Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population

Abstract

; for the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium IMPORTANCE Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. OBJECTIVE To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. DESIGN, SETTING, AND PARTICIPANTS Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. EXPOSURES Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. MAIN OUTCOMES AND MEASURES The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). RESULTS Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = −.07; SE = .02; P = .002). CONCLUSIONS AND RELEVANCE Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Polygenic prediction of the risk of perinatal depressive symptoms

“…and BD2018 predicted the risk of MDD in children and adults (Musliner et al, 2019), though the PRS for BD2018 predicted the…”

“…Recent studies have investigated the polygenic prediction of MDD (Halldorsdottir et al, 2019;Musliner et al, 2019) and BD and SCZ (Musliner et al, 2019) using PRSs calculated using the same GWAS summary statistics as we did (Ripke et al, 2014;Ruderfer et al, 2018;Wray et al, 2018). While these studies were conducted outside the perinatal period, they are relevant due to the partially shared genetic component among the different disorders (Cross-Disorder Group of the Psychiatric Genomics et al, 2013;Lee et al, 2019;Viktorin et al, 2016), risk factors and biological mechanisms of vulnerability (Roy & Campbell, 2013;Schiller et al, 2015;Serati, Redaelli, Buoli, & Altamura, 2016;Yim et al, 2015).…”

Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study

“…Adding to emerging psychiatric research integrating genetic and EHR data (Musliner et al, 2019), we found that polygenic risk for depression was prospectively associated with depression outcomes in a healthcare system, such that individuals with the highest polygenic loading for depression showed over 50% higher odds of incident depression in a two-year window than those at low polygenic risk. This association persisted even when accounting for EHR evidence of prior depression, suggesting that polygenic risk scores have potential not only to explain lifetime depression but also the likelihood of incident episodes-though remains to be further tested.…”

The importance of a developmental perspective in Psychiatry: what do recent genetic-epidemiological findings show?

“…The most recent molecular genetic study of youth depression was based on the Danish iPsych cohort that utilized health record registry data and included those with a clinic recorded diagnosis of depression from age 10 years onwards [34]. These investigators also observed somewhat higher schizophrenia PRS in earlier-onset depression (those aged 10 to 15 years) with MDD PRS showing strongest associations for depression with age-at-onset between 16 and 25 years.…”