Title |
De novo mutations in schizophrenia implicate synaptic networks
|
---|---|
Published in |
Nature, January 2014
|
DOI | 10.1038/nature12929 |
Pubmed ID | |
Authors |
Menachem Fromer, Andrew J. Pocklington, David H. Kavanagh, Hywel J. Williams, Sarah Dwyer, Padhraig Gormley, Lyudmila Georgieva, Elliott Rees, Priit Palta, Douglas M. Ruderfer, Noa Carrera, Isla Humphreys, Jessica S. Johnson, Panos Roussos, Douglas D. Barker, Eric Banks, Vihra Milanova, Seth G. Grant, Eilis Hannon, Samuel A. Rose, Kimberly Chambert, Milind Mahajan, Edward M. Scolnick, Jennifer L. Moran, George Kirov, Aarno Palotie, Steven A. McCarroll, Peter Holmans, Pamela Sklar, Michael J. Owen, Shaun M. Purcell, Michael C. O’Donovan |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 39 | 30% |
United Kingdom | 14 | 11% |
Ireland | 5 | 4% |
Australia | 4 | 3% |
Canada | 4 | 3% |
France | 4 | 3% |
Italy | 2 | 2% |
Switzerland | 2 | 2% |
Denmark | 2 | 2% |
Other | 10 | 8% |
Unknown | 46 | 35% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 74 | 56% |
Scientists | 50 | 38% |
Practitioners (doctors, other healthcare professionals) | 4 | 3% |
Science communicators (journalists, bloggers, editors) | 4 | 3% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 27 | 2% |
United Kingdom | 10 | <1% |
Spain | 7 | <1% |
Germany | 5 | <1% |
Italy | 4 | <1% |
Netherlands | 3 | <1% |
France | 2 | <1% |
Sweden | 2 | <1% |
Japan | 2 | <1% |
Other | 16 | <1% |
Unknown | 1570 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 349 | 21% |
Researcher | 300 | 18% |
Student > Bachelor | 232 | 14% |
Student > Master | 160 | 10% |
Student > Doctoral Student | 83 | 5% |
Other | 317 | 19% |
Unknown | 207 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 472 | 29% |
Medicine and Dentistry | 308 | 19% |
Biochemistry, Genetics and Molecular Biology | 226 | 14% |
Neuroscience | 213 | 13% |
Psychology | 65 | 4% |
Other | 111 | 7% |
Unknown | 253 | 15% |