2021
Behavioral disinhibition is a trait associated with both ADHD and several genes that affect dopamine signaling. A new study by three American medical researchers set out to examine how these ADHD risk genes - DRD4 (dopamine 4 receptor density), DAT1 (dopamine 1 transporter), and DBH(dopamine beta-hydroxylase) - affect estimated life expectancy in young adulthood.
The method used was a longitudinal study of 131 hyperactive children and 71 matched controls through early adulthood. The original evaluations were done in 1979-1980, when both groups were children in the 4 to 12 age range. They were reevaluated in1987-1988 as adolescents aged 12 to 20. The next follow-up was in 1992-1996 in early adulthood, aged 19 to 25. The final follow-up was in 1998-2004, for adults aged 24 to 32. All agreed to physical examinations that formed the basis for calculating estimated life expectancy using actuarial tables that factor in the effects of smoking, body mass index, alcohol, and other risk factors of on expected longevity. Participants also provided blood samples that enabled gene typing.
For the DAT1 gene, participants who had the homozygous-repeat allele (9/9) had a five-year reduction in estimated life expectancy relative to those with the ten-repeat allele (10/10). Those with the intermediate (9/10) configuration had a three-year reduction in estimated life expectancy.
For the DBH Taq1 gene, those with a heterozygous (A1/A2) combination had almost a three-year reduction in estimated life expectancy relative to those with homozygous (A1/A1 or A2/A2)configurations.
For DRD4, on the other hand, no significant differences were found in estimated life expectancy.
In a related study, several background traits were found to be significantly predictive of variance estimated life expectancy. The largest of these was behavioral disinhibition, followed by verbal IQ, self-rated hostility, and a nonverbal fluency test. But no significant differences were found between any of the gene polymorphisms on any of these four measures, indicating that the present gene associations were independent of the background traits.
The researchers next sought to determine which variables used in the estimated life expectancy calculations were associated with the two significant genes. For DBH, one variable stood out. Those with the A1/A2 heterozygous pairings had almost twice the alcohol consumption of those with homozygous pairings (p = 0.023).
For DAT1, two variables stood out. Overall, the 9/9 pairings smoked two and a half times as much as the 10/10pairings, with the 9/10 pairings midway between the extremes (p = 0.036). They were also 73 percent more likely to be smokers relative to the 10/10 pairings, and 61 percent more likely relative to the 9/10 pairings. They also had significantly less education than the 10/10 pairings, with the 9/10 pairings again being intermediate (p = 0.027).
An obvious limitation of the study was its small sample size. The authors cautioned, our findings should be considered quite preliminary and in need of much greater research before being given much weight in the literature or public policy.
"With these limitations in mind, they concluded, the present study demonstrated that two ADHD risk genes (DB Hand DAT1) independently contributed to a reduction in ELE [estimated life expectancy] beyond the second-order variables of behavioral disinhibition, IQ, hostility, and nonverbal fluency that contributed in the related study to variation in ELE. The gene polymorphisms seemed to be influencing ELE through their affiliation with first-order or more proximal factors related to ELE such as education, smoking, alcohol use, and possibly exercise."
Russell A. Barkley, Karen Müller Smith, and Mariellen Fischer, ADHD risk genes involved in dopamine signaling and metabolism are associated with reduced estimated life expectancy at young adult follow-up in hyperactive and control children, American Journal of Medical Genetics(2019), DOI:10.1002/aiming.b.32711.
Precocious puberty (PP) is defined as the onset of secondary sex characteristics before age 8 in girls or age 9 in boys.
Because it accelerates skeletal maturation by prematurely shutting down the cartilage growth plate at the tip of long bones, it tends to lead to shorter height in adulthood. It is also known to place an additional psychological burden on children, especially girls. Girls are four to 38 times more likely to develop PP than boys.
Taiwan has a single-payer national health insurance system, called National Health Insurance, that encompasses 99.6% of the island’s population. The Ministry of Health and Welfare uses it to maintain the National Health Insurance Research Database (NHIRD), enabling researchers to conduct nationwide population studies.
Using this database, a Taiwanese study team investigated the relationship between ADHD and precocious puberty among children and adolescents (under 18). And because methylphenidate (MPH) is the only psychostimulant approved for the treatment of ADHD in Taiwan, the team also explored the effect of MPH on this relationship.
Most diagnoses of ADHD in the NHIRD are made by board-certified psychiatrists, enhancing diagnostic validity.
Of the more than 3.3 million persons born in Taiwan between 1997 and 2001, 186,681 were diagnosed with ADHD. Of these, 122,302 were prescribed MPH.
After adjusting for sex, low-income households, and neuropsychiatric comorbidities, children diagnosed with ADHD were twice as likely to be diagnosed with PP. This held equally true for boys and girls.
