Genome-wide association study in bipolar patients stratified by co-morbidity

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Genomics

Background:

• Bipolar disorder is a highly heritable psychiatric condition.
• Common comorbidities may indicate distinct patient subgroups with shared genetic risk factors.

Purpose of the Study:

• To investigate the association between single nucleotide polymorphisms (SNPs) and patient subgroups defined by comorbidities in bipolar disorder.
• To identify potential genetic risk alleles contributing to specific presentations of bipolar disorder.

Main Methods:

• Analysis of a Caucasian sample from the GAIN bipolar disorder study (1000 cases, 1034 controls).
• Testing for associations between SNPs and patient subgroups characterized by comorbid conditions.
• Utilized a recessive genetic model for association testing.

Main Results:

• A rare variant (rs1039002) near the phosphodiesterase 10A (PDE10A) gene on chromosome 6q27 was significantly associated with bipolar disorder with psychosis and/or substance abuse (p=1.7×10⁻⁸).
• Another rare variant (rs12563333) near the MAP/microtubule affinity-regulating kinase 1 (MARK1) gene on chromosome 1q41 approached genome-wide significance in the same subgroup.
• SNP rs2727943 on chromosome 3p26.3 was associated with bipolar disorder with alcohol dependence and other comorbidities (p=3.3×10⁻⁸).

Conclusions:

• Bipolar disorder heterogeneity, defined by comorbidities, can aid in identifying genetic risk alleles.
• Rare genetic variants may play a role in susceptibility to bipolar disorder.
• Findings highlight specific genes (PDE10A, MARK1, CNTN6 region) potentially involved in bipolar disorder pathophysiology.