Patterns of Convergence and Divergence Between Bipolar Disorder Type I and Type II: Evidence From Integrative Genomic Analyses

Abstract

Aim: Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about the genetic structure of BD subtypes. We aimed to investigate the genetic overlap and distinction of bipolar type I (BD I) & type II (BD II) by conducting integrative post-GWAS analyses. Methods: We utilized single nucleotide polymorphism (SNP)-level approaches to uncover correlated and distinct genetic loci. Transcriptome-wide association analyses (TWAS) were then approached to pinpoint functional genes expressed in specific brain tissues and blood. Next, we performed cross-phenotype analysis, including exploring the potential causal associations between two BD subtypes and lithium responses and comparing the difference in genetic structures among four different psychiatric traits. Results: SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184, and RPL10AP3, shared by BD I and II, and one locus (MAD1L1) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes affecting BD I and II through expression in specific brain regions (nucleus accumbens for BD I). Cross-phenotype analyses indicated that BD I and II share continuous genetic structures with schizophrenia and major depressive disorder, which help fill the gaps left by the dichotomy of mental disorders. Conclusion: These combined evidences illustrate genetic convergence and divergence between BD I and II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.

Keywords: Mendelian randomization; bipolar disorder; bipolar type I; bipolar type II; genome-wide association studies; transcriptome-wide association analysis.

FIGURE 1

Workflow of key methodological steps in this study. PGC: psychiatric genomics consortium, BD I: bipolar disorder type I, BD II: bipolar disorder type II, SCZ: schizophrenia, MDD: major depressive disorder.

FIGURE 2

Manhattan plots showing the association statistics for single marker analysis of BD I and II genetic overlap (Figure 2A) and distinctness (Figure 2B). The y-axis shows the GWAS −log10 p-values per SNP across chromosomes 1-22. (A) SNPs with conditional p-value < 1 × 10⁻² are shown with large black points. (B) SNPs identified by case–case genome-wide association analysis (CC-GWAS) with p < 5 × 10⁻⁸. The figures show the localization of significant loci. Details about the loci are provided in Tables 1 and 2.

FIGURE 3

Shared and trait-specific eQTLs of BD I and BD II. (A) Genomic regions that are specific to BD I (blue points), specific to BD II (green points), and shared (red points). (B) Associated 13 brain regions with BD I and BD II: cortex, frontal cortex, anterior cingulate cortex, caudate, putamen, hypothalamus, amygdala, hippocampus, substantia nigra, cerebellum, cerebellar hemisphere, spinal cord cervical c-1 (orange area), and BD I specific brain region: nucleus accumbens (light blue area). (C) Prioritized genes for shared and trait-specific regions. Genes presented reached significance (after FDR correction) in the TWAS test and were identified by two methods (FUSION and e-MAGMA). The numbers represent trait-specific genes identified by at least one method. Details are in Supplementary Tables S8–S12.