Clinical characteristics indexing genetic differences in schizophrenia: a systematic review

Genome-wide studies are among the best available tools for identifying etiologic processes underlying psychiatric disorders such as schizophrenia. However, it is widely recognized that disorder heterogeneity may limit genetic insights. Identifying phenotypes indexing genetic differences among patients with non-affective psychotic disorder will improve genome-wide studies of these disorders. The present study systematically reviews existing literature to identify phenotypes that index genetic differences among patients with schizophrenia and related disorders. We systematically reviewed family-based studies and genome-wide molecular-genetic studies investigating whether phenotypic variation in patients with non-affective psychotic disorders (according to DSM or equivalent systems) was associated with genome-wide genetic variation (PROSPERO number CRD42019136169). An electronic database search of PubMed, EMBASE, and PsycINFO from inception until 17 May 2019 resulted in 4347 published records. These records included a total of 813 relevant analyses from 264 articles. Two independent raters assessed the quality of all analyses based on methodologic rigor and power. We found moderate to strong evidence for a positive association between genetic/familial risk for non-affective psychosis and four phenotypes: early age of onset, negative/deficit symptoms, chronicity, and functional impairment. Female patients also tended to have more affected relatives. Severity of positive symptoms was not associated with genetic/familial risk for schizophrenia. We suggest that phenotypes with the most evidence for reflecting genetic difference in participating patients should be measured in future large-scale genetic studies of schizophrenia to improve power to discover causal variants and to facilitate discovery of modifying genetic variants.