Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

Abstract

Bipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic polygenic risk score (PRS) analysis using multiple PRSs from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank (N = 968) and Genetic Association Information Network (N = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p = 0.003) and BMI (OR = 0.87; p = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p = 7e-5) and MDD (OR = 1.23; p = 4e-5) and lower BD PRS (OR = 0.8; p = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p = 1e-6) and anhedonia (OR = 1.22; p = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity contributes to clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

Dissecting the genetic architecture of suicide attempt and repeated attempts in Korean patients with bipolar disorder using polygenic risk scores

“…Individual risk estimation using genomic data would improve the performance of current suicide risk evaluation. However, the PRS profiles in the present study and other genomic studies (Mullins et al 2019 ; Coombes et al 2020 ; Lopes et al 2020 ; Ruderfer et al 2020 ) explained only a small portion of the variance in SA. Therefore, to be used as a prediction model of SA, the explanatory power needs to be increased by refining suicide-related phenotypes and investigating more homogeneous populations in terms of psychiatric illnesses.…”

“…In the current study, the association between PRS-OCD and lifetime SA particularly reflected an association with repeated attempts (Nagelkerke’s R 2 = 4.91% and OR = 1.53). The effect size seemed notable compared to that of previous studies on SA using PRSs for other phenotypes, e.g., MDD, schizophrenia, anxiety disorder, anhedonia, and low educational attainment (Mullins et al 2019 ; Coombes et al 2020 ; Lopes et al 2020 ). Unfortunately, no prior study has examined the association between PRS-OCD and SA, or repeated attempts.…”

“…Recent large-scale studies (Mullins et al 2019 ; Coombes et al 2020 ) supported the positive association between the PRS-MDD and SA in BD samples. In our study, the trend in association did not reach statistical significance (OR = 1.23, 95% CI = 0.99–1.53).…”

Association of polygenic risk scores, traumatic life events and coping strategies with war-related PTSD diagnosis and symptom severity in the South Eastern Europe (SEE)-PTSD cohort

“…PRS have been so far successfully applied in a variety of psychiatric diseases, such as schizophrenia, bipolar disorder, anxiety and affective phenotypes, to assess the specific genetic background of a disorder but also to explore genetic overlap between psychiatric diseases (e.g. Forstner et al 2019 ; Coombes et al 2020 ; Xavier et al 2018 ). Recently, genome-wide meta-analyses from the Psychiatric Genomic Consortium (PGC) including a large number of global studies provided PRS for PTSD (Duncan et al 2018 ; Nievergelt et al 2019 ).…”

Lithium and Valproate in Bipolar Disorder: From International Evidence-based Guidelines to Clinical Predictors

“…Clinical and pharmacogenomic studies have investigated this research field. However, pharmacogenomic studies, despite enormous potential to improve our understanding of the mood stabilizer-responding subtype of BP, are unlikely to have immediate application in clinical practice [ 18 , 19 ].…”