Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

Abstract

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.

Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia

“…Unaffected members from the multimembers affected family all of north Indian origin were also recruited alongside. In addition, ~1000 SZ cases and ~1050 ethnically matched controls of north Indian origin available in the laboratory and used in a few previous genetic association studies (John et al, 2016; Kukshal et al, 2013a, 2013b) were also included in the study. Further, ~310 sporadic SZ cases mostly of African-American/Caucasian origin (henceforth referred to as American samples) recruited at Western Psychiatric Institute and Clinic (WPIC), University of Pittsburgh School of Medicine, USA were used in this study.…”

Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment

“…This highlights the importance of regulatory changes in the development of SZ (Albert & Kruglyak, ). Alternations in gene expression of multiple brain‐related genes have been detected in SZ (John et al, ). Abnormal expression may be partially explained by epimutations.…”

“…MicroRNAs are important in normal brain development and function and are known to target multiple gens at once. Thus, it is likely that individual genetic variations in miRNAs could seriously affect brain function and thus contribute to the development of mental disorders (Beveridge, Gardiner, Carroll, Tooney, & Cairns, ; Esteller, ; Hrovatin & Kunej, ; John et al, ; Krol, Loedige, & Filipowicz, ). Genetic variations in miRNAs have been associated with various mental disorders, including SZ (Esteller, ; Hrovatin & Kunej, ).…”

Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

“…In this study 11 non consanguineous families with multiple members affected with SZ were recruited from Dr. RML Hospital New Delhi, following the diagnosis and sample recruitment procedure detailed previously (John et al, 2018(John et al, , 2017(John et al, , 2016Kukshal et al, 2013). Details of the families used in the study are given in Supplementary Figure 1.…”