Polygenic risk and conversion from depression to bipolar disorder

TY - CONF

T1 - Polygenic risk and conversion from depression to bipolar disorder

AU - Musliner, Katherine

AU - Vilhjálmsson, Bjarni Jóhann

AU - Agerbo, Esben

AU - Zandi, Peter P

AU - Mortensen, Preben Bo

AU - Børglum, Anders

AU - Østergaard, Søren Dinesen

N1 - Conference code: 32

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Background: Early identification and treatment of individuals with bipolar disorder (BD) has the potential to improve treatment efficacy as well as long-term prognosis and outcome. Most individuals with BD experience a depressive episode prior to their first hypomanic, manic or mixed episode, and many of these patients are therefore first diagnosed with- and treated for major depression (MD). Knowing which individuals with MD who are at increased risk for converting to BD could prove an effective strategy for early identification and intervention, which is likely to improve prognosis. In this study, we examined whether polygenic liabilities for three mental disorders (BD, MD and schizophrenia (SZ)) are associated with conversion from MD to BD. Methods: Participants included 15,424 unrelated individuals (69% female, 10-35 years old) from the iPSYCH2012 sample who were diagnosed with MD (ICD-10 codes F32-F33) in Danish psychiatric hospitals between 1991 and 2016. Patients were followed from their first in- or outpatient MD diagnosis until their first BD diagnosis, death, emigration, or Dec 31 2016, whichever came first. Cumulative incidence of BD was calculated using Kaplan Meier curves with death as a competing event. Hazard ratios were calculated using Cox regressions with death as a competing event. All regression models were adjusted for the first 5 ancestral principal components (PCs) and stratified by birth year. Polygenic risk scores (PRS) for MD, BD and SZ were calculated using the most recent summary statistics from the PGC and 23andMe and operationalized as standardized continuous variables (M=0, SD=1), and quartiles. Results: Results suggest that higher PRS for BD is significantly associated with increased hazard of converting from MD to BD. For each 1 SD increase in PRS-BD, hazard of converting to BD increased by 19% (HR=1.19, 95% CI: 1.09-1.29; p < .0001). Compared to the bottom quartile of PRS-BD, MD patients in the top quartile were 65% more likely to convert to BD (HR=1.65, 95% CI: 1.31-2.07; p < .0001). Compared to the overall cumulative incidence of BD (6.6%, 95% CI: 5.7-7.6%), the cumulative incidence among individuals in the top quartile of PRS-BD was 8.9% (95% CI: 6.7-11.4%; Gray's test for equality: χ2=21.8, p > .0001). Polygenic risk scores for MD (1.03, 95% CI: 0.95-1.12: p = .42) and SZ (1.08, 95% CI: 0.99-1.17; p=.08) were not significantly associated with conversion to BD. Conclusions: Polygenic risk scores for BD may prove useful for early identification of individuals diagnosed with MD who are at increased risk for BD. However, more research is needed to evaluate the predictive capacity of these scores in a clinical setting, both on their own and in combination with other known risk factors for conversion. The fact that PRS-MD and PRS-SZ were not associated with conversion to BD suggests that the effect of genes on conversion risk is disorder specific.

AB - Background: Early identification and treatment of individuals with bipolar disorder (BD) has the potential to improve treatment efficacy as well as long-term prognosis and outcome. Most individuals with BD experience a depressive episode prior to their first hypomanic, manic or mixed episode, and many of these patients are therefore first diagnosed with- and treated for major depression (MD). Knowing which individuals with MD who are at increased risk for converting to BD could prove an effective strategy for early identification and intervention, which is likely to improve prognosis. In this study, we examined whether polygenic liabilities for three mental disorders (BD, MD and schizophrenia (SZ)) are associated with conversion from MD to BD. Methods: Participants included 15,424 unrelated individuals (69% female, 10-35 years old) from the iPSYCH2012 sample who were diagnosed with MD (ICD-10 codes F32-F33) in Danish psychiatric hospitals between 1991 and 2016. Patients were followed from their first in- or outpatient MD diagnosis until their first BD diagnosis, death, emigration, or Dec 31 2016, whichever came first. Cumulative incidence of BD was calculated using Kaplan Meier curves with death as a competing event. Hazard ratios were calculated using Cox regressions with death as a competing event. All regression models were adjusted for the first 5 ancestral principal components (PCs) and stratified by birth year. Polygenic risk scores (PRS) for MD, BD and SZ were calculated using the most recent summary statistics from the PGC and 23andMe and operationalized as standardized continuous variables (M=0, SD=1), and quartiles. Results: Results suggest that higher PRS for BD is significantly associated with increased hazard of converting from MD to BD. For each 1 SD increase in PRS-BD, hazard of converting to BD increased by 19% (HR=1.19, 95% CI: 1.09-1.29; p < .0001). Compared to the bottom quartile of PRS-BD, MD patients in the top quartile were 65% more likely to convert to BD (HR=1.65, 95% CI: 1.31-2.07; p < .0001). Compared to the overall cumulative incidence of BD (6.6%, 95% CI: 5.7-7.6%), the cumulative incidence among individuals in the top quartile of PRS-BD was 8.9% (95% CI: 6.7-11.4%; Gray's test for equality: χ2=21.8, p > .0001). Polygenic risk scores for MD (1.03, 95% CI: 0.95-1.12: p = .42) and SZ (1.08, 95% CI: 0.99-1.17; p=.08) were not significantly associated with conversion to BD. Conclusions: Polygenic risk scores for BD may prove useful for early identification of individuals diagnosed with MD who are at increased risk for BD. However, more research is needed to evaluate the predictive capacity of these scores in a clinical setting, both on their own and in combination with other known risk factors for conversion. The fact that PRS-MD and PRS-SZ were not associated with conversion to BD suggests that the effect of genes on conversion risk is disorder specific.

M3 - Poster

T2 - 32nd ECNP Congress

Y2 - 7 September 2019 through 10 September 2019

ER -