The genetic architecture of depression is likely to be highly complex. Genetic architecture refers to the number of genetic loci associated with a phenotype, the effect size of each locus, and the manner in which these loci behave (e.g., whether they have additive or multiplicative effects). While all psychiatric disorders are thought to be polygenic, or influenced by multiple genes, the genetic basis of depression may reflect an even larger number of loci of individually small effect. Results from studies that have calculated polygenic risk scores (capturing aggregate effects of loci across the genome) support such a hypothesis.64,110 Therefore, it is likely that much larger samples than those examined to date will be needed to detect these individually small effects. Simulations suggest that, to have comparable power to GWAS of schizophrenia or bipolar disorder, studies of depression will need to have sample sizes as much as five times larger.52 Experience with GWAS for other disorders has established that, once a critical sample size threshold is crossed, larger and larger sample size yields more and more loci.
