Giulio Genovese 1 , 2 , 3 , Menachem Fromer 4 , 5 , Eli A. Stahl 4 , 5 , Douglas M. Ruderfer 4 , 5 , Kimberly Chambert 1 , Mikael Landén 6 , Jennifer L. Moran 1 , Shaun M. Purcell 4 , 5 , Pamela Sklar 4 , 5 , Patrick F. Sullivan 7 , 8 , Christina M. Hultman 8 , Steven A. McCarroll 1 , 2 , 3
03 October 2016
By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls ( P = 1.3 × 10 −10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.