POSTER (Image):

POSTER PRESENTATION (Video)

PRESENTER: Yimei Lu

AUTHORS: Yimei Lu, Paul Kim, Kenny Do, Travis Mize, Jain-Shing Wu, Jingchun Chen^* *: corresponding author: jingchun.chen@unlv.edu

MENTOR: Jingchun Chen

ABSTRACT:

Background: Schizophrenia (SCZ) is a serious mental disorder with high heritability but the largest genome-wide association studies (GWASs) found that common variants [minor allele frequency (MAF) > 1%] alone explain ~23 % of the variance in SCZ liability. Thus, most of the heritability remains missing. Strategies for identifying this missing heritability have been proposed, including searches for rare variants using whole-genome sequencing (WGS).

Methods: In this study, we studied 20 Chinese SCZ families. In each family, at least 2 affected siblings and at least 1 unaffected sibling, along with their parents, were conducted WGS. GATK protocols and ANNOVAR were used to align sequence reads and annotate variants. The variants on the sex chromosomes were excluded for this analysis. We focused on genetic variants that meet the following criteria: 1). present in at least two affected children but not in the unaffected siblings within each family; 2). shared by at least 2 families; 3). MAF< 0.01 based on the GnomAD database (https://gnomad.broadinstitute.org/); 4). reached nominal p < 5.13×10⁻⁵ with Fisher’s exact test. Furthermore, we did the downstream pathway analysis through Metascape program (https://metascape.org/) and String(https://string-db.org/).

Results: 762 rare variants/252 unique genes were found significantly associated with SCZ (p < 5.13×10⁻⁵) on 20 SCZ families. Only 1 % of the variants were located in the exonic region of the genes. Some variants have been reported in previous studies, while we also identified some novel variants/genes that haven’t been reported, including intergenic variants near EMBP1(C/T at chr 1:121357925, A/G at chr 1:121357942) and near VTCN1(C/T, 1:117802127). We confirmed our analysis with Integrated Genome Viewer (IGV) program. Furthermore, we found that the 252 identified genes were enriched in pathways with synaptic transmission and signaling through pathway and network analysis, which gives us new insight of the genetic risk of the disease.

Discussion: Family-based WGS of Chinese SCZ families identified that 762 rare variants/252 genes were significantly associated with SCZ in Chinese population. Among top of the lists, some genes, like ADGRB3, has been reported in previous studies, which demonstrate that our data is consistent with previous studies. The intergenic variants near EMBP1 and near VTCN1 are on the top of the list.EMBP1 (Embigin pseudogene 1) gene is a pseudogene and it’s highly expressed in liver. VTCN1 negatively regulates T-cell-mediated immune response. Currently, no studies indicated these two genes related with SCZ or any neural disease. Pathway analysis indicated that those associated genes might involve in synaptic transmission and signaling. Further investigation of these rare variants, genes, and pathways would help to further understand the genetic risk and heritability of this disease.

POSTER (Image):

POSTER PRESENTATION (Video):

PRESENTER: Adrienne S. Bugayong

AUTHORS: Adrienne S. Bugayong^1,3, Peipei Pan¹, Lorena P. Samentar^1,3, Arnold Salazar¹, Durin Uddin¹, Josue Portillo¹,  Nora B. Caberoy^1,2

MENTOR: Dr. Nora B. Caberoy¹

ABSTRACT:

A spontaneous mutation in tubby gene causes blindness, hearing loss, and obesity in mice. A combination of these phenotype is seen in rare human syndromes with unknown mechanisms. Thus, the overall goal of this study is to elucidate the role of tubby in the development of these disease phenotypes. Tubby has extra-and intracellular functions, but these do not fully explain how a single mutation in the gene led to three diseases. Thus, this study aims to define the molecular pathways involving tubby by identifying its interacting proteins and the genes that it regulates. Here, we identified Estrogen Related Receptor Beta (Esrrβ) as one of the proteins that interact with tubby in vitro and in vivo. Tubby and Esrrβ both colocalize in the retina. We also demonstrated that Esrrβ is a gene regulated by tubby. Esrrβ expression is decreased in tubby mutant mice in both mRNA and protein levels. Further analysis showed that tubby binds to the promoter of Esrrβ through the estrogen-related receptor response element (ERRE) and activates transcription of Esrrβ. In addition, we also show that tubby translocates into the nucleus and associates with the basal transcription machinery. These findings indicate that tubby is a transcription factor that regulates expression of Esrrβ. Esrrβ is associated with retinal degeneration, hearing loss, and obesity which are similar to tubby mutant phenotypes. Our findings provide a novel mechanistic insight on how tubby maintains healthy vision, and hearing, and proper energy balance through Esrrb induction.