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, 28 (22), 3853-3865

Phenome-wide Investigation of Health Outcomes Associated With Genetic Predisposition to Loneliness

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Phenome-wide Investigation of Health Outcomes Associated With Genetic Predisposition to Loneliness

Abdel Abdellaoui et al. Hum Mol Genet.

Abstract

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Figures

Figure 1
Figure 1
QQ-plot and Manhattan plot of meta-analysis on loneliness. (A) The QQ-plot shows a considerable inflation of association statistics (λ = 1.28), which is mostly due to true polygenic signal rather than population stratification (LD-score regression intercept = 0.99). (B) Manhattan Plot of the Loneliness GWAS meta-analysis showing 19 independent genome-wide significant associations from 16 loci.
Figure 2
Figure 2
Enrichment of gene expression for 53 specific tissue types using MAGMA and LD-score regression.
Figure 3
Figure 3
Enrichment of 24 annotations not specific to cell types, ordered by size (proportion of SNPs).
Figure 4
Figure 4
Genetic correlations as computed with LD-score regression. Red stars are significant after Bonferroni correction.
Figure 5
Figure 5
Results of the Phewas on the polygenic score for loneliness, corrected for gender, age, first 10 PCs, and batch.
Figure 6
Figure 6
Two-Sample Mendelian Randomization results for the causal effect of (A) BMI on loneliness and (B) body fat on loneliness.

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