Polygenic influences on clinical features of schizophrenia in diverse populations

Schizophrenia is a common complex psychiatric syndrome that is clinically heterogeneous. Individual presentations embrace diverse constellations of positive, negative, and affective symptoms, and patients vary with respect to... [ view full abstract ]

Schizophrenia is a common complex psychiatric syndrome that is clinically heterogeneous. Individual presentations embrace diverse constellations of positive, negative, and affective symptoms, and patients vary with respect to onset, course and outcome, and response to treatment. Despite considerable advances in our understanding of the multifactorial architecture of schizophrenia, research on clinical features of schizophrenia has seen considerably less progress, largely owing to comparably much smaller sample sizes. We extend previous findings from the Psychiatric Genomics Consortium (PGC) Schizophrenia Phenotype Working Group, Bipolar Disorder Working Group, and Cross-Disorder Group to the Genomic Psychiatry Cohort (GPC) studies of schizophrenia and bipolar disorder. Subsequent mega-analyses combine available clinical data on substance use, age-of-onset, and symptom dimensions from the PGC and GPC in what represent the largest such studies to date, and the first to incorporate large numbers of cases with African (N=6,152) or Latino (N=1,234) ancestry. We consider the evidence of associations between symptom level items and both specific variants and aggregate genetic factors, as well as pleiotropic polygenic effects. The largest of these studies, of age-of-onset of psychotic symptoms, attained a combined discovery sample size of over 20,000 schizophrenia cases of European, African, and Latino ancestry.