A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region

Abstract

Background Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. Methods We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1,370 controls and 2,006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). Results The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10−8 for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10−6 for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10−7 and 4.3×10−6, respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. Limitations While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. Conclusions These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness.

Challenges in diagnosis and treatment of comorbid eating disorders and mood disorders

“…For Dora, social rejection and social criticism “hurt” on a physical level. Her personality traits and history aligned with the subphenotype described by Liu et al of individuals with co‐occurring bipolar disorder and eating disorders who experience early onset of mood symptoms, suicidality, and comorbid anxiety and eating disorders …”

“…Over half of individuals with eating disorders meet diagnostic criteria for a mood disorder at some time during their lives . Conversely, a 10‐times greater rate of eating disorder diagnoses are identified in individuals with bipolar disorder compared to the general population . Depending on the individual's clinical presentation at any point in time and the orientation of the evaluating clinician, either the eating disorder or the mood disorder may be the primary focus of diagnosis and treatment.…”

Etiological influences on continuity and co‐occurrence of eating disorders symptoms across adolescence and emerging adulthood

“…These results of genetic continuity carry implications for molecular genetic studies of eating disorders (Boraska et al, ; Duncan et al, ; Liu, Study, Kelsoe, & Greenwood, ) They provide preliminary support for broadening phenotypes included in molecular genetic studies to encompass a wide range of eating pathology phenotypes, to increase power to detect shared susceptibility loci (Smoller et al, ) Furthermore, given substantial stable genetic influences across adolescence and young adulthood, molecular genetic studies might not benefit from stratifying developmental samples by age. Identifying specific genes or polygenic risk scores may in turn inform precision medicine, for example, by using genetic markers to predict disease risk or treatment response.…”

Genetics of Anorexia Nervosa

“…Despite the lack of genome-wide significant results, a majority of the replication results were in the same direction as the discovery results—a finding unlikely to be due to chance [20]. A smaller GWAS of 184 cases with bipolar disorder and a comorbid eating disorder also found suggestive hits within SOX2OT [23]. …”