A systematic review on genome-wide association studies exploring comorbidity in bipolar disorder

The comorbidities associated with bipolar disorder (BD) can worsen patients’ prognosis and increase economic costs to society. Currently, efforts are being made to identify new endophenotypes characterized by the presence of BD and another concomitant condition. We performed a search on PubMed and GWAS catalog databases to find genome-wide association studies carried out on patients with BD with any other comorbid condition. We extracted the associated SNPs that attained statistical significance and listed them to appraise their potential to define new BD endophenotypes based on the presence of comorbidities. Six articles fulfilled the inclusion criteria, and all included only patients with BD type-I (BDI). The identified comorbid conditions were migraine, externalizing disorders and eating disorders. BDI with comorbid migraine was associated with rs1160720 in the NBEA gene. BDI with comorbid anorexia or bulimia nervosa was associated with rs4854912 and rs13100379 in the SOX2-OT gene. BDI with comorbid substance abuse was associated with rs1039002 in the PDE10A gene, rs12563333 upstream of the MARK1 gene, and rs13220542 downstream of the MAP3K7 gene. BDI with comorbid alcohol dependence and substance abuse was associated with rs2727943, which is located between CNTN4 and CNTN6. However, such associations were not strong enough to replicate. The main limitations are the small size and poor description of the samples used in the included articles. Some genes involved in neurotransmission, stress response, neurogenesis and synaptic plasticity may be associated with comorbid BDI. However, evidence is too weak to consider new endophenotypes in BDI.