Dataset Information

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.

SUBMITTER: Coombes BJ

PROVIDER: S-EPMC7501305 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores.

Coombes Brandon J BJ Markota Matej M Mann J John JJ Colby Colin C Stahl Eli E Talati Ardesheer A Pathak Jyotishman J Weissman Myrna M MM McElroy Susan L SL Frye Mark A MA Biernacka Joanna M JM

Translational psychiatry 20200918 1

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). Pa ...[more]

PMID: 32948743

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Project description:ImportanceMajor depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive.ObjectiveTo examine whether AD and MDD overlap genetically, using a polygenic score approach.Design, settings, and participantsAssociation analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P?<?.05 to P???.99 in each AD GWAS data set.Main outcomes and measuresAssociation between MDD PRS and AD.ResultsParticipants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P?=?1.7?×?10-6, R2?=?0.026; SAGE: best P?=?.001, R2?=?0.01; Yale-Penn: best P?=?.035, R2?=?0.0018; and NHRVS: best P?=?.004, R2?=?0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P?=?3.3?×?10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P?=?7.6?×?10-6, R2?=?0.023; Yale-Penn: best P?=?.08, R2?=?0.0013; and NHRVS: best P?=?.006, R2?=?0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P?=?.007).Conclusions and relevanceThese results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

Dataset Information

Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores.

Publications

Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores.

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