Polygenic risk scores may predict progression to bipolar, psychotic disorders

Tailored polygenic risk scores appeared to accurately predict progression to bipolar disorder or psychotic disorders, according to study results published in American Journal of Psychiatry.

“A substantial proportion of the population-level variance in bipolar disorder and psychotic disorders, particularly schizophrenia, is attributable to genetic factors,” Katherine L. Musliner, PhD, MPH, of the Lundbeck Foundation Initiative for Integrative Psychiatric Research in Denmark, and colleagues wrote. “Previous research has demonstrated overlap among the genetic architectures of depression, bipolar disorder and schizophrenia; however, a portion of risk variants may be disorder specific. This raises the possibility that measures of genetic liability could be used to identify patients with depression who are likely to develop bipolar disorder or psychotic disorders and possibly even differentiate between those who are at increased risk for one disorder type over the other.”

Other studies of clinical predictors of progression to bipolar disorder or schizophrenia produced consistent results suggesting that parental history is likely among the strongest predictors, further supporting the hypothesis that progression risk is partly linked to genetic factors.

In the current study, Musliner and colleagues sought to determine the extent to which genetic liability according to polygenic risk scores was associated with this progression among individuals with unipolar depression. They examined data of 16,949 individuals, of whom 69% were women and for whom the age range at first depression diagnosis was 10 to 35 years, who were included in the iPSYCH Danish case-cohort study. Participants had received a depression diagnosis in Danish psychiatric hospitals between 1994 and 2016. The investigators generated polygenic risk scores for major depression, bipolar disorder and schizophrenia using the most recent results from the Psychiatric Genomics Consortium. They estimated hazard ratios for the disorder-specific polygenic risk scores, with adjustment for two other scores, and estimated absolute risk for progression using the cumulative hazard.

Median patient follow-up was 7 years. Results showed absolute risks for progression to bipolar disorder and psychotic disorders of 7.3% and 13.8%, respectively. The researchers applied mutual adjustment for the other polygenic risk scores and found only the score for bipolar disorder predicted progression to bipolar disorder (adjusted HR [aHR] for a one-standard-deviation increase in polygenic risk score = 1.11; 95% CI, 1.03-1.21). Moreover, only the score for schizophrenia predicted progression to psychotic disorders (aHR = 1.1; 95% CI, 1.04-1.16). Parental history still significantly predicted progression to bipolar disorder (aHR = 5.02; 95% CI, 3.53-7.14) and psychotic disorders (aHR = 1.63; 95% CI, 1.3-2.06) after adjustment for polygenic risk scores.

“These results suggest that the effects of genetic liability on the hazard of progression may be somewhat disorder specific, which is consistent with findings from previous family studies, as well as recent results from imaging studies,” Musliner and colleagues wrote. “However, it is worth noting that the [polygenic risk score] for schizophrenia was significantly associated with progression to bipolar disorder before adjusting for the other [polygenic risk score] variables and was only partly attenuated (although no longer significant) after mutual adjustment. In contrast, the effect of the PRS for bipolar disorder on the hazard of progression to psychotic disorders was small even before mutual adjustment, and it was close to null thereafter.

“This suggests that the [polygenic risk score] for bipolar disorder is specifically a risk factor for progression to bipolar disorder, whereas the [polygenic risk score] for schizophrenia may be more generally associated with progression to either outcome.”