Genetic predisposition to neuroticism, insomnia linked to treatment-resistant depression

Key takeaways:

• Overall, 11 polygenic scores were associated with treatment-resistant depression.
• Genetic predisposition for insomnia and neuroticism increased the risk.
• Higher education and intelligence appeared protective.

Genetic predisposition to traits such as depressive affect, neuroticism and insomnia appeared significantly associated with greater risk for treatment-resistant depression, according to a study published in JAMA Psychiatry.

On the other hand, traits related to cognition and education demonstrated a protective association against treatment-resistant depression (TRD), Bohan Xu, PhD, data scientist with the Population Neuroscience and Genetics Center at the Laureate Institute for Brain Research in Tulsa, Oklahoma, and colleagues wrote.

Although treatment-resistant depression contributes to substantially more clinical visits and hospitalizations, as well as a 30% to 50% higher mortality rate, than treatment-responsive major depressive disorder (trMDD), its etiology remains unknown.

This inspired the researchers to utilize genetically derived polygenic scores (PGS) to conduct an observational cohort study investigating the genetic factors associated with TRD across various traits.

The study included 292,663 participants (median age, 57 years; interquartile range, 41-69 years; 60.1% women; 52.1% white) recruited from the NIH’s All of Us Research Program who had electronic health record and genomic data. The researchers split the population into three cohorts based on genetic ancestry: 124,945 in the whole-genome sequencing (WGS) European set; 104,388 in the WGS genetically diverse set; and 63,330 with microarray but not WGS.

They selected 61 PGS to examine from seven domains: education and cognition (two PGS); metabolic, somatic complaints and inflammation traits (17 PGS); personality (19 PGS); psychiatric disorders (nine PGS); sleep patterns (two PGS); substance use (six PGS) and temperament (six PGS).

The researchers found that, despite a high degree of similarity in the association patterns, 11 PGS in the WGS European set — belonging to the domains of education/cognition, sleep, personality and temperament — were more strongly associated with TRD than trMDD.

However, none of the PGS for psychiatric disorders significantly differentiated TRD from trMDD.

Specifically, logistic regressions showed a genetic predisposition for insomnia (OR = 1.11; 95% CI, 1.07-1.15) and specific neuroticism, including its item-level subscores (OR = 1.11; 95% CI, 1.07-1.16) increased the likelihood of developing TRD. A similar observation was made regarding genetic propensity related to temperament, including lethargy (OR = 1.14; 95% CI, 1.1-1.18), tenseness (OR = 1.15; 95% CI, 1.1- 1.21) depressed mood (OR = 1.1; 95% CI, 1.05-1.14) and unenthusiasm (OR = 1.11; 95% CI, 1.07-1.15).

However, Xu and colleagues found that genetic propensity for higher education (OR = 0.88; 95% CI, 0.85-0.91) and intelligence (OR = 0.91; 95% CI, 0.88-0.94) as well as cognitive performance (OR = 0.91; 95% CI, 0.89-0.95) were associated with protection against TRD.

These associations were consistent in the genetically diverse microarray sets and across different TRD definitions.

Further, of 28,964 participants with MDD from the two WGS sets combined who had at least two time points on record, 3,854 developed TRD within 944 days (95% CI, 883-992) on average, the researchers wrote. The previously identified 11 PGS were significantly associated with time to TRD onset, except for two neuroticism subitems, indicating that “the genetic propensity of those traits was associated with the progression of treatment responsiveness, as the emergence of TRD,” the researchers wrote.

The researchers noted several limitations to this study, including that TRD status was determined using an EHR algorithm, which may have led to misclassifications, and that PGS may not reflect traits driven mainly by environmental factors.

“The association between high levels of neuroticism and TRD suggests a common emotional/cognitive process that may be the target of treatment strategies,” Xu and colleagues wrote. “The identification of insomnia as a treatable risk factor offers a viable pathway for clinical intervention.”