Schizophrenia, bipolar disorder, and other severe mental diseases are heritable, highly complex disorders that are among the leading causes of disability in the world. For a study, researchers sought to evaluate the reach of the existing neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration healthcare system and to investigate links between the PRS and broad categories of human illness using phenome-wide association studies.

The computerized health data of the Veterans Health Administration were thoroughly examined between October 1999 and January 2021, and an embedded cohort of 9,378 people with bipolar 1 disorder or schizophrenia was discovered. About 400,000 people participated in the Million Veteran Program, and the performance of schizophrenia, bipolar disorder, and major depression PRSs were examined. Associations between the PRSs and 1,650 illness categories based on ICD-9/10 billing codes were also investigated. The last step was to use genomic structural equation modeling to create new PRSs that measure both generic and disorder-specific genetic variables. Between January 2021 and January 2022, an analysis was conducted. ICD-9/10 billing codes and diagnoses based on in-person structured clinical interviews were compared. Summary data from genome-wide association studies of schizophrenia, bipolar disorder, and major depression were used to create PRSs.

About 459,667 of the 707,299 research participants had their genotypes determined as of the time of writing; of these, 84,806 had a mostly African ancestry (mean [SD] age, 58 [12.1] years), and 314,909 had a predominantly European ancestry (mean [SD] age, 66.4 [13.5] years). ICD-9/10 codes enabled 8,962 (95.6%) of the 9,378 people with verified diagnoses of schizophrenia or bipolar 1 disorder to be located (2 or more). PRSs were significantly linked with having been given a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar illness (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295) among people of European ancestry. Participants of African ancestry had significantly lower corresponding effect sizes for bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P< 10-10) and schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P< 10-38). Various mental and physical health issues were linked to higher risk in neuropsychiatric PRSs.

The validity of an electronic health records-based phenotyping strategy was proven in US veterans using diagnoses supported by in-person structured clinical interviews and current neuropsychiatric PRSs, emphasizing the potential of PRSs for separating biological and mediated pleiotropy.

Reference: jamanetwork.com/journals/jamapsychiatry/fullarticle/2796413