Rare genes of major effect in neuropsychiatric diseases

In comparison to the early and rapid successes with single-gene, Mendelian disorders, research into complex genetic disorders has seemed interminably slow, contradictory, and intractable (1). Neuropsychiatric disorders have demonstrated this recalcitrant behavior well and, indeed, to researchers in the field it sometimes feels like they are even more “complex” than other “complex genetic disorders” such as diabetes, cancers, asthma, coronary artery disease, and autoimmune conditions. The aspects of disorders, which make them genetically “complex” can be thought of in two ways. First, the underlying genetic risk factors are numerous and often without a direct genotype-to-phenotype correlation. Second, the complex disorder phenotype may be broader and more diffuse-certainly at a clinical level where it is often a clinicaldiagnostic end point (e.g., obesity, blood pressure, stroke, behavior, and communicated cognitions) rather than a unifying pathophysiology (e.g., cystic fibrosis lung pathology).