Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

The conventional distinction between schizophrenia and manic depression has received little objective support from recent studies of phenomenology, outcome, or familial homotypy. Instead, much clinical, epidemiological, and morphological evidence suggests that within the broad range of Schneiderian schizophrenia there exists one form (congenital schizophrenia) that can be distinguished from other types, the manifestations of which are confined to adult life. We hypothesize that congenital schizophrenia is a consequence of aberrant brain development during fetal and neonatal life. Such patients show structural brain changes and cognitive impairment, and in their male predominance, early onset, and poor outcome, they reflect Kraepelin's original description of dementia praecox. We contend that adult-onset schizophrenia is itself heterogeneous. One important component is a relapsing and remitting disorder that is more frequent in females than in males, exhibits positive but not negative symptoms, and has much in common etiologically with affective psychosis. There also exists a very-late-onset group in which degenerative brain disorder is implicated.

The influence of sociodemographic, clinical and treatment factors on the quality of life of patients with schizophrenia has yet to be fully defined. We evaluated the quality of life of patients with schizophrenia who were attending a catchment area rehabilitation centre, in order to establish its clinical correlates. These patients had a poor to moderate quality of life which was inversely related to negative symptom severity, illness duration, the cumulative length of previous hospitalization and patient age. Patients residing in hostels or group homes had a poorer quality of life than those living independently or with their family. The presence of tardive dyskinesia was associated with a poorer quality of life. This association merits further investigation.