A SNP, Gene and Polygenic Risk Score Approach of Oxytocin-Vasopressin Genes in Adolescents’ Loneliness

Background

Evolutionary theories suggest that inclusion in social groups is an essential prerequisite for survival, since this brings mutual opportunities for (social) care, protection and assistance. One of the consequences of the subjective experience of lacking those significant social relations is loneliness. Not much is known regarding underlying biological pathways to adolescents’ loneliness. Insight in underlying molecular mechanisms could help understanding loneliness and informing intervention efforts aimed at reducing loneliness.

Method

Two longitudinal adolescent samples were used to examine the associations between loneliness and genes within the oxytocin-vasopressin (OT-AVP) pathway. The discovery sample consisted of 1,030 adolescents with a mean age of 13.8 years (SD = .94). The replication sample comprised 393 adolescents, with a mean age of 12.8 years (SD = .43). Feelings of loneliness were assessed annually, for three consecutive years.

Latent growth curve modeling was used to assess both baseline levels and development of loneliness over time. Genes (OXTR, OXT, AVPR1A, AVPR1B) were examined using SNP-based, gene-based and polygenic risk score (PRS) approaches. In the PRS approach, a summed risk score for each individual is calculated, based on their number of risk alleles multiplied by effect sizes from a previous genome-wide association study.

Results

In both samples, a small but significant increase in feelings of loneliness over time was observed. Females scored significantly higher on loneliness than males, at assessments 2 and 3 (but not at assessment 1).

We did find OXTR SNP- and gene-set associations with the developement of loneliness in both samples. However, these did not survive correction for multiple testing. In addition, a significant association of the AVPR1A gene on the baseline level of loneliness was found in Sample 1. Again, this finding did not survive correction for multiple testing. The PRS approach provided no evidence for relations between the OT-AVP pathway and loneliness.

Conclusion

Using two comparable adolescent samples, this multi-modal genetic approach has not consistently shown that genes within the OT-AVP pathway are associated with baseline levels or development of loneliness over time. However, we do encourage to use the strengths of this study; examining the same biological pathway in two independent samples of developing adolescents, and combining SNP-based, gene-based, and polygenic risk score approaches to provide step-by-step insight in the respective roles of OT-AVP pathway genes.

We further recommend alternative phenotyping methods (e.g., state levels of loneliness or chronic loneliness), to include environmental factors (e.g., social support, company), to consider epigenetic studies, and to examine possible endophenotypes (e.g., amygdala responsiveness to emotional faces) in relation to adolescents’ loneliness.

Contact: m.verhagen@bsi.ru.nl

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