16 octobre 2013

Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders

Traduction partielle : G.M.

Mol Psychiatry. 2013 Oct 15.

Excès de nouveaux variants rares de perte de fonction  dans les gènes synaptiques dans la schizophrénie et les troubles du spectre autistique


Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.


La schizophrénie (SZ ) et les troubles du spectre autistique (TSA ) sont des troubles neurodéveloppementaux complexes qui peuvent partager une pathologie sous-jacente suggérée par des variantes génétiques de risque communs. 

We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). 

As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder

Ces données appuient la formation et la maintenance  des synapses en tant que mécanismes moléculaires clés pour la SZ et les TSA.

Pmid: 24126926 
Doi: 10.1038/mp.2013.127

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