Polygenic contribution to the relationship of loneliness and social isolation with schizophrenia

Abstract

Previous research suggests an association of loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate a LNL-ISO polygenic score contribution to schizophrenia risk in an independent case-control sample (N = 3,488). We then subset schizophrenia predisposing variation based on its effect on LNL-ISO. We find that genetic variation with concordant effects in both phenotypes shows significant SNP-based heritability enrichment, higher polygenic contribution in females, and positive covariance with mental disorders such as depression, anxiety, attention-deficit hyperactivity disorder, alcohol dependence, and autism. Conversely, genetic variation with discordant effects only contributes to schizophrenia risk in males and is negatively correlated with those disorders. Mendelian randomization analyses demonstrate a plausible bi-directional causal relationship between LNL-ISO and schizophrenia, with a greater effect of LNL-ISO liability on schizophrenia than vice versa. These results illustrate the genetic footprint of LNL-ISO on schizophrenia.

The role of loneliness and social isolation in mediating the relationship between childhood maltreatment and schizophrenia: A genetically informed approach.

“…Unexpectedly, when controlling for childhood maltreatment, we observed no relationship between loneliness/isolation and schizophrenia. This finding contradicts previous research, which reports a positive—and potentially causal—association between the two traits (Andreu-Bernabeu et al, 2022; Boyda & McFeeters, 2015; Steenkamp et al, 2022). The discrepancy in findings may be driven by differences in the type of data analyzed (i.e., genetic instead of phenotypic), the type of mediator used (e.g., loneliness/isolation as opposed to difficulties in social engagement), and/or the choice of covariates (i.e., controlling for childhood maltreatment or not).…”

Socioeconomic status and severe mental disorders: a bidirectional multivariable Mendelian randomisation study

“…This is consistent with recent research suggesting that genetic liability to higher EA could affect health and social outcomes independently of educational milestones or changes in wages 46. A combined liability-threshold model which includes putative rare variants with large effects59 and involves potential gene–environmental interaction effects such as the stigma and discrimination associated with some diagnostic categories,60 the disability associated with early symptoms and drug abuse,51 61 the potential impact of isolation and social defeat62 63 and a likely negative expectation effect towards SMD such as SCZ,64 could provide more accurate estimates in the future.…”

The co-occurrence of multidimensional loneliness with depression, social anxiety and paranoia in non-clinical young adults: A latent profile analysis

“…There did not exist a profile that had elevated loneliness but low symptoms. Together with evidence that loneliness is associated with emotional instability and hypervigilance to social threats, which predispose the development of affective and psychotic disorders [e.g., ( 8 , 21 , 65 )], and that there are polygenetic overlaps between loneliness with these disorders ( 66 , 67 ), the current findings lend support to the idea that loneliness may be a general risk factor that pertains to various psychopathologies ( 68 , 69 ).…”