Further research is also required on the genetic and environmental factors that modulate the AAO in BD, which is likely to be multifactorial and determined by many genes with small effect sizes or other variants not measured well by SNP arrays, such as rare alleles or copy number variations545556. Future studies then should investigate other candidate genes that have been suggested to modulate the AAO such as those encoding the apolipoprotein E57, the dopamine receptors DRD1, DRD2 and DRD3585960, CACNA1C61, the brain derived neurotrophic factor (possibly in interaction with sexual abuse)6263, the catechol-O-methyltransferase64, the glucocorticoid and mineralocorticoid receptors65, HTR2A and HTR2C16, Period366, the glycogen synthase kinase 3-beta676869 or SNAP257071. Interestingly, we recently demonstrated the interaction between a variant of the Toll-like receptor gene (TLR2) and sexual abuse on the AAO of BD72. Several other environmental factors can also contributed to the modulation of the AAO such as solar insolation, light exposure737475 or exposure to stimulants76, as well as antidepressants77. Among investigated environmental factors that modulate the AAO of BD, the role of early cannabis misuse has been widely proposed47879808182. The
