Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank

Adriano Winterton,Ole A Andreassen,Ann-Marie G De Lange,Francesco Bettella,Nils Eiel Steen,Lars T Westlye,Daniel S Quintana,Marit Haram

doi:10.1038/s41398-021-01725-9

Adriano Winterton, Ole A Andreassen + Show 6 more

Open Access

https://doi.org/10.1038/s41398-021-01725-9

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Abstract

Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin’s role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.

Highlights

Schizophrenia (SCZ) and bipolar disorders (BD) are associated with reduced life expectancies [1, 2], partly caused by an increased risk for cardiovascular disease (CVD) [3]
One-third of patients with psychotic disorders suffer from metabolic syndrome (MetS) [4], a collection of co-occurring metabolic risk factors [5] for the development of CVD and type-2 diabetes mellitus (T2D) [5]
Evidence of MetS risk factors in untreated individuals with first-episode psychosis [10], in antipsychotic-naive patients [11], and in healthy first-degree relatives [12] suggests that the risk factors are, in part, independent from antipsychotic treatments and lifestyle factors, which point to other influences

Summary

INTRODUCTION

Schizophrenia (SCZ) and bipolar disorders (BD) are associated with reduced life expectancies [1, 2], partly caused by an increased risk for cardiovascular disease (CVD) [3]. To explore the role of the oxytocin system in the shared genetic liability between schizophrenia, bipolar disorder, T2D, and cardiovascular risk factors, we meta-analysis of the European Caucasian subset of the DIAGRAM 2012 GWAS [55]. Calculated the genetic contribution of oxytocin-pathway single-nucleotide polymorphisms (SNPs) to polygenic risk for schizophrenia and bipolar disorder, as well as T2D, to analyze and compare central and peripheral contributions and their associations with anthropometric and behavioral CVD risk factors. We applied this polygenic pathway-specific approach in a very large sample (UK Biobank) with 488,377 genotyped individuals with well-characterized anthropometric This unsupervised approach incorporates all computed scores across a range of tuning parameters and is agnostic regarding the outcome of interest, helping control type-1 error rates [59] and capturing the greatest variation of the oxytocin-pathway PGSs computed under a range of

METHODS

Winterton et al 3

RESULTS

DISCUSSION