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Supplementary Text File Supplemenary information: Functions of prioritised genes Family #1 1. SETDB1: Encodes histone methyl transferase and involved in the regulation of a large neuron specific topological chromatin domain(Jiang et al., 2017)and known to regulate mood related behaviours and NMDA receptor subunit NR2B expression (Jiang et al., 2017) 2. LRP2: is a member of the LDL receptor family, the gene is involved in various neurodevelopmental processes and signalling (Auderset et al., 2016; Fisher and Howie, 2006; Gomes et al., 2016; Spoelgen, 2005; Spuch et al., 2012) 3. TTC21B: Involved in various neurodevelopmental processes (Driver et al., 2017; Stottmann et al., 2009). 4. ADAMTS3: Encodes a member of the ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) protein family. Recently the protein is reported to inactivate Reelin (RELN), which is involved in cell positioning and neuronal migration during brain development and modulate NMDA receptor function (Campo et al., 2009; Chen, 2005). A segregating rare variant in RELN is reported in a family with SZ and in an animal model showing behavioral abnormalities related to neuropsychiatric disorders (Sakai et al., 2016; Z. Zhou et al., 2016). 5. LRRTM2: Through the interaction with PSD-95 LRRTM2 regulates surface expression of AMPA receptors and through the LRRTM2 interaction with Neurexin1 the gene also has an important role in excitatory synapse development(de Wit et al., 2009) and maintenance of long-term potentiation (Soler-Llavina et al., 2013). The knockout micealso showed behavioural abnormalities (Voikar et al., 2013). 6. TIAM2: encodes guanine nucleotide exchange factor and is involved in neurite outgrowth, neuronal migration and synapse formation in the cerebral cortex (Goto et al., 2011; Kawauchi et al., 2003). 7. GRIN3A: encodes a subunit of the N-methyl-D-aspartate (NMDA) receptors. Knockout mice showed abnormal behavioural and cognitive functions (Mohamad et al., 2013) 8. UNC13B: is a presynaptic protein and is involved in vesicle priming for exocytosis and thus involved in neuro transmission and plasticity (Breustedt et al., 2010; Chen et al., 2013; Jahn and Fasshauer, 2012). Rare missense variants are reported in a multiply affected SZ family from Japan. 9. SHANK2: encodes protein is a member of the Shank family of synaptic proteins, in the postsynaptic density of excitatory synapses, which functions as a molecular scaffold. Because of NMDAR hypofunction and concomitant impairment of NMDAR signalling, Shank2–/– mice showed impaired long-term potentiation (LTP) and long-term depression (LTD). The mutant mice were hyperactive and recapitulated many of the behavioural phenotypes associated with autism spectrum disorder (Schmeisser et al., 2012; Won et al., 2012). Rare variants in this gene are also reported in SZ (Peykov et al., 2015) 10. AKAP5: This gene is involved in AMPA Receptor Phosphorylation and Cell-Surface Targeting (Diering et al., 2014). Knockout mice showed defect in synaptic plasticity, learning and memory related abnormalities (Weisenhaus et al., 2010) 11. PRODH: is located in 22q11, the strongest known risk factor of SZ (Levinson et al., 2011). This catalyses the first step in proline catabolism and activates NMDA and AMPA receptors and may act as a neuromodulator (Cohen and Nadler, 1997; Nadler et al., 1992). The proline is also a precursor for the neurotransmitter glutamate. The same variant rs2904551 is already reported in patients with SZ(Bender et al., 2005; Jacquet et al., 2002; Ota et al., 2014). Deletion of this gene in mice showed various psychiatry relevant phenotypes (Crabtree et al., 2016; Gogos et al., 1999; Paterlini et al., 2005; Williams, 2011) 12. FLNA: involved in neural progenitor proliferation (Lian et al., 2016)and neuronal migration (Lian et al., 2016). The protein is known to interact with glutamate receptor type 7 (Enz, 2002), dopamine D2 and D3 receptors(Lin et al., 2001) and Kv4.2 potassium channels(Lin et al., 2001). Family #2 1. GABRR3: This gene encodes a subunit of the GABA(C) receptor. Gamma amino butyric acid (GABA) is one of the neurotransmitters in the central nervous system and it regulates synaptic neurotransmission in the neurons. Alteration in the GABA neurotransmitter system is observed in SZ (Wassef et al., 2003) 2. CASR: involved in synaptic plasticity, neurotransmission, neuronal growth (Ruat and Traiffort, 2013) and promotes resting spontaneous glutamate release(Ruat and Traiffort, 2013). 3. DOCK3: regulates BDNF-TrkB signalling and, neurite and axonal outgrowth (Namekata et al., 2012, 2010). It interacts with NMDA receptors containing NR2D subunit and reduces the surface expression of NR2D (Bai et al., 2013) 4. PDE8B: encodes cyclic nucleotide phosphodiesterase (PDE). It is involved in the hydrolysis of the second messenger cAMP and is involved in various cognitive functions (Tsai et al., 2012) 5. MAGI2: involved in the recruitment of AMPA and NMDA-type glutamate receptors (Deng et al., 2006). Structural variations reported in patients with SZ and bipolar disorder (Karlsson et al., 2012; Walsh et al., 2008). Common variants in this gene reportedly increased risk of cognitive impairment in patients with SZ (Koide et al., 2012). 6. GLI3: involved in development of the cerebral cortex, hypothalamus, corpus callosum (Amaniti et al., 2013; Haddad-TÃ3volli et al., 2015; Wilson et al., 2012), and maintenance and fate specification of cortical progenitors (Wang et al., 2011) 7. VPS13B: Has an important role in the development of the central nervous system 8. CALHM1: involved in the regulation of Ca²⁺-dependent MEK, ERK, RSK and MSK signalling in cerebral neurons (Dreses-Werringloer et al., 2013). Involved in memory, long-term potentiation and NMDA and AMPA receptors phosphorylation and knockout mice showed a severe impairment in memory flexibility(Vingtdeux et al., 2016) 9. INA: is involved in intracellular transport to axons and dendrites and morphogenesis of neurons. 10. CACNG7: encodes a type II transmembrane AMPA receptor regulatory protein (TARP), involved in synaptic expression of cerebellar AMPA receptors and function (Kato et al., 2007; Studniarczyk et al., 2013; Yamazaki et al., 2010) 11. PLAUR: encodes the receptor for urokinase plasminogen activator and the gene is involved in the development of GABAergic interneurons and knockout mice have shown various behavioural abnormalities (Eagleson et al., 2011, 2010) Family #3 1. KIRREL: is a member of the nephrin-like protein family and the protein has an important role in synaptogenesis (Gerke et al., 2006). 2. GBX2: Involved in various neurodevelopmental processes, including neuronal differentiation, migration, growth etc. (Hagan et al., 2017; Sunmonu et al., 2011). 3. CELSR3: conditional knock out of Celsr3, in the mouse hippocampus has shown ∼50% reduction? of glutamatergic synapses and deficits in fear conditioning, spatial learning and memory(Thakar et al., 2017).Their roles in brain development, interneuron migration, glutamatergic synapse formation etc. are previously reported (Feng et al., 2012; Jia et al., 2014; Thakar et al., 2017; Ying et al., 2009). The gene is also known to regulate the expression of NRG1 and its receptor ErbB4 (Ying et al., 2009). 4. SCN11A: encodes a member of the sodium channel alpha subunit gene family and it is required for BDNF evoked depolarization (Blum et al., 2002) 5. UBA6: Involved in development of hippocampus and amygdala. Knockout mice showed various behavioural abnormalities relevant to autism like increased anxiety, impaired communication and decreased social interaction (Hagan et al., 2017; Sunmonu et al., 2011) 6. CDCA7L: involved in negative regulation of monoamine oxidase A (MAOA) gene expression and implicated in depressive disorder (Johnson et al., 2011; Ou et al., 2006) 7. MINK1: is a postsynaptically enriched protein and required for dendritic arborization and surface expression of AMPA receptors and has a role in maintaining the morphological integrity of dendrites and synaptic transmission (Hussain et al., 2010). 8. NTN1: is a member of laminin-related secreted proteins. Netrin-1 is implicated in the organization, plasticity and function of mesocorticolimbic DA neurons in rodents(Flores, 2011). Family #4 1. LRRC7: It is known to influence the function of mGluRs and CaMKII at synapses and involved in the localisation of mGluR5 and DISC1 in the PSD fraction. Knockout mice showed various relevant endophenotypes of schizophrenia and autism spectrum disorders(Carlisle et al., 2011). 2. KIF1A: is a member of the kinesin family. It is an anterograde motor protein and involved in the transport of membranous organelles along axonal microtubules. In the brain, interacts with AMPA receptors and therefore could potentially act as a neuronal AMPAR transport in neurons (Shin et al., 2003). It is involved in synapse maturation, postsynaptic density maturation and perisynaptic scaffold organization (Zhang et al., 2017, 2016). 3. SCN10A: encodes a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit, and is involved in action potential initiation and propagation in excitable cells. Hypermorphic mutation of this gene in mice is reported to have a phenotype resembling catatonia in schizophrenic humans (Blasius et al., 2011). 4. FZD9: is a receptor for WNT2 and is involved in Wnt-5a-mediated increase in dendritic spine density in hippocampal neurons (Ramírez et al., 2016) and the gene is involved in various cognitive functions (Ramírez et al., 2016).The knockout mice showed defects in visuospatial learning
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