Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Abstract

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10^-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h²=0.35; BD II SNP-h²=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Figure 1

ICCBD sample description and analysis pipeline. The top panel (table) shows the composition of the ICCBD data set by site, genotyping platform and phenotype. The three ICCBD sites are represented by color, and the BD subtypes by shade. The bottom panel uses this representation of the dataset to diagram the workflow of the study and the portions of the ICCBD data set included in each analysis presented in the manuscript. Thickened borders designate the included subset, while excluded subsets are colored in grey. The coloring of text in the bottom panel is intended to illustrate how the same method (e.g., SNP-based heritability) was utilized for multiple purposes (i.e., ensuring similarity to previous GWAS, and comparing BD I to BD II). BD, bipolar disorder; GWAS, genome-wide association studies; ICCBD, International Cohort Collection for Bipolar Disorder; SNP, single-nucleotide polymorphism.

Figure 2

Association results for the ICCBD–PGCBD meta-analysis (13 902 cases, 19 279 controls). Horizontal axis shows chromosome and position. Vertical axis shows the –log10 P-value for association with BD. The table shows detailed statistics of the index SNP from each independent locus. The color of chromosome and SNP in the table corresponds the color of points for that locus in the Manhattan plot. BD, bipolar disorder; ICCBD, International Cohort Collection for Bipolar Disorder; PGCBD, the Psychiatric Genomics Consortium Bipolar Disorder Group; SNP, single-nucleotide polymorphism.

Figure 3

SNP heritability and genetic correlation estimations for BD I and BD II. We estimated the SNP-h² for BD I (n=2,811 cases) and BD II (n=1398 cases), as well as the genetic correlation (r_g) explained by SNPs between BD I and BD II (r_g-I/II) and between random subsets of BD cases (r_g-mix). (a) Sample splitting procedures for SNP-based heritability and genetic correlation estimation. (b) SNP-based heritability estimates for BD I and BD II. We observed a significant difference in the SNP-h² of BD I and BD II (BD I SNP-h²=0.35, SE=0.02; BD II SNP-h²=0.25, SE=0.04; two-sided t-test P=0.02). (c) SNP-based heritability estimates for BD I and BD II stratified by cohort. (d) Genetic correlation estimates. The distributions of the 100 r_g-I/II and the 10 000 r_g-mix estimates are presented. A significant difference between the distributions was observed (P=6.25 × 10⁻⁴⁵ for a two-sided t-test of mean difference between the empirical r_g-I/II and r_g-mix distributions). BD, bipolar disorder; BDRN, Bipolar Disorder Research Network; SNP, single-nucleotide polymorphism; SWEBIC, Swedish Bipolar Disorder Cohort.

Figure 4

Comparison of BD subtypes with one another and controls using bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) polygenic scores. Regression analyses of phenotype (top: BD subtype vs controls; bottom: BD subtype vs BD subtype) on polygenic scores derived from three previous GWAS (blue—BD, red—SCZ and green—MDD) were performed using MDS components and study site as covariates. The t-statistic plotted on the x axis is the ratio of the coefficient of the polygenic score variable and its standard error from the generalized linear model regression equation. The direction of the plotted bars indicates the phenotype in the comparison with the higher polygenic scores. The P-values for whether scores differed significantly between phenotypes are shown at the far right. Nagelkerke’s R² values were derived from a corresponding logistic regression analysis performed for each phenotype comparison, and are used as to estimate the variance in phenotype explained by the polygenic score. GWAS, genome-wide association studies.