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).

Chronotype and sleep quality as a subphenotype in association studies of clock genes in mood disorders

“…Analyzed polymorphisms are as follows: 9 polymorphisms of CLOCK gene (rs1801260, rs3805148, rs6849474, rs11932595, rs12648271, rs6850524, rs12649507, rs4340844, rs534654), 18 polymorphisms of ARNTL gene (rs1481892, rs4146388, rs10766075, rs4757142, rs7396943, rs11824092, rs7947951, rs7937060, rs1562438, rs3816360, rs7126303, rs3789327, rs11022778, rs11600996, rs11022779, rs11022780, rs7107287, rs1982350), 6 polymorphisms of TIMELESS gene (rs2291739, rs2291738, rs7302060, rs10876890, rs11171856, rs2279665) and 9 polymorphisms of PER3 gene (rs836755, rs228727, rs10864315, rs4908694, rs228682, rs228642, rs2172563, rs2640909, rs10462021). Detailed description of protocol and analyzed polymorphisms and are presented in previous references (Dmitrzak-Weglarz et al 2015, Maciukiewicz et al 2014. TaqMan SNP (single nucleotide polymorphism) genotyping was performed using an ABI Prisms 7900HT Sequence Detection System.…”

“…Based on our previous studies, we selected OPCRIT items describing sleep problems during illness episodes such as: reduced need for sleep, initial insomnia, middle insomnia (broken sleep), early morning waking and excessive sleep (Maciukiewicz et al 2014). We found no significant effect of gender or age of onset on chronotype or sleep quality.…”

Genetic polymorphisms associated with circadian rhythm dysregulation provide new perspectives on bipolar disorder

“…The authors also found the same variant, in an epistatic interaction with a variant of the CLOCK (rs11932595) gene, contributed to sleep disorders in BD patients. This demonstrates not only the impact of genetic variations individually, but how they may interact to create endophenotypes within the BD spectrum . In addition to these factors, Pawlak et al .…”

“…BD associated with seasonal pattern (manic episodes during spring and summer and depression in the fall and winter seasons) is clearly associated with an interrupted CR, predisposition to which has been demonstrated to be increased by the presence of polymorphisms in the ARNTL (rs2279287) gene . Maciukiewicz et al., evaluating the relationship between polymorphisms in circadian genes and other BD patient characteristics, found an association of an ARNTL (rs11932595) gene variant with depression and appetite disorder. The authors also found the same variant, in an epistatic interaction with a variant of the CLOCK (rs11932595) gene, contributed to sleep disorders in BD patients.…”

Molecular circadian rhythm shift due to bright light exposure before bedtime is related to subthreshold bipolarity

“…A number of studies conclude that disruptions45, phase shift67, or instability8 of circadian rhythms are related to BD. Moreover, genetic studies have suggested an association between circadian genes and BD9101112. The therapeutic effects of mood stabilizers such as lithium or valproate in treating BD are believed to be due to effects on the rhythmic properties of circadian genes and molecular clocks via the inhibition of glycogen synthase kinase-3β1314.…”