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

Abstract

Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. 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. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Myosin XVI binds directly to F-actin and also regulates stress fiber remodeling in fibroblasts and neurite outgrowth in neurons via its interaction with phosphatidylinositol 3-kinase (PI3K) and the WAVE complex 129 . Genetic association between the MYO16 gene and autism has been found in two large cohorts (AGRE and ACC) of European ancestry and replicated in two other major cohorts (CAP and CART) 130 , as well as in other studies [131][132][133][134] .…”

Increased Dosage of High-Affinity Kainate Receptor Genegrik4Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features

“…Therefore, altered synaptic transfer through neuronal networks may arise as a consequence of an excess of GluK4 function at particular glutamatergic synapses during network formation and maturation, perturbing the development of neuronal projections and likely resulting in a permanent change in synaptic gain. Several studies in patients of ASD and schizophrenia support the notion of both diseases involve biological pathways engaged in synaptogenesis and glutamate neurotransmission (Kenny et al, 2014). Particularly relevant for ASD-linked behaviors may be the overexpression of GluK4 and the effects that it could induce in striatum.…”

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

“…In the first step, the DNA was prepared as an Illumina sequencing library, and in the second step, the sequencing library was enriched for the desired target using the Agilent SureSelect enrichment protocol (as described by Kenny et al, 2014 9 ) See Supplementary Information. Next generation sequencing was then conducted on an Illumina HiSeq2000 at the Queensland Brain Institute, Brisbane, Australia.…”

“…Sequencing variants were classified as rare if they had a minor allele frequency (MAF) of <.01 in the combined case-control sample 9,25,26 . Our sample size of 337 subjects has power in excess of 80% to detect rare variants with a minor allele frequency ≥ .0024.…”

“…Promising results for analyses focusing on SNVs and InDels are just beginning to emerge for psychiatric phenotypes. For example Kenny et al 9 recently employed next generation sequencing and observed an increased overall burden of SNVs and InDels in both schizophrenia and autism spectrum disorder. Hence these two classes of rare variation represent a sensible starting point for investigations of the role of rare variants in ADHD.…”