Table 4.
NRXN1 | REEP3 | CTTNBP2 | HTR2A | |
---|---|---|---|---|
Gene product/brain relevance | Synaptic cell-adhesion protein/synapse functioning and development in the cortical-striatal pathway40, 41 | Microtubule-binding protein/possible role in synaptic plasticity, calcium signaling, shaping tubular ER membranes in neurons46 | Cortical actin (cortactin)-binding protein/synaptic maintenance48 | G-protein-coupled serotonin receptor/cortical neuron excitation63 |
Disease relevance | Neurodevelopmental disorders incl. ASD42, 64 | ASD45 | Interacts with CDH2, implicated in canine CD8, 9, 65 | ASD, OCD35, canine CD (5-HT3 receptors)49 |
Reason for inclusion as candidatea | (1) Model (mouse) organism gene; (2) ASD gene | (2) ASD gene | (1) Model (mouse) organism gene | (1) Model (dog) organism gene; (2) human candidate—SSRI target |
Type of burden identified | Coding variants—missense variants over-represented to one isoform, NRXN1a-2 | Regulatory variants | Regulatory variants | Coding variants—missense variant in perfect linkage to a common variant rs6314 associated with response to SSRIs50 |
Validation of variants identified in present study | By comparison to ExAC—genome-wide-significant association | By EMSA—disrupt regulatory elements bound by various TF, including GATA2 | By EMSA—alter epigenetic marks active in the cortico-striatal pathway | By genotyping independent cohort; too few polymorphic sites for validation with ExAC |
Hypothesized impact of variants identified | Inaccurate cellular localization of NRXN1, or altered binding competition to its partner, modifying synaptic adhesion43 | REEP3 expression in GABA neurons inhibited by variants that reduce GATA2 binding47, leading to excitatory/inhibitory imbalance in CSTC circuit30 | Altered CTTNBP2 expression in cortical-striatal circuit in brain66 | Altered binding affinity of HTR2A, changing the activation of downstream calcium signaling in neurons32 |
aFor explanation of each category, see “Results” section