Journal Article

A polygenic burden of rare disruptive mutations in schizophrenia

Duncan, Laramie, Banks, Eric, Scolnick, Edward M., Sullivan, Patrick F., Collins, Mark O., Fromer, Menachem, Garimella, Kiran, Solovieff, Nadia, Choudhary, Jyoti S., Ruderfer, Douglas, Kähler, Anna, Fennell, Tim, O’Dushlaine, Colm, Haggarty, Stephen J., DePristo, Mark, Purcell, Shaun M., Chambert, Kimberly, Komiyama, Noboru H., Moran, Jennifer L., Lander, Eric S., Gabriel, Stacey, Roussos, Panos, Bergen, Sarah E., Genovese, Giulio, McCarroll, Steven A., Grant, Seth G. N., Stahl, Eli, Sklar, Pamela, Fernández, Esperanza, Hultman, Christina M., Magnusson, Patrik K. E., Shakir, Khalid

2014

Overview

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1 ) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease. Exome sequence analysis of more than 5,000 schizophrenia cases and controls identifies a polygenic burden primarily arising from rare, disruptive mutations distributed across many genes, among which are those encoding voltage-gated calcium ion channels and the signalling complex formed by the ARC protein of the postsynaptic density; as in autism, mutations were also found in homologues of known targets of the fragile X mental retardation protein. Pathogenic mechanisms in schizophrenia Two major sequencing studies of the exome — the protein-coding portion of the genome — in schizophrenia sufferers and their relatives are published in this issue of Nature . Together they provide strong pointers to specific pathogenic mechanisms that disrupt the glutamatergic synapses in schizophrenia. In particular, mutations that influence the action of the scaffold protein ARC (activity-regulated cytoskeleton-associated protein) are prominently involved, as are mutations in targets of the fragile X mental retardation protein (FMRP). Defects in FMRP have previously been shown to be associated with autism spectrum disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 45/43 / 631/208/205 / 631/208/514/2254 / 692/499 / 692/699/476/1799 / Algorithms / Autistic Disorder - genetics / Bipolar disorder / Calcium Channels - genetics / Confidence intervals / Cytoskeletal Proteins - genetics / Disease / Disks Large Homolog 4 Protein / DNA Copy Number Variations - genetics / Exome sequencing / Female / Fragile X Mental Retardation Protein - metabolism / Gene mutations / Genes / Genetic aspects / Genetic factors / Genetic screening / Genome-Wide Association Study / Genomes / Health aspects / Health risk assessment / Humanities and Social Sciences / Humans / Intellectual Disability - genetics / Intracellular Signaling Peptides and Proteins - genetics / Male / Membrane Proteins - genetics / Mental disorders / multidisciplinary / Multifactorial Inheritance - genetics / Multifactorial traits / Mutation / Mutation - genetics / Nerve Tissue Proteins - genetics / Population / Psychological aspects / Receptors, N-Methyl-D-Aspartate - genetics / Risk factors / Schizophrenia / Schizophrenia - genetics / Science / Studies