Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell (IPSC)-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD), in comparison with healthy controls. The BD patients also had morphological brain abnormalities in magnetic resonance imaging. Time-lapse analysis of migrating cells was conducted, through which we were able to identify several parameters to be abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind aberrant cellular phenotype identified. Our analysis showed downregulation of a network of genes, centering on EGF/ERBB proteins. Present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype; which could contribute to the functional and structural changes in the brain, reported in bipolar disorder.

Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by ≥ 3 affected members. Across the sample, gene and gene-set-wide case–control association analysis was performed with Sequence Kernel Association Test (SKAT). In 14/16 families with ≥ 3 sequenced affected individuals, we identified a total of 78 rare predicted deleterious variants in 78 unique genes shared by ≥ 3 members with SMI. Twenty (25%) genes were implicated in monogenic CNS syndromes in OMIM (OMIM-CNS), a fraction that is a significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set SKAT, statistically significant association was noted for OMIM-CNS gene-set (SKAT-p = 0.005) but not the synaptic gene-set (SKAT-p = 0.17). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes.

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IntroductionWhole Exome Sequencing (WES) studies have provided important insights into the genetic architecture of neuropsychiatric syndromes identifying rare and novel variants in the protein-coding sequence of the genome that impact function. Variants and genes that are central to the shared biology of these clinical syndromes may be identified by WES in families with multiple affected individuals with serious mental illnesses (F-SMI).MethodsWe performed WES in 250 individuals (affected = 186, family-control = 64) from 100 families, each with ≥2 members with SMI, and 60 unrelated population-controls. Within pedigree prioritization employed criteria of 1. rarity (Minor Allele Frequency <0.1%, GnomAD South-Asian sample, 15308 exomes); 2. functional consequence (‘Loss of Function’ or ‘missense deleterious in 4/5 in silico predictions). 3. sharing by ≥3 affected members within a family. Across the sample, gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship.ResultsIn 17 families with ≥3 exome samples, we identified 79 rare predicted deleterious variants in 79 unique genes shared by ≥3 affected members and absent in 60 unrelated controls. Twenty (25.32%) genes were implicated in monogenic neurodevelopmental syndromes in Online Mendelian Inheritance in Man representing a statistically significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set wise SKAT, statistically significant association was noted for genes related to synaptic function (SKAT-p = 0.017).DiscussionIn F-SMI based WES study, we identify private, rare, protein altering variants in genes previously implicated in monogenic Mendelian neuropsychiatric syndromes; suggesting pleotropic influences in neurodevelopment between complex and monogenic syndromes.