Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. In this study, we introduce a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data (total 29,415 cases and 40,101 controls) we identify 50 novel associated loci and 145 loci in total. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to functional mutations. Using MAGMA we also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. The set of genes identified as targets of Fragile X Mental Retardation Protein (FMRP) were enriched independent of the Loss of Function Intolerant gene set. Following stepwise conditional regression, we highlight another five gene sets that are independently associated with schizophrenia. Three of these derive from the Mouse Genome Informatics database and relate to behavioural and neurophysiological correlates of learning; Abnormal Behaviour (MP:0004924), Abnormal Nervous System Electrophysiology (MP:0002272) and Abnormal Long Term Potentiation (MP:0002207). The remaining two independently associated genes sets were voltage-gated calcium channel complexes and the 5-HT2C receptor complex. We explore the relationship amongst the gene sets using partitioned LD score regression and show that collectively they account for 60% of the genic SNP-based heritability of schizophrenia. The findings provide novel insights into the biology and genetic architecture of schizophrenia, highlighting the importance of mutation intolerant genes.