Alterations Of White Matter Integrity And Polygenic Risk For Patients With Bipolar Disorder

Objective: Bipolar disorder(BD)is a severe mood disorder with manic episode as well as depressive episode which has high prevalence,high recurrence rate,high disability rate and high death rate and it is a serious burden to families and society,yet its pathogenic mechanism still remains unclear.At present,the diagnosis of BD mainly depends on the assessment of clinical symptoms due to the lack of characteristic changes of imaging and biomarkers.Previous studies found that white matter alterations occurred in many brain regions in BD patients including commissural fibers,association fibers and projection fibers and the structural changes of the brain may be associated with the pathophysiological mechanism of BD.However,the sample sizes of most single centers were limited and the findings of studies were not consistent.Moreover,BD is a polygenic disease with high heritability and many studies showed that multiple genetic variants were related to white matter abnormalities.Therefore,it is important for us to find genetic variants in BD patients in order to explore the biological mechanism of BD.However,previous studies were mainly focus on exploring the variants of a single gene and it was hard to explain the complex polygenic genetic mechanism of BD due to the limited prediction of risk and explain of heredity grade.In recent years,more and more studies used polygenic risk scores(PRS)to evaluate the risk of diseases.Polygenic risk scores(PRS)show the additive effects of hundreds or thousands of genome-wide genetic variants and they can be used to assess the genetic risk of psychiatric disorders.Previous studies were mainly focus on exploring the relationship between PRS and clinical symptoms in patients with psychiatric diseases.However,there is no report of correlation analysis between the abnormalities of white matter integrity and PRS in BD patients.The combination of the findings of genetic variants and imaging changes could help us to further explore the internal biological mechanism of brain structural alterations caused by genetic variants.In this study,we intend to use diffusion tensor imaging(DTI)to study the changes of white matter integrity and structural alterations of the brain in BD patients and apply PRS to evaluate the genetic risk of BD,as well as the association between white matter alterations and PRS.The findings of study may provide new neuroimaging evidence for exploring the inherent biological mechanism of white matter changes observed in BD patients and its relation with genetic variants.Furthermore,the results of study may also provide theoretical supports and supplements for future imaging genetic studies and contribute to the diagnosis of BD as assistant support,as well as providing a new research direction to find target of drug therapy in the future.Methods: There were 136 BD patients who met the diagnostic and statistical manual of mental disorders-IV version(DSM-?)diagnostic criteria across the age of 13-30 years and 222 healthy controls(HC)matched with age and gender recruited through advertisements involved in the study.Demographic data collecting,clinical symptoms assessing,magnetic resonance imaging(MRI)scanning,blood samples collecting and genetic data collecting were performed for all participants.Due to the rejection of blood sample collection by some participants and some special situations occurred during the process of experiment,there were 124 participants including 52 BD patients and 72 HC who have finished genetic data collecting.DTI images were obtained by a GE 3.0T MRI machine from all participants and the images were preprocessed by PANDA.Data processing was performed by SPM to assess fractional anisotropy(FA)values and statistical analysis was applied by SPSS.We aimed to study the disruptions of white matter integrity and the affected brain regions,as well as alterations of white matter fiber tracts,in BD patients by comparing FA values between BD patients and HC by two-sample t test.After extracting genomic DNA,genotyping,imputation and quality controls of single nucleotide polymorphism(SNP)and sample,PRSice was used to generate PRS of different thresholds(0.00001,0.0001,0.001,0.01 and 0.1)in participants who have finished genetic data collecting.Partial correlation analyses were performed to study the relationship between the changes of white matter integrity and PRS in BD patients and to further explore the internal mechanism of brain structural changes due to genetic variants.Results: 1.Statistical analyses of demographic data found that there were no significant differences in age and gender between BD patients and HC(P > 0.05)and there were significant differences between them in the scores of all the clinical scales,which showed remarkable increases in the scores of Young Mania Rating Scale(YMRS),17-item Hamilton Depression Rating Scale(HAMD-17)and Hamilton Anxiety Scale(HAMA)(P < 0.05).2.Two-sample t test demonstrated that there were significant differences in FA values between BD patients and HC in the corpus callosum(CC),superior occipital gyrus white matter(O1-WM),left inferior fronto-occipital fasciculus(IFOF),anterior cingulate(AC)and thalamus(TH)(P < 0.005,GRF corrected).3.Partial correlation analyses showed that there were significant negative correlations between FA values in the TH,genu of CC(GCC)and left IFOF and PRS with the threshold of 0.00001(TH: r =-0.325,p = 0.021;GCC and IFOF: r =-0.334,p = 0.018)in BD patients.Conclusion: 1.Significantly decreased FA values were found in BD patients in multiple brain regions indicating that white matter disruptions were occurred in CC,O1-WM,left IFOF,AC and TH compared to those of HC.The findings showed that there were extensive brain structural alterations including commissural fibers,association fibers and projection fibers observed in BD patients.The abnormalities may contribute to the pathophysiological process of BD and may show as neurobiological changes of BD.The alterations occurred during the normal development of white matter may lead to disruptions of white matter integrity and brain structural changes,which may affect brain functional activities and finally result in the onset of BD.The findings provided imaging changes of BD patients as assistant method to diagnosis BD,as well as reliable imaging evidence and theoretical support to further explore the pathogenic mechanism of BD.2.There were significant negative correlations between FA values in multiple brain regions and PRS showing that the disruptions of white matter integrity in the TH,GCC and left IFOF were associated with higher polygenic risk in BD patients,indicating that PRS could be used to predict alterations of white matter in patients with BD.The white matter disruptions may be related to genetic variants which may contribute to the changes during normal development of white matter and lead to the alterations of white matter integrity and finally result in the onset of BD and clinical symptoms.Previous studies mainly focus on exploring the variants of a single gene and the explain of heredity grade as well as the prediction of risk was limited.PRS,as a new method to assess genetic risk of BD,can better explain the complex polygenic genetic mechanism of BD.The findings provide new imaging genetic evidence to further explore the pathophysiological mechanism of BD,as well as a new research direction to find target of drug therapy in the future.