What is the contribution of common genetic variation to the genetic architecture of psychiatric intermediate phenotypes? We now have answers to this question. Brain structural variation is a plausible intermediate phenotype — similar differences in brain structure have been found in unaffected individuals at increased genetic risk of psychiatric illness and affected individuals [24–26]. These phenotypes have been subject to GWAS [27–30], and the loci identified “have comparable effect sizes to those observed in other genome-wide association studies of complex traits” [27]. One marker explains just 0.58% of intracranial volume per risk allele and required 21,151 subjects (combined cases and controls in discovery and replication samples) to be identified [27]. Mapping of measures of cognitive performance [31] similarly shows genetic effects no larger than those found for psychiatric disease. Two consortia, one based in Europe (the Wellcome Trust Case Control Consortium; http://www.wtccc.org.uk/ccc2/projects/ccc2_pe.html) and one in the United States (the Consortium on the Genetics of Endophenotypes in Schizophrenia [32, 33]), have gathered cognitive, neuroanatomical and neurophysiological phenotypes that may act on the causal pathway to schizophrenia. The European consortium has so
