Polygenic risk for depression predicting temperament trajectories over 15 years - A general population study.

BACKGROUND: A great number of case-control and population-based studies have shown that depression patients differ from healthy controls in their temperament traits. We investigated whether polygenic risk for depression predicts trajectories of temperament traits from early adulthood to middle age. METHODS: Participants came from the population-based Young Finns Study (n = 2212). The calculation for Polygenic risk for depression (PRS) was based on the most recent genome-wide association study. Temperament traits of Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were assessed with the Temperament and Character Inventory in 1997, 2001, 2007, and 2012 (participants being 24-50-year-olds). As covariates, we used depressive symptoms as assessed by a modified version of the Beck Depression Inventory, psychosocial family environment from parent-filled questionnaires, and socioeconomic factors from adulthood. RESULTS: High PRS predicted higher Persistence from early adulthood to middle age (p = 0.003) when controlling for depressive symptoms, psychosocial family environment, and socioeconomic factors. PRS did not predict trajectories of Novelty Seeking (p = 0.063-0.416 in different models) or Reward Dependence (p = 0.531-0.736). The results remained unaffected when participants with diagnosed affective disorders were excluded. Additionally, we found an interaction between PRS and depressive symptoms when predicting the Harm Avoidance subscale Anticipatory Worry, indicating that the association of Anticipatory Worry with depressive symptoms is stronger in individuals with higher (vs. lower) PRS. LIMITATIONS: There was some attrition due to the long follow-up. CONCLUSIONS: High polygenic risk for major depression may predict differences in temperament trajectories among those who have not developed any severe affective disorders.

Polygenic risk for schizophrenia, social dispositions, and pace of epigenetic aging: Results from the Young Finns Study.

Schizophrenia is often regarded as a disorder of premature aging. We investigated (a) whether polygenic risk for schizophrenia (PRSsch ) relates to pace of epigenetic aging and (b) whether personal dispositions toward active and emotionally close relationships protect against accelerated epigenetic aging in individuals with high PRSsch . The sample came from the population-based Young Finns Study (n = 1348). Epigenetic aging was measured with DNA methylation aging algorithms such as AgeAccelHannum , EEAAHannum , IEAAHannum , IEAAHorvath , AgeAccelHorvath , AgeAccelPheno , AgeAccelGrim , and DunedinPACE. A PRSsch was calculated using summary statistics from the most comprehensive genome-wide association study of schizophrenia to date. Social dispositions were assessed in terms of extraversion, sociability, reward dependence, cooperativeness, and attachment security. We found that PRSsch did not have a statistically significant effect on any studied indicator of epigenetic aging. Instead, PRSsch had a significant interaction with reward dependence (p = 0.001-0.004), cooperation (p = 0.009-0.020), extraversion (p = 0.019-0.041), sociability (p = 0.003-0.016), and attachment security (p = 0.007-0.014) in predicting AgeAccelHannum , EEAAHannum , or IEAAHannum . Specifically, participants with high PRSsch appeared to display accelerated epigenetic aging at higher (vs. lower) levels of extraversion, sociability, attachment security, reward dependence, and cooperativeness. A rather opposite pattern was evident for those with low PRSsch . No such interactions were evident when predicting the other indicators of epigenetic aging. In conclusion, against our hypothesis, frequent social interactions may relate to accelerated epigenetic aging in individuals at risk for psychosis. We speculate that this may be explained by social-cognitive impairments (perceiving social situations as overwhelming or excessively arousing) or ending up in less supportive or deviant social groups.

Polygenic risk for schizophrenia predicting social trajectories in a general population sample.

BACKGROUND: We investigated (a) whether polygenic risk for schizophrenia predicts different trajectories of social development among those who have not developed psychoses and (b) whether possible associations are PRSSCZ-specific or evident also for any polygenic risk for mental disorders, e.g. for major depression. METHODS: Participants came from the population-based Young Finns Study (n = 2377). We calculated a polygenic risk score for schizophrenia (PRSSCZ) and for major depression (PRSDEP). Diagnoses of psychotic disorders were derived from the hospital care register. Social development from adolescence to middle age was measured by (a) perceived social support from friends, family, and a close other, (b) perceived sociability, and (c) family structure (partnership status, number of children, age of first-time parenthood). RESULTS: Among those without manifest psychoses, high PRSSCZ predicted lower experienced support from friends (B = -0.04, p = 0.009-0.035) and family (B = -0.04, p = 0.009-0.035) especially after early adulthood, and also lower perceived sociability (B = -0.05, p = 0.010-0.026). PRSSCZ was not related to family structure. PRSDEP did not predict any domain of social development. CONCLUSIONS: Individuals at high PRSSCZ (not converted to psychosis) seem to experience a lower preference to be with others over being alone. Individuals with high (v. low) PRSSCZ seem to have a similar family structure in terms of partnership status or number of children but, nevertheless, they experience less support from their family. Among those not converted to psychosis in a typical age period, high PRSSCZ may predict a 'later risk phase' and reduced functional resilience when approaching middle age.

Polygenic liabilities underlying job stress and exhaustion over a 10-year follow-up: A general population study.

We investigated whether individuals, who have a high polygenic loading for schizophrenia and major depression (PGL) but have not developed the respective disorders, are still susceptible to experience milder forms of ill-being in terms of job strain or exhaustion. We used the population-based Young Finns Study data (n = 928). PGL was assessed with a cumulative score of the polygenic risk scores for schizophrenia and depression. Participants (24-49-year-olds) evaluated their exhaustion levels and perceived job characteristics over a 10-year follow-up (2001, 2007, 2011). Participants with diagnosed psychotic or affective disorders were excluded. We found that high PGL did not predict less favorable perceptions of job environment (job strain, demands, control, satisfaction, social support at work) but high PGL predicted a higher trajectory of exhaustion in early adulthood and middle age. Additionally, high (vs. low) PGL predicted a stronger increase in exhaustion at increased levels of job strain. These findings remained after controlling for sex, socioeconomic factors, health behaviors, and cognitive performance. In conclusion, individuals with high PGL may have an elevated liability to experience exhaustion especially in early adulthood and middle age (despite they perceive their job environment similarly than others), and especially and at high levels of job strain.

Childhood family environment predicting psychotic disorders over a 37-year follow-up - A general population cohort study.

BACKGROUND: Childhood adverse effects and traumatic experiences increase the risk for several psychiatric disorders. We now investigated whether prospectively assessed childhood family environment per se contributes to increased risk for psychotic disorders in adulthood, and whether these family patterns are also relevant in the development of affective disorders. METHODS: We used the Young Finns Data (n = 3502). Childhood family environment was assessed in 1980/1983 with previously constructed risk scores: (1) disadvantageous emotional family atmosphere (parenting practices, parents' life satisfaction, parents' mental disorder, parents' alcohol intoxication), (2) adverse socioeconomic environment (overcrowded apartment, home income, parent's employment, occupational status, educational level), and (3) stress-prone life events (home movement, school change, parental divorce, death, or hospitalization, and child's hospitalization). Psychiatric diagnoses (ICD-10 classification) over the lifespan were collected up to 2017 from the national registry of hospital care. Non-affective psychotic disorder and affective disorder groups were formed. RESULTS: Frequent stress-prone life events predicted higher likelihood of non-affective psychotic disorders (OR = 2.401, p = 0.001). Adverse socioeconomic environment or emotional family atmosphere did not predict psychotic disorders. Only disadvantageous emotional family atmosphere predicted modestly higher likelihood of affective disorders (OR = 1.583, p = 0.013). CONCLUSIONS: Our results suggest that childhood family environment and atmosphere patterns as such contribute to the risk for developing adulthood mental disorders with relative disorder specificity. The results emphasize the importance of both individual and public health preventive initiatives, including family support interventions.

Metabolic trajectories in childhood and adolescence: Effects on risk for schizophrenia.

Abnormal glucose and lipid metabolism is common in antipsychotic-naive first-episode patients with schizophrenia, but it is unclear whether these changes can already be seen in premorbid or prodromal period, before the first psychotic episode. We examined insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride trajectories in children and adolescents (9-18 years old), who were later diagnosed with schizophrenia, any non-affective psychosis (NAP) or affective disorder (AD). The study population consisted of a general population-based cohort "The Cardiovascular Risk in Young Finns Study", started in 1980 (n = 3596). Psychiatric diagnoses were derived from the Health Care Register up to the year 2018. Multivariate statistical analysis indicated no significant differences in insulin or lipid levels in children and adolescents who later developed schizophrenia (n = 41) compared to the cohort control group (n = 3202). In addition, no changes in these parameters were seen in the NAP (n = 74) or AD (n = 156) groups compared to the controls, but lower triglyceride levels in childhood/adolescence associated with earlier diagnosis of psychotic disorder in the NAP group. Taken together, our results do not support any gross-level insulin or lipid changes during childhood and adolescence in individuals with later diagnosis of schizophrenia-spectrum disorder. Since changes in glucose and lipid metabolism can be observed in neuroleptic-naive patients with schizophrenia, we hypothesize that the more marked metabolic changes develop during the prodrome closer to the onset of the first psychotic episode. The findings have relevance for studies on developmental hypotheses of schizophrenia.

Magical thinking in individuals with high polygenic risk for schizophrenia but no non-affective psychoses-a general population study.

A strong genetic background for psychoses is well-established. Most individuals with a high genetic risk for schizophrenia, however, do not develop the disorder. We investigated whether individuals, who have a high genetic risk for schizophrenia but no non-affective psychotic disorders, are predisposed to develop milder forms of deviant thinking in terms of magical thinking. Participants came from the population-based Young Finns Study (n = 1292). The polygenic risk score for schizophrenia (PRS) was calculated on the basis of the most recent genome-wide association study (GWAS). Psychiatric diagnoses over the lifespan were collected up to 2017 from the registry of hospital care. Magical thinking was evaluated with the Spiritual Acceptance Scale (e.g., beliefs in telepathy, miracles, mystical events, or sixth sense) of the Temperament and Character Inventory in 1997, 2001, and 2012 (participants were 20-50-year-olds). We found that, among those who did not develop non-affective psychotic disorders, high PRS predicted higher magical thinking in adulthood (p = 0.001). Further, PRS predicted different developmental courses: a low PRS predicted a steady decrease in magical thinking from age 20 to 50 years, while in individuals with high PRS the decrease in magical thinking ceased in middle age so that their level of magical thinking remained higher than expected for that age. These findings remained when controlling for sex, childhood family environment, and adulthood socioeconomic factors. In conclusion, if high PRS does not lead to a non-affective psychotic disorder, it predicts milder forms of deviant thinking such as elevated magical thinking in adulthood, especially in middle age. The finding enhances our understanding of different outcomes of high genetic psychosis risk.

Sex difference in brain CB1 receptor availability in man.

The endocannabinoid system (ECS) has a widespread neuromodulatory function in the central nervous system and is involved in important aspects of brain function including brain development, cortical rhythms, plasticity, reward, and stress sensitivity. Many of these effects are mediated via the cannabinoid CB1 receptor (CB1R) subtype. Animal studies convincingly show an interaction between the ECS and sex hormones, as well as a sex difference of higher brain CB1R in males. Human in vivo studies of sex difference have yielded discrepant findings. Gender differences in CB1R availability were investigated in vivo in 11 male and 11 female healthy volunteers using a specific CB1R tracer [18F]FMPEP-d2 and positron emission tomography (PET). Regional [18F]FMPEP-d2 distribution volume was used as a proxy for CB1R availability. In addition, we explored whether CB1R availability is linked to neuropsychological functioning. Relative to females, CB1R availability was on average 41% higher in males (p = 0.002) with a regionally specific effect larger in the posterior cingulate and retrosplenial cortices