Genetic and environment effects on structural neuroimaging endophenotype for bipolar disorder: a novel molecular approach

Abstract

We investigated gene–environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects. The blood samples underwent genome-wide genotyping and methylation quantification. We derived polygenic risk score (PRS) and methylation profile score (MPS) as weighted summations of risk single nucleotide polymorphisms and methylation probes, respectively, which were considered as molecular measures of genetic and environmental risks for BD. Linear regression was used to relate PRS, MPS, and their interaction to 44 brain structure measures quantified from magnetic resonance imaging (MRI) on 47 BDS subjects, and the results were compared with those based on family history and childhood trauma. After multiplicity corrections using false discovery rate (FDR), MPS was found to be negatively associated with the volume of the medial geniculate thalamus (FDR = 0.059, partial R2 = 0.208). Family history, trauma scale, and PRS were not associated with any brain measures. PRS and MPS show significant interactions on whole putamen (FDR = 0.09, partial R2 = 0.337). No significant gene–environment interactions were identified for the family history and trauma scale. PRS and MPS generally explained greater proportions of variances of the brain measures (range of partial R2 = [0.008, 0.337]) than the clinical risk factors (range = [0.004, 0.228]).

Can neurological soft signs and neurocognitive deficits serve as a combined endophenotype for Han Chinese with bipolar disorder?

“…This may be related to familial characteristics of endophenotypes, which enables patients and their families more likely to display the endophenotype than healthy individuals. In addition, the pathogenesis of the BD is complicated, involving multiple biological, psychological, and environmental factors (Hu et al., 2022). When NSS and cognitive deficit are used as predictors, it is therefore still difficult to accurately distinguish patients from FDR.…”

Can neurological soft signs and neurocognitive deficits serve as a combined endophenotype for Han Chinese with bipolar disorder?

“…This may be related to familial characteristics of endophenotypes, which enables patients and their families more likely to display the endophenotype than healthy individuals. In addition, the pathogenesis of the bipolar disorder is complicated, involving multiple biological, psychological, and environmental factors (Hu et al, 2022). When NSS and cognitive deficit are used as predictors, it is therefore still difficult to accurately distinguish patients from first-degree relatives.…”

Advancing translational research in neuroscience through multi-task learning

“…This approach has been repeatedly applied in psychiatric research. In particular, regularization-based analysis for biomarker identification has been applied with a focus on various disorders, e.g., schizophrenia ( 22 ), bipolar disorder ( 23 ), and major depressive disorder ( 24 ). Compared to the conventional univariate analysis, a key factor contributing to the success of these approaches is that regularization-based machine learning allowed the unbiased integration of weakly outcome-associated signals distributed over the high-dimensional space (e.g., the entire genome) into a comparatively stronger risk score.…”