However, children diagnosed with ADHD and prescribed MPH were more than a third less likely to subsequently be diagnosed with PP than those diagnosed with ADHD but not prescribed MPH.
For girls with ADHD, who without an MPH prescription were nine times more likely than boys with ADHD to be diagnosed with PP, an MPH prescription reduced that ratio to five times more likely than boys with ADHD and prescribed MPH.
That suggests a strong protective effect of MPH.
The team concluded, “Our study found that children with ADHD were at a greater risk of PP, and girls with ADHD were a particularly vulnerable group. … MPH appeared to be protective against PP in patients with ADHD, especially in girls. However, these preliminary results need further validation.”
Maternal infections and inflammatory responses during pregnancy have been proposed as risk factors for neurodevelopmental disorders such as ADHD.
Taiwan has a single-payer health insurance system that covers virtually the entirety of its population. Its Ministry of Health and Welfare maintains the National Health Insurance Research Database (NHIRD), with detailed information on outpatient services, hospitalizations, and medical treatment for nearly 99% of all residents.
A Taiwanese study team used NHIRD to examine to examine the relationship between maternal hospitalization for infection, and early childhood infection, and subsequent ADHD in offspring. The study cohort originated with all 3,260,879 individuals born between 2001 and 2018.
The team excluded births from foreign mothers, still births, births with congenital defects, low birth weights, abnormally late births, twins, triplets, and other multiple births, culminating in a final population cohort of 2,885,662 live-born single infants across 1,893,171 families, and 1,864,660 individuals with full siblings from 872,169 families comprising the full sibling cohort.
Study participants were followed until diagnosis of a neurodevelopmental disorder, their death, or the end of 2021.
After adjusting for sex, birth year, paternal and maternal ages, birthweight, birth season, parity, delivery method, 1 minute APGAR score (evaluating baby’s appearance, pulse, grimace, activity and respiration at birth), gestational age, pregnancy and delivery complications, parental history of neurodevelopmental disorders, maternal asthma and diabetes, urbanization level of the residential area, and family’s insurance amount, offspring of mothers hospitalized for infections had 14% greater odds of being subsequently diagnosed with ADHD.
However, in the full sibling cohort of over 1.8 million, this association vanished. That held true for each of the three trimesters of pregnancy. It also held true for bacterial infections. Surprisingly, offspring of mothers hospitalized for viral infections were 24% less likely to be diagnosed with ADHD than their siblings not exposed to maternal viral infection. Because of that, they also had a 6% lower risk overall.
After the same adjustments, early childhood infection was associated with 16% greater odds of being diagnosed with ADHD.
Nevertheless, in the full sibling cohort of over 1.8 million, this association again vanished. That held true overall, as well as separately for childhood infections in months 1-6 and months 7-12. The association vanished altogether both for bacterial infections as well as for viral infections.
The authors concluded, “the results of this nationwide birth cohort study with population and sibling analyses suggest that the association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors.”
Most previous studies of suicide and self-harm risk among persons with ADHD have focused on adolescents and adults. They’ve also tended to be cross-sectional, analyzing data from a population at a specific point in time.
An Australian study team took a different approach, conducting a before-and-after study through the birth cohort of the Longitudinal Study of Australian Children (LSAC), comprising 5,107 children who have been followed up every two years since birth.
The diagnosis of ADHD was based on parents reporting that their child had received a diagnosis of ADHD at or before age ten.
Suicide and self-harm were defined as children’s self-report at age 14 of any thought or attempt of suicide and self-harm respectively over the past year.
The team adjusted for the following confounders: socioeconomic status, birth weight, ADHD medication history, maternal education level, maternal age at birth, experience in bullying victimization at age 12, and depression score based on Short Mood and Feelings Questionnaire (SMFQ).
Of the 5,107 participants, 3,696 had all the valid data required for analysis and were included in the final cohort. Of these, 3.6% were diagnosed with ADHD by age 10.
With diagnosis of ADHD at age 10 and all other factors held constant:
Both depression and exposure to bullying were statistically significant mediators for the relationship. Nevertheless, depression and exposure to bullying each accounted for well under 10% of the overall effect.
Neither socioeconomic status nor maternal factors had any significant mediating effect on outcomes.
Conclusion:
The authors concluded, “This study provides compelling evidence that children diagnosed with ADHD at the age of 10 years face significantly elevated risks of experiencing suicidal thoughts, planning, or attempts, as well as self-harm, by the age of 14 years, which underscores the critical importance of recognizing and addressing these heightened risks in children with ADHD.”
While factors like depression and bullying contribute, ADHD itself remains a key risk factor. Early intervention and strong mental health support are crucial to protecting these children’s well-being.
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