Loneliness may not be a direct cause of disease

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Sep 17 2024

Managing risk factors related to loneliness could still improve long-term health outcomes, researchers claim. 

In a recent study published in Nature Human Behaviour, researchers evaluated whether the relationships between aloneness and the risk of numerous illnesses correlated with causal effects.

Background

Loneliness is a social detachment resulting in a mismatch between intended social relationships and actual social connections. It can trigger complicated biochemical and behavioral mechanisms such as excessive stress response, inflammation, and suppressed reward or motivation, all of which impair general health and increase vulnerability to numerous illnesses.

Health professionals consider loneliness a health risk, although its causative consequences are unknown. Observational studies suggest a rise in the risk of mental and physical ailments, as well as early mortality; however, most focus on specific diseases. The links between aloneness and severe illnesses like chronic renal disease are unclear.

About the study

In the present study, researchers assessed whether genetic and observational evidence agree on the relationship between aloneness and the risk of multiple diseases.

The researchers combined hospitalization, behavioral, and genetic data from the United Kingdom Biobank to determine the relationships of loneliness with multiple diseases. Mendelian randomizations (MR) with Benjamini-Hochberg corrections assessed genetic data. MR pleiotropy Residual Sum and Outlier (MR-PRESSO), the Latent Heritable Confounder MR (LHC-MR), and MR-Egger analyses addressed horizontal pleiotropy.

Two questions were derived from the University of California, Los Angeles (UCLA) Loneliness Scale, administered using digital questionnaires, and assessed loneliness. The questions inquired whether the participants ever felt lonely and how often they could confide in someone close to them. The International Classification of Diseases-tenth revision (ICD-10) codes identified diseases.

Researchers compared the findings with the Health and Retirement Study (HRS) and the China Health and Retirement Longitudinal Study (CHARLS) data. They derived the population-attributable fraction (PAF). Cox proportional hazard models determined the adjusted hazard ratios (aHR), controlling for age, gender, body mass index (BMI), education, employment status, smoking habits, alcohol consumption, and physical exercise.

Researchers performed negative control analyses to address confounding bias. The home-to-workplace travel frequency and the side of the head for using mobile phones were control exposures. Injury in transport accidents was the negative control outcome. Sensitivity analyses excluded individuals with missing covariate information, events in the initial two years, and single-nucleotide polymorphisms (SNPs) related to depression. The 10-year cumulative incidence rates (CIR per 1,000 individuals) indicated the disease burden of loneliness. Researchers stratified individuals by age (below or above 60 years), sex, and adiposity.

Results

Among 476,100 individuals with a mean age of 57 years, 55% were female, and 5.0% were lonely. Lonely individuals tended to be physically inactive, obese, and less educated female smokers. Over 12 years (median) of follow-up, aloneness was related to increased risks for 13 illness categories (aHR, 1.1 to 1.6; PAF, 0.7% to 2.8%). Compared to individuals who were not lonely, those feeling aloneness showed the highest risk of mental and behavioral illness incidence (aHR, 1.6; PAF, 2.8%).

Loneliness also increases the risk for infections and disorders of the respiratory, nervous, hematopoietic, endocrinal, auditory, musculoskeletal, digestive, circulatory, ophthalmic, genitourinary, and dermatological systems (aHR between 1.1 and 1.3; PAF between 0.7% and 1.4%). Researchers noted associations between loneliness and 30 of 56 diseases (aHR between 1.2 and 2.2; PAF between 0.9% and 5.4%). Post-traumatic stress disorder (PTSD, PAF, 5.4%; aHR, 2.2), depression (PAF, 5.2%; aHR, 2.2), anxiety (PAF, 3.8%; aHR, 1.8), chronic obstructive pulmonary disease (COPD, PAF, 2.4%; aHR, 1.5), and schizophrenia (PAF, 3.8%; aHR, 1.8) showed the strongest associations with loneliness.  

Of the 30 diseases significantly associated with aloneness, 26 had genetic data for MR analyses. Researchers identified non-causal associations between genetic susceptibility to loneliness for 20 of 26 diseases. These diseases included obesity, cardiovascular disease, diabetes mellitus type 2, chronic kidney disease, chronic liver disease, neurological disorders, and common illnesses. Genetic susceptibility to loneliness was only potentially causally associated with the remaining six diseases, i.e., hypothyroidism, asthma, depression, sleep apnea, substance abuse, and hearing loss.

Analyzing CHARLS and HRS datasets and the sensitivity and stratified analyses yielded similar results. Baseline depression, health behaviors, socioeconomic factors, and comorbid conditions primarily explained the relationship between aloneness and disease risk. The team noted the highest CIRs for digestive (CIR, 360) and circulatory diseases. (CIR, 335). Transcriptome-wide association studies (TWAS) showed significant expression of loneliness-related genetic factors in the brain, thyroid, digestive system, and visceral adipose tissues.

Conclusion

The study findings revealed that loneliness was associated with an elevated risk of 13 illness categories (30 diseases), including behavioral and mental problems, infections, and respiratory, endocrine, and nervous system diseases. However, most correlations were not causal, as indicated by MR analysis.

The findings found a discrepancy between genetic and observational evidence for the link between aloneness and illness risk. The study suggests that loneliness may be a proxy marker instead of a direct risk factor for most illnesses studied.