Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

Myrna M Weissman,Joanna M Biernacka,Colin Colby,Ardesheer Talati,J John Mann,Matej Markota,Jyotishman Pathak,Brandon J Coombes,Eli Stahl,Mark A Frye,Susan L Mcelroy

doi:10.1038/s41398-020-00996-y

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.

Highlights

Many psychiatric disorders have moderate to high heritability; the genetics of psychiatric disorders are complex and highly polygenic, with each risk variant only conferring a small effect[1]
Psychiatric disorders have a high level of overlapping clinical heterogeneity, with shared genetic risk explaining some of the clinical overlap, and certain combinations of alleles may contribute to the same psychopathological symptoms in multiple psychiatric disorders
The GAIN-Bipolar disorder (BD) cases had a higher rate of psychosis and early-onset BD, while Mayo Clinic cases had higher rates of rapid cycling, which is more prevalent in women[53]

Summary

Introduction

Many psychiatric disorders have moderate to high heritability; the genetics of psychiatric disorders are complex and highly polygenic, with each risk variant only conferring a small effect[1]. Some psychiatric disorders may lie on a continuum rather than being disorders with distinct genetics and biological mechanisms[2,3]. To accommodate this genetic complexity, investigations of psychiatric disorders have increasingly relied on polygenic risk scores (PRSs), leveraging knowledge from prior large genome-wide association studies (GWASs) to predict genetic risk of particular disorders in a new sample[4]. One approach is to examine potential relationships of clinical phenotypes to different genetic profiles

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Discussion

Conclusion