Genetics of Schizophrenia

Abstract

The past three decades have witnessed an explosion in human genetics research, particularly research designed to identify genetic variants causing or increasing risk for disease. These efforts began spectacularly with early successes identifying relatively infrequent diseases following classical Mendelian patterns of inheritance. Now more common diseases with complex modes of inheritance are being addressed. Schizophrenia, with an estimated heritability factor of approximately 70 percent, belongs to this category. As with other genetically complex disorders, gene-mapping efforts have achieved mixed success for schizophrenia. Research has proceeded from classical family-based linkage analyses, indicating specific regions of the genome possibly harboring susceptibility genes, to genetic association designs. The latest series of investigations involves dense sets of common polymorphisms across the entire genome comparing cases and controls. These genome-wide association studies (GWAS) have revealed several plausible risk variants, most notably in the Human Leukocyte Antigen region. Still, the identified risk variants do not fully account for estimated heritability. Thus, much of the inherited risk for schizophrenia remains undetected. The reasons for our inability to solve the so-called missing heritability problem are discussed and designs for future studies are suggested.