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.

A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder

“…Recently, three GWAS’s of BD implicated an intergenic region at the MIR2113/POU3F2 locus in 6q16.1 8–10 . In parallel, multiple GWAS’s of educational attainment and intelligence pinpointed the same locus 11–13 .…”

Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

“…Information on SNP-EA, SNP-general intelligence and SNP-disorder associations was obtained from GWAS summary statistics 21,27,28,[47][48][49] . These aggregated results are briefly summarised here and described in detail in Table 1 and Supplementary Table 1.…”

“…Other psychiatric disorders: To assess the specificity of MVR association profiles, we also investigated GWAS summary statistics for Major Depressive Disorder (MDD) 48 , Schizophrenia (SCZ) 49 and Bipolar Disorder (BD) 49 . Cases were identified based on international consensus criteria.…”

“…For MDD, cases were identified based on a lifetime diagnosis of MDD, established using DSM-III, DSM-IV, ICD-9 and/or ICD-10 criteria 48 . For SCZ, the majority of cases were diagnosed using DSM-III, DSM-III-R, DSM-IV, ICD-10, and SCID criteria 42,49 . BD cases were diagnosed according to DSM-III, DSM-IV-TR, DSM-IV, SCID, ICD-10 and/or RDC criteria 49,59 .…”

“…For SCZ, the majority of cases were diagnosed using DSM-III, DSM-III-R, DSM-IV, ICD-10, and SCID criteria 42,49 . BD cases were diagnosed according to DSM-III, DSM-IV-TR, DSM-IV, SCID, ICD-10 and/or RDC criteria 49,59 . For all three data sets, genotype imputation was performed using the IMPUTE2 / SHAPEIT pipeline against the 1000 Genomes Project (v3) template.…”