Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Transl Psychiatry. 2017 Jan 10;7(1):e993. doi: 10.1038/tp.2016.242.


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.

MeSH terms

  • Aminopeptidases / genetics
  • Ankyrins / genetics
  • Bipolar Disorder / classification
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / psychology
  • Calcium Channels, L-Type / genetics
  • Calmodulin-Binding Proteins / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 10 / genetics
  • Cytoskeletal Proteins
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Psychotic Disorders / genetics*
  • Psychotic Disorders / psychology


  • ADD3 protein, human
  • ANK3 protein, human
  • Ankyrins
  • CACNA1C protein, human
  • Calcium Channels, L-Type
  • Calmodulin-Binding Proteins
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SYNE1 protein, human
  • Aminopeptidases
  • X-Pro aminopeptidase