Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder

Abstract

Bipolar affective disorder (BD) is a severe psychiatric disorder characterized by periodic changes in mood from depression to mania. Disruptions of biological rhythms increase risk of mood disorders. Because clinical representation of disease is heterogeneous, homogenous sets of patients are suggested to use in the association analyses. In our study, we aimed to apply previously computed structure of bipolar disorder symptom dimension for analyses of genetic association. We based quantitative trait on: main depression, sleep disturbances, appetite disturbances, excitement and psychotic dimensions consisted of OPCRIT checklist items. We genotyped 42 polymorphisms from circadian clock genes: PER3, ARNTL, CLOCK and TIMELSSS from 511 patients BD (n = 292 women and n = 219 men). As quantitative trait we used clinical dimensions, described above. Genetic associations between alleles and quantitative trait were performed using applied regression models applied in PLINK. In addition, we used the Kruskal–Wallis test to look for associations between genotypes and quantitative trait. During second stage of our analyses, we used multidimensional scaling (multifactor dimensionality reduction) for quantitative trait to compute pairwise epistatic interactions between circadian gene variants. We found association between ARNTL variant rs11022778 main depression (p = 0.00047) and appetite disturbances (p = 0.004). In epistatic interaction analyses, we observed two locus interactions between sleep disturbances (p = 0.007; rs11824092 of ARNTL and rs11932595 of CLOCK) as well as interactions of subdimension in main depression and ARNTL variants (p = 0.0011; rs3789327, rs10766075) and appetite disturbances in depression and ARNTL polymorphism (p = 7 × 10−4; rs11022778, rs156243).