The difficulties in identifying genes that explain the moderate heritability of major mental health disorders, including mood disorders and schizophrenia, combined with the clinical complexity and pleomorphism of these disorders, forced a rethinking of research approaches in terms of gene association studies. It is also now apparent that major mental health disorders are likely to be caused by many genes with each having a small effect, instead of one or two genes having large effects. Another model seen in childhood schizophrenia is that genetic copy number variants that may be pathogenic can differ between families. This raises the possibility of vastly more genetic pathways to a single disorder.

One approach to facilitate identification of candidate genes was to seek endophenotypes that might be associated with one ...