2026-05-06

112_ Associations of polygenic risk for a General Psychopathology (p-)factor with longitudinal psychiatric symptoms

Research Question and Aims

Schizophrenia (SZ), bipolar disorder (BD) and major depressive disorder (MDD) are disorders that all together have a lifetime prevalence of 20 – 24 % in the general population (Möller, 2017). Behavioral genetic studies as well as molecular studies demonstrate that all three disorders show substantial heritability, which is correlated across the disorders (PMID: 41372416; PMID: 35396580;
https://www.leitlinien.de/themen/depression/archiv/pdf/depression-vers3-0-lang.pdf (doi: 10.6101/AZQ/000493); PMID: 20349221; PMID: 23933821; PMID: 19150704; PMID: 22777127). Patients suffer from different symptom constellations, that can belong to the affective as well as to the psychotic disorders and occur with varying severity. Due to this overlapping pattern, extensions to the current nosological systems have been proposed by initiatives such as RDoC and HiTOP. Scientifically, the concept of a latent transdiagnostic p-factor, indexing an individual’s overall propensity to mental disorders has recently been proposed (PMID: 29621902). The p-factor forms the basis for all psychiatric disorders and influences the development of those. Using different methods, Selzham et al. were able to show that the p – factor has a underlying polygenic basis and “represents the pinnacle of the hierarchical genetic architecture of psychopathology” (PMID: 30279410). An individual’s polygenic vulenerability to the p- factor can be quantified with the help of polygenic risk scores (PRS) a method of statistical genetics that makes it possible to aggregate many small genetic variants across the whole genome of a person. PRS for the p-factor have already been calculated for PsyCourse participants and have been used in publications (PMID: 41840026 and https://doi.org/10.21203/rs.3.rs-6843541/v1). The magnitude p-Factors PRS also differ significantly between broad diagnostic groups in the PsyCourse Study (PMID: 41840026, Figure 2e). While it is encouraging that p-Factor PRS differ between broad diagnostic groups cross-sectionally, it is unclear whether the magnitude of p-Factor PRS also influences psychiatric symptoms, especially their longitudinal course. This goal of this project is to research, in psychiatric patients, whether there is an association in the variability of depressive, manic and/or psychotic symptoms and the PRS for the p – factor over time. The proposed project will use all clinical participants of the PsyCourse Study and will also analyze the effects of p-factor PRS in stratified broad diagnostic groups (affective and psychotic). We will also explore the effects of medication.

Analytic Plan

The statistical analysis will be performed by linear mixed models (LMMs), as these are the most suitable for datasets with missing values and dependent observations (i.e. longitudinal data). Relevant confounding factors like age, sex and population stratification (operationalized through ancestry principal components of the genomic data) will be considered in the regression models. The LMMs include random slopes as well as random intercepts. Subject and center will be used as random variables.

Resources needed

v1_id
v1_stat
v1_center
v1_tstlt
v1_sex
v1_yob
v1_school
v1_prof_dgr
v1_ed_status
v1_outpat_psy_trm
v1_age_1st_out_trm
v1_daypat_inpat_trm
v1_age_1st_inpat_trm
v1_dur_illness
v1_1st_ep
v1_ever_smkd
v1_age_smk
v1_alc_pst12_mths
v1_lftm_alc_dep
v1_evr_ill_drg
v1_sti_cat_evr
v1_can_cat_evr
v1_opi_cat_evr
v1_kok_cat_evr
v1_hal_cat_evr
v1_inh_cat_evr
v1_tra_cat_evr
v1_var_cat_evr
v1_evr_hvy_usr
v1_scid_dsm_dx
v1_scid_dsm_dx_cat
v1_scid_ever_halls
v1_scid_ever_delus
v1_scid_ever_psyc
gsa_id
visit
Antidepressants
Antipsychotics
gaf
idsc_sum
Mood_stabilizers
panss_sum_gen
panss_sum_neg
panss_sum_pos
panss_sum_tot
partner
ymrs_sum