Genetic liability to bipolar disorder and onset of postpartum mental disorders

Introduction Childbirth triggers a broad range of diagnoses jointly defined as postpartum mental disorders (PMDs),1 but immediate onset within the first 30 days after delivery has been linked to an increased probability of converting to bipolar disorder (BD) diagnoses later.2 Building on these specific observations, we hypothesised that PMDs occurring within the first month after delivery have a higher bipolar genetic liability, measured as polygenic score (PGS), compared with those diagnosed 31–365 days post partum, and further speculated this association is specific to the PGS for BD compared with genetic liability to other severe mental disorders, such as major depressive disorder (MDD) and schizophrenia (SCZ). Methods We conducted a cohort study linking Danish national registers to the Integrative Psychiatric Research (iPSYCH) study,3 which included 93 608 individuals diagnosed with a major mental illness and a random sample of 50 615 subjects from the entire Danish population born during 1981–2005 (the subcohort). DNA was extracted from the blood and genotyped. We identified 2974 women with genetic data who had PMD, defined as any hospital admission or outpatient contact for mental illness (International Classification of Diseases, 10th Revision (ICD-10) codes F00–F99, excluding F10–F19 and F70–F79) 0–12 months after delivery.4 We similarly defined previous psychiatric history as hospital contact for mental illness at any time before the delivery. DNA was extracted from the blood and genotyped. We derived LDpred2-auto5 PGS from the latest genome-wide association study (GWAS) by Psychiatric Genomics Consortium. We also calculated PGS using the iPSYCH individual data. We then combined the PGS obtained from summary statistics and individual-level data through a linear combination.6The sample size for the discovery GWAS without the iPSYCH sample can be found elsewhere.6 We converted PGSs into z-scores using PGS distributions in women from the subcohort born during 1981–1997. We used logistic regression to estimate the odds ratios (ORs) of PMD that occurred within 30 days vs 31–365 days after delivery by the BD PGSs in the form of both per SD increase (continuous variable) and tertiles and adjusted for all the covariates listed in table 1 and the first 10 principal components to account for population stratification.7 To show the degree of specificity for genetic liability to BD, we also calculated PGSs for MDD and SZ as negative controls, as we did not expect to find an association between these estimates and the specific early onset of PMD. Given PMD among women without a psychiatric history prior to childbirth may be a distinct psychiatric phenotype, we, for additional comparative purposes, examined the associations in women with and without previous psychiatric history separately. Since we specified the hypotheses a priori, no corrections for multiple comparisons are needed.