Schizophrenia (SZ) is a chronic mental illness with behavioral abnormalities. Recent common variant based genome wide association studies and rare variant detection using next generation sequencing approaches have identified numerous variants that confer risk for SZ, but etiology remains unclear propelling continuing investigations. Using whole exome sequencing, we identified a rare heterozygous variant (c.545G > T; p.Cys182Phe) in Trace amine associated receptor 1 gene (TAAR1 6q23.2) in three affected members in a small SZ family. The variant predicted to be damaging by 15 prediction tools, causes breakage of a conserved disulfide bond in this G-protein-coupled receptor. On screening this intronless gene for additional variant(s) in ~800 sporadic SZ patients, we identified six rare protein altering variants (MAF < 0.001) namely p.Ser47Cys, p.Phe51Leu, p.Tyr294Ter, p.Leu295Ser in four unrelated north Indian cases (n = 475); p.Ala109Thr and p.Val250Ala in two independent Caucasian/African-American patients (n = 310). Five of these variants were also predicted to be damaging. Besides, a rare synonymous variant was observed in SZ patients. These rare variants were absent in north Indian healthy controls (n = 410) but significantly enriched in patients (p = 0.036). Conversely, three common coding SNPs (rs8192621, rs8192620 and rs8192619) and a promoter SNP (rs60266355) tested for association with SZ in the north Indian cohort were not significant (P > 0.05). TAAR1 is a modulator of monoaminergic pathways and interacts with AKT signaling pathways. Substantial animal model based pharmacological and functional data implying its relevance in SZ are also available. However, this is the first report suggestive of the likely contribution of rare variants in this gene to SZ.

MicroRNAs (miRNAs) bind to 3′UTRs of genes and negatively regulate their expression. With ~50% of miRNAs expressing in the brain, they play an important role in neuronal development, plasticity, cognition and neurological disorders. Conserved miRNA targets are present in > 60% genes in humans and are under evolutionary pressure to maintain pairing with miRNA. However, such binding may be affected by genetic variant(s) in the target sites (MiRSNPs), thereby altering gene expression. Differential expression of a large number of genes in postmortem brains of schizophrenia (SZ) patients compared to controls has been documented. Thus studying the role of MiRSNPs which are underinvestigated in SZ becomes attractive. We systematically selected 35 MiRSNPs with predicted functional relevance in 3′UTRs of genes shown previously to be associated with SZ, genotyped and tested their association with disease, using independent discovery and replication samples (total n = 1017 cases; n = 1073 controls). We also explored genetic associations with two sets of quantitative traits, namely tardive dyskinesia (TD) and cognitive functions disrupted in SZ in subsets of the study cohort. In the primary analysis, a significant association of MiRSNP rs7430 at PPP3CC was observed with SZ in the discovery and the replication samples [discovery: P = 0.01; OR (95%CI) 1.24 (1.04–1.48); replication: P = 0.03; OR (95%CI) 1.20 (1.02–1.43)]. In the exploratory analyses, five SNPs were nominally associated with TD (P values 0.04–0.004). Separately, 12 SNPs were associated with one or more of the eight cognitive domains (P values 0.05–0.003). These associations, particularly the SNP at PPP3CC merit further investigations.

Candidate gene and genome-wide association study based common risk variant identification is being complemented by whole exome sequencing (WES)/whole genome sequencing based rare variant discovery in elucidation of genetic landscape of schizophrenia (SZ), a common neuropsychiatric disorder. WES findings of de novo mutations in case-parent trios have further implied genetic etiology, but do not explain the high genetic risk in general populations. Conversely, WES in multiplex families may be an insightful strategy for the identification of highly penetrant rare variants in SZ and possibly enhance our understanding of disease biology. In this study, we analyzed a 5-generation Indian family with multiple members affected with SZ by WES. We identified a rare heterozygous missense variant (NM_003255: c.506C>T; p.Pro169Leu; MAF = 0.0001) in Tissue Inhibitor of Metalloproteinase 2 (TIMP2, 17q25.3) segregating with all 6 affected individuals but not with unaffected members. Linkage analysis indicated a maximum logarithm of the odds score of 1.8, θ = 0 at this locus. The variant was predicted to be damaging by various in silico tools and also disrupt the structural integrity by molecular dynamics simulations. WES based screening of an independent SZ cohort (n = 370) identified 4 additional rare missense variants (p.Leu20Met, p.Ala26Ser, p.Lys48Arg and p. Ile217Leu) and a splice variant rs540397728 (NM_003255:c.232-5T>C), also predicted to be damaging, increasing the likelihood of contribution of this gene to SZ risk. Extensive biochemical and knockout mouse studies suggesting involvement of TIMP2 in neurodevelopmental and behavioral deficits, together with genetic evidence for TIMP2 conferring SZ risk from this study may have possible implications for new therapeutics.

The contribution of both common and rare risk variants to the genetic architecture of schizophrenia (SZ) has been documented in genome-wide association studies, whole exome and whole genome sequencing approaches. As SZ is highly heritable and segregates in families, highly penetrant rare variants are more likely to be identified through analyses of multiply affected families. Further, much of the gene mapping studies in SZ have utilized individuals of Caucasian ancestry. Analysis of other ethnic groups may be informative. In this study, we aimed at identification of rare, penetrant risk variants utilizing whole exome sequencing (WES) in a threegeneration Indian family with multiple members affected. Filtered data from WES, combined with in silico analyses revealed a novel heterozygous missense variant (NM_080841:c.1730C>G:p.T577R; exon18) in Protein tyrosine phosphatase, receptor type A (PTPRA 20p13). The variant was located in an evolutionary conserved position and predicted to be damaging. Screening for variants in this gene in the WES data of an independent SZ cohort (n = 350) of matched ethnicity, identified five additional rare missense variants with MAF < 0.003, which were also predicted to be damaging. In conclusion, the rare missense variants in PTPRA identified in this study could confer risk for SZ. This has also derived support from concordant *

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Subjects with familial primary concomitant strabismus recruited in this study may provide a valuable resource to unravel the genetic determinants of this condition, which is a common disorder of early childhood with high ophthalmic morbidity.

Clinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease.More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.Polyphen2_HDIV, Polyphen2_HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, M-CAP and fathmm-MKL_coding and CADD scaled score =>15; or CADD scaled score>=10 and <15 but predicted to be damaging by at least two different software listed above) for further analysis. All these tools were part of Kggseq (Li et al., 2012). All these variants are henceforth referred to as "deleterious shared variants".

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