Abstract :
Today multinational studies using genome-wide association scan (GWAS) for >1000,000 polymorphisms on
>100,000 cases with major psychiatric diseases versus controls, combined with next-generation sequencing have
found ~100 genetic polymorphisms associated with schizophrenia (SCZ), bipolar disorder (BD), autism,
attention deficit and hyperactivity disorder (ADHD), etc. However, the effect size of each genetic mutation has
been generally low (<1%), and altogether could portray a tiny fraction of these mental diseases. Furthermore,
none of these polymorphisms was specific to disease phenotypes indicating that they are simply genetic risk
factors rather than causal mutations.
The lack of identification of the major gene(s) in huge genetic studies increased the tendency for reexamining
the roles of environmental factors in psychiatric and other complex diseases. However, this time at
cellular/molecular levels mediated by epigenetic mechanisms that are heritable, but reversible while interacting
with the environment. Now, gene-specific or whole-genome epigenetic analyses have introduced hundreds of
aberrant epigenetic marks in the blood or brain of individuals with psychiatric diseases that include aberrations
in DNA methylation, histone modifications and microRNA expression. Interestingly, most of the current
psychiatric drugs such as valproate, lithium, antidepressants, antipsychotics and even electroconvulsive therapy
(ECT) modulate epigenetic codes.
The existing data indicate that, the impacts of environment/nurture, including the uterine milieu and early-life
events might be more significant than genetic/nature in most psychiatric diseases. The lack of significant results
in large-scale genetic studies led to revise the bolded roles of genetics and now we are at the turning point of
genomics for reconsidering environmental factors
