Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

Keywords: bipolar disorder; polygenic risk; psychosis; schizophrenia; subphenotypes.

Figure 1.. Associated Genomic Loci Shared and Divergent Between BD and SCZ

a) Odds ratios (OR) from independent data sets of BD (blue) and SCZ (red) for each of the 114 genome-wide significant variants in the BD and SCZ vs controls GWAS. b) Manhattan plot for SCZ vs BD GWAS.

Figure 2.. Polygenic Risk Score Dissection of Clinical Symptom Dimensions

Effect size (calculated by dividing regression estimate by standard error) from regression analysis including ancestry covariates for each subphenotype and PRS for BD (x-axis) and SCZ (y-axis). Point size represents −log10(p-value) with SCZ (red) and BD (blue). Numbered subphenotypes are 1) comorbid migraine, 2) panic attacks 3) suicide attempt 4) mixed states 5) rapid cycling 6) comorbid eating disorder 7) comorbid OCD 8) year of birth 9) suicide ideation 10) panic disorder 11) number of suicide attempts 12) depressive symptoms (SCZ) 13) episodes depressive 14) episodes total 15) positive symptoms (SCZ) 16) irritable mania 17) age of onset depression 18) family history 19) episodes mixed mania 20) unipolar mania 21) alcohol substance dependence 22) age of onset mania 23) age at interview 24) number of hospitalizations. All subphenotypes are in BD except those labeled (SCZ).