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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.

ABSTRACT: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n?~?260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

SUBMITTER: de Jong S

PROVIDER: S-EPMC6175827 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.

de Jong Simone S Diniz Mateus Jose Abdalla MJA Saloma Andiara A Gadelha Ary A Santoro Marcos L ML Ota Vanessa K VK Noto Cristiano C Curtis Charles C Newhouse Stephen J SJ Patel Hamel H Hall Lynsey S LS O Reilly Paul F PF Belangero Sintia I SI Bressan Rodrigo A RA Breen Gerome G

Communications biology 20181008

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (<i>n</i> ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying ...[more]

PMID: 30320231

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Project description:Family and genetic studies indicate overlapping liability for major depressive disorder and bipolar disorder. The purpose of the present study was to determine whether this shared genetic liability influences clinical presentation.A polygenic risk score for bipolar disorder, derived from a large genome-wide association meta-analysis, was generated for each subject of European-American ancestry (n = 1,274) in the Sequential Treatment Alternatives to Relieve Depression study (STAR*D) outpatient major depressive disorder cohort. A hypothesis-driven approach was used to test for association between bipolar disorder risk score and features of depression associated with bipolar disorder in the literature. Follow-up analyses were performed in two additional cohorts.A generalized linear mixed model including seven features hypothesized to be associated with bipolar spectrum illness was significantly associated with bipolar polygenic risk score [F = 2.07, degrees of freedom (df) = 7, p = 0.04]. Features included early onset, suicide attempt, recurrent depression, atypical depression, subclinical mania, subclinical psychosis, and severity. Post-hoc univariate analyses demonstrated that the major contributors to this omnibus association were onset of illness at age ? 18 years [odds ratio (OR) = 1.2, p = 0.003], history of suicide attempt (OR = 1.21, p = 0.03), and presence of at least one manic symptom (OR = 1.16, p = 0.02). The maximal variance in these traits explained by polygenic score ranged from 0.8% to 1.1%. However, analyses in two replication cohorts testing a five-feature model did not support this association.Bipolar genetic loading appeared to be associated with bipolar-like presentation in major depressive disorder in the primary analysis. However, the results were at most inconclusive because of lack of replication. Replication efforts were challenged by different ascertainment and assessment strategies in the different cohorts. The methodological approach described here may prove useful in applying genetic data to clarify psychiatric nosology in future studies.

Dataset Information

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.

Publications

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder.

Similar Datasets

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