Fig. 3.

Pathways by which clock gene variation could affect the illness progression of BD. (1) Clock gene variants may be causally related to BD and directly lead to the emergence of symptoms and mediate some aspects of the illness. (2) Clock genes may act in a pleiotropic manner to alter rhythms in biological processes like neurotransmission, endocrine systems, immune response, and others that affect relevant physiology and modulate the course BD. (3) Chronobiological factors also affect behaviors that affect interactions with environmental cofactors such as sunlight, diet, and socialization. These environmental factors interact with genetic and other biological substrates (including BD-specific risk alleles) to affect the course and progression of BD. It is unclear whether these environmental effects are mediators, modulators, or both. Of note, the three pathways outlined above are not mutually exclusive and could in principle run concurrently. BD, bipolar disorder.