Menachem Fromer 1 , Andrew J Pocklington 2 , David H Kavanagh 2 , Hywel J Williams 2 , Sarah Dwyer 2 , Padhraig Gormley 3 , Lyudmila Georgieva 2 , Elliott Rees 2 , Priit Palta 4 , Douglas M Ruderfer 5 , Noa Carrera 2 , Isla Humphreys 2 , Jessica S Johnson 6 , Panos Roussos 6 , Douglas D Barker 7 , Eric Banks 8 , Vihra Milanova 9 , Seth G Grant 10 , Eilis Hannon 2 , Samuel A Rose 7 , Kimberly Chambert 7 , Milind Mahajan 6 , Edward M Scolnick 7 , Jennifer L Moran 7 , George Kirov 2 , Aarno Palotie 11 , Steven A McCarroll 12 , Peter Holmans 2 , Pamela Sklar 13 , Michael J Owen 2 , Shaun M Purcell 14 , Michael C O'Donovan 2
Feb 13 2014
Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.