Circulating Blood-Based Proteins in Psychopathology and Cognition: A Mendelian Randomization Study.

Importance: Peripheral (blood-based) biomarkers for psychiatric illness could benefit diagnosis and treatment, but research to date has typically been low throughput, and traditional case-control studies are subject to potential confounds of treatment and other exposures. Large-scale 2-sample mendelian randomization (MR) can examine the potentially causal impact of circulating proteins on neuropsychiatric phenotypes without these confounds.

Objective: To identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) as well as cognitive task performance (CTP).

Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics.

Background: Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive performance and educational attainment and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility.

Methods: In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO).

Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics.

Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive ability/education and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility. In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO).

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance.

Background: Research on peripheral (e.g., blood-based) biomarkers for psychiatric illness has typically been low-throughput in terms of both the number of subjects and the range of assays performed.

Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance.

Schizophrenia is a clinically and genetically heterogeneous neuropsychiatric disorder, with a polygenic basis but identification of the specific determinants is a continuing challenge. In this study, we analyzed a multigenerational family, with all healthy individuals in the first two generations, and four progeny affected with schizophrenia in the subsequent two generations, using whole exome sequencing. We identified five rare protein sequence altering heterozygous variants, in five different genes namely SMARCA5, PDE1B, TNIK, SMARCA2 and FLRT shared among all affected members and predicted to be damaging.

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study.

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.

Rare Variants in Tissue Inhibitor of Metalloproteinase 2 as a Risk Factor for Schizophrenia: Evidence From Familial and Cohort Analysis.

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.

Pedigree Analysis of Familial Primary Concomitant Horizontal Strabismus in Northern India.

Purpose: Familial clustering of common forms of primary strabismus like esotropia (ET) and exotropia (XT) is observed in a proportion of the strabismus cohort. The genetic components of this remain unidentified. Linkage studies have demonstrated susceptibility locus for primary strabismus at the STBMS1 locus on 7p22.

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

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.

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition.

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.