scholarly journals Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Brandon J. Coombes ◽  
Matej Markota ◽  
J. John Mann ◽  
Colin Colby ◽  
Eli Stahl ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Psychiatric Disorders ◽  
Suicide Attempts ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Rapid Cycling ◽  
Clinical Heterogeneity ◽  
Polygenic Risk ◽  
Clinical Observations ◽  
History Of

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.

scholarly journals Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

2020 ◽  
Author(s):  
Brandon J. Coombes ◽  
Matej Markota ◽  
J. John Mann ◽  
Colin Colby ◽  
Eli Stahl ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Psychiatric Disorders ◽  
Suicide Attempts ◽  
Risk Scores ◽  
Rapid Cycling ◽  
Clinical Heterogeneity ◽  
Polygenic Risk ◽  
Clinical Observations ◽  
History Of ◽  
Dsm Iv

AbstractBipolar 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 PRS analysis using multiple polygenic risk scores (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 underlies the clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.

scholarly journals Delineating genetic and familial risk for psychopathology in the ABCD study

2020 ◽  
Author(s):  
Clare E Palmer ◽  
Robert John Loughnan ◽  
Carolina Makowski ◽  
Wesley Thompson ◽  
Deanna Barch ◽  
...  
Keyword(s):  
Family History ◽  
Psychiatric Disorders ◽  
Genetic Risk ◽  
Familial Risk ◽  
Risk Scores ◽  
Typically Developing ◽  
Polygenic Risk ◽  
Hyperactivity Disorder ◽  
History Of ◽  
Risk Predictors

Psychiatric disorders place a huge burden on those affected and their families, as well as society. Nearly all psychiatric disorders have a heritable component and lifetime prevalence rates of several disorders are higher among first degree biological relatives of individuals with a diagnosis. Given that many psychiatric disorders have their onset in adolescence, estimating genetic risk during childhood may identify at-risk individuals for early intervention that can reduce this burden. Here we measured genetic risk for psychopathology using both polygenic risk scores (PRS) and family history in a large typically developing sample of 9-10 year old children from the Adolescent Brain and Cognitive Development (ABCD) StudySM and determined associations with a large battery of behavioural phenotypes. By including all genetic risk predictors in the same model, we were able to delineate unique behavioral associations across these measures. Polygenic risk for Attention Deficit Hyperactivity Disorder (ADHD) and depression (DEP) was associated with unique patterns of both externalizing and internalizing behaviors. Family history of conduct problems, depression and anxiety/stress additionally predicted unique behavioral variance across similar measures. These findings provide important insight into the potential predictive utility of PRS and family history in early adolescence and suggest that they may be signaling differential, additive information that could be useful for quantifying risk during development.

scholarly journals Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia

2015 ◽  
Vol 72 (7) ◽  
pp. 635 ◽  
Author(s):  
Esben Agerbo ◽  
Patrick F. Sullivan ◽  
Bjarni J. Vilhjálmsson ◽  
Carsten B. Pedersen ◽  
Ole Mors ◽  
...  
Keyword(s):  
Socioeconomic Status ◽  
Family History ◽  
Psychiatric Disorders ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
History Of ◽  
Parental Socioeconomic Status

scholarly journals Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder

2021 ◽  
Author(s):  
Bronwyn J. Overs ◽  
Gloria Roberts ◽  
Kate Ridgway ◽  
Claudio Toma ◽  
Dusan Hadzi-Pavlovic ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
High Risk ◽  
Risky Behavior ◽  
Suicide Attempts ◽  
High Risk Group ◽  
Anterior Cingulate ◽  
European Ancestry ◽  
Risk Scores ◽  
Suicidal Behaviors ◽  
Polygenic Risk

Aims: Bipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) - a quantitative index of genomic risk - and variability in brain structures implicated in SA. Methods: Participants (n=206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives ('high-risk'), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson Linnér et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. Results: SA-in-MDD and SA-in-BD PRS negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the 'high-risk' group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group. Conclusions: This study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.

scholarly journals Potential use of clinical polygenic risk scores in psychiatry – ethical implications and communicating high polygenic risk

2018 ◽  
Author(s):  
Andrea C Palk ◽  
Shareefa Dalvie ◽  
Jantina De Vries ◽  
Alicia R Martin ◽  
Dan J Stein
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Information ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Ethical Implications ◽  
Risk Scoring ◽  
Therapeutic Recommendations ◽  
Clinical Potential ◽  
Potential Use

Psychiatric disorders present distinct clinical challenges which are partly attributable to their multifactorial aetiology and the absence of laboratory tests that can be used to confirm diagnosis or predict risk. Psychiatric disorders are highly heritable, but also polygenic, with genetic risk conferred by interactions between thousands of variants of small effect that can be summarized in a polygenic risk score. We discuss four areas in which the use of polygenic risk scores in research and clinical contexts could have ethical implications , with a particular focus on potential challenges that could arise with the feedback and interpretation of high polygenic risk for a psychiatric disorder . While there would be extensive overlap with the challenges of feeding back genetic findings in general, the potential clinical use of polygenic risk scoring warrants discussion in its own right, given the recency of this possibility. To this end, we discuss how lay interpretations of risk and genetic information could intersect. Consideration of these factors would be necessary for ensuring effective and constructive communication and interpretation of polygenic risk information which, in turn, could have implications for the uptake of any therapeutic recommendations. Recent advances in polygenic risk scoring have major implications for its clinical potential, however, care should be taken to ensure that communication of polygenic risk does not feed into problematic assumptions regarding mental disorders or support reductive interpretations.

scholarly journals Potential use of clinical polygenic risk scores in psychiatry – ethical implications and communicating high polygenic risk

2018 ◽  
Author(s):  
Andrea C Palk ◽  
Shareefa Dalvie ◽  
Jantina De Vries ◽  
Alicia R Martin ◽  
Dan J Stein
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Information ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Ethical Implications ◽  
Risk Scoring ◽  
Therapeutic Recommendations ◽  
Clinical Potential ◽  
Potential Use

Psychiatric disorders present distinct clinical challenges which are partly attributable to their multifactorial aetiology and the absence of laboratory tests that can be used to confirm diagnosis or predict risk. Psychiatric disorders are highly heritable, but also polygenic, with genetic risk conferred by interactions between thousands of variants of small effect that can be summarized in a polygenic risk score. We discuss four areas in which the use of polygenic risk scores in research and clinical contexts could have ethical implications , with a particular focus on potential challenges that could arise with the feedback and interpretation of high polygenic risk for a psychiatric disorder . While there would be extensive overlap with the challenges of feeding back genetic findings in general, the potential clinical use of polygenic risk scoring warrants discussion in its own right, given the recency of this possibility. To this end, we discuss how lay interpretations of risk and genetic information could intersect. Consideration of these factors would be necessary for ensuring effective and constructive communication and interpretation of polygenic risk information which, in turn, could have implications for the uptake of any therapeutic recommendations. Recent advances in polygenic risk scoring have major implications for its clinical potential, however, care should be taken to ensure that communication of polygenic risk does not feed into problematic assumptions regarding mental disorders or support reductive interpretations.

scholarly journals Applying polygenic risk scoring for psychiatric disorders to a large family with Bipolar Disorder and Major Depressive Disorder

2017 ◽  
Author(s):  
Simone de Jong ◽  
Mateus Jose Abdalla Diniz ◽  
Andiara Calado Saloma Rodrigues ◽  
Ary Gadelha ◽  
Marcos L Santoro ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Psychiatric Disorders ◽  
Risk Scores ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Common Variation ◽  
The Family ◽  
Risk Scoring

ABSTRACTWe aim to investigate the application of polygenic risk scoring within a family context. Polygenic risk profiles could aid in unraveling the role that common variation confers on disease risk within a pedigree that would have traditionally been viewed through the prism of monogenic inheritance only. We illustrate our discussion by analyzing polygenic risk scores for schizophrenia, major depressive disorder and bipolar disorder in a large pedigree (n~260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. We apply polygenic risk scores to study patterns of assortative mating and anticipation, whereby it appears increased polygenic risk for psychiatric disorders is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations in the family. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity of a disease increases over the generations of a family. Joint analyses of both rare and common variation may be the most powerful way to understand the familial genetics of mood and psychiatric disorders.

scholarly journals Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders

2018 ◽  
Vol 213 (3) ◽  
pp. 535-541 ◽  
Author(s):  
Maria Stella Calafato ◽  
Johan H. Thygesen ◽  
Siri Ranlund ◽  
Eirini Zartaloudi ◽  
Wiepke Cahn ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Predictive Models ◽  
Genetic Variants ◽  
Psychotic Disorders ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Early Interventions ◽  
Polygenic Risk ◽  
Increases In Risk ◽  
Shared Genetic

BackgroundThere is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.MethodUsing the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.ResultsPatients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.ConclusionsAlthough polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

scholarly journals Gambling problems in bipolar disorder in the UK: Prevalence and distribution

2015 ◽  
Vol 207 (4) ◽  
pp. 328-333 ◽  
Author(s):  
Lisa Jones ◽  
Alice Metcalf ◽  
Katherine Gordon-Smith ◽  
Liz Forty ◽  
Amy Perry ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Problem Gambling ◽  
Severity Index ◽  
Gambling Problems ◽  
Rapid Cycling ◽  
Probable Significance ◽  
History Of ◽  
Gambling Severity ◽  
The Uk

BackgroundNorth American studies show bipolar disorder is associated with elevated rates of problem gambling; however, little is known about rates in the different presentations of bipolar illness.AimsTo determine the prevalence and distribution of problem gambling in people with bipolar disorder in the UK.MethodThe Problem Gambling Severity Index was used to measure gambling problems in 635 participants with bipolar disorder.ResultsModerate to severe gambling problems were four times higher in people with bipolar disorder than in the general population, and were associated with type 2 disorder (OR = 1.74, P = 0.036), history of suicidal ideation or attempt (OR = 3.44, P = 0.02) and rapid cycling (OR = 2.63, P = 0.008).ConclusionsApproximately 1 in 10 patients with bipolar disorder may be at moderate to severe risk of problem gambling, possibly associated with suicidal behaviour and a rapid cycling course. Elevated rates of gambling problems in type 2 disorder highlight the probable significance of modest but unstable mood disturbance in the development and maintenance of such problems.

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