Whole-Exome Sequencing Identifies Potential Candidate Genes Associated With Carly-Onset Bipolar Disorder

Background:Bipolar Disorder is a severe and common psychiatric disease.It manifests mania episodes,or hypomania episodes plus an episode of major depression.It afflicts approximately 1%of the global population and usually occurs in adolescence or early adulthood.15-20%of them eventually die of suicide.Due to its unclear etiology and pathogenesis,we still lack the biomarkers for diagnosis and treatment,and the misdiagnosis rate of BD is high.In-depth studies for underlying pathogeny of BD are urgently needed.Numerous studies indicated heritability contributes up to～80%of lifetime risk for BD and was considered an important factor for the development of BD.In recent years,genetic studies showed that rare mutations maybe have bigger effects.Meanwhile,as an important clinical subgroup of BD,early-onset BD has more serious clinical symptoms,more commodities,higher risk of suicide,and worse treatment response.It is difficult to achieve early diagnosis and intervention in clinical practice,and its genetic effect is also higher than that of late-onset BD.With the development of sequencing technology,Whole-exome Sequencing is a good strategy to identify disease-related rare functional variants and pathway in early-onset BD which would help us understand the underlying pathogenisis and biomarkers of BD,as well as drug target.Object:In this study,we selected 91early-onset BD patients,aiming to identif disease-related rare functional variants and pathway in the Chinese Han population.Methods:A total of 91 patients with BD were enrolled from the affiliated brain Hospital of Guangzhou Medical University from January 2012 to May 2019.The structured clinical interviews with the fifth edition of American Diagnostic and Statistical Manual of Mental Disorders were used to determine the clinical diagnosis.Each subject was collected whole blood of 2ml.After genomic DNA was extracted by phenol-chloroform method,all subjects were sequenced with Illumina ASA genechip.Firstly,KGGSeq was used for quality control,filtering common variants,annotation,and variant pathogenicity prediction.Secondly RUNNER was used for rare variant load analysis to identify BD-related risk genes,We also used the KGGSeq to combined with multi-omics data in order to identity genes which significantly express in brain.At last we used DAVID software to perform richment analysis for all candidate genes to explore whether BD-related risk genes are enriched in some signaling pathways,so as to lay the foundation for further research.Results:We identified 4 BD-related genes including MACF1(q=2.85×10^-13),NKX2-3(q=9.90×10^-5),JUP(q=9.40x10^-2),EN2(q=9.6x10^-2),Combined with multi-omicsdata,KIAA1671(q=4.5×10^-2)which is significantly expressed in brain tissue is added。These BD-related risk genes involved in calcium signal transduction,reward processing system,monoaminergic neuron development,synaptic development and other functions.They have been reported in schizophrenia,depression disorder,bipolar disorder,and autism spectrum disorders,suggesting that they p-lay an important role in the occurrence and development of bipolar disorder.I-n order to preliminarily clarify the internal relationship between the six candidate genes,The DAVID software was used to perform richment analysis of these genes,unfortunately,GO and KEGG analyses did not find any significant BD-related pathway.Conclusion:In this study,RUNNER was used to analyze the burden of rare variants inpatients with early-onset bipolar disorder,and five risk genes associated with early-onset BD were identified.These genes are involved in many processes such as calciumion signaling channels,reward processing,and monoaminergic neuro development,which deserve further attention.