This conceptual insight extends the current theories of genetic susceptibility for mental traits and disorders. These are traditionally based on the assumption that a specific set of genes are implicated for a given mental disorder with varying degrees of genetic overlap across disorders, reflected by their genetic correlations.8,16,29 However, this is inconsistent with the extent of genetic overlap observed when accounting for mixed effect directions, which may provide a better conceptual framework for the neurobiology of mental traits and disorders. The brain is a complex organ with abundant pleiotropy across different brain regions,30 brain functions,31 and mental traits.32 Thus, it is likely that differences in activity in the same neurobiological systems alter diverse mental traits and disorders but the magnitude and direction of effect may differ across and within diagnostic categories, exemplified by evidence of increased glutamatergic neurotransmission in schizophrenia33 but decreased transmission in MD.34 This is also consistent with the fact that most genetic variants associated with mental disorders reside within regulatory elements rather than coding regions.35 Allelic variation may therefore “tune” neurobiological pathways in different directions, resulting in
