Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder

Abstract

Objective: Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD.

Methods: We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway.

Results: Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality.

Conclusion: This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Keywords: AANAT; Bipolar disorder; Circadian rhythm; Melatonin pathway; Seasonality.

Figure 1.

Scaled graphical representation of the 10 Kb genomic region surrounding the AANAT including association analysis results. Relative positions of SNPs directly genotyped in this study and imputed SNPs are presented. Coding exons of the genes in the regions are shown in gray, noncoding exons in black. SNPs that showed significant association with seasonality of BD are highlighted in the red circle. Bottom of diagram, there is the LD pattern of the region determined and visualized using the Haploview, and LD blocks were defined according to Gabriel criteria[53]. SNP: single nucleotide polymorphism, BD: bipolar disorder, LD: linkage disequilibrium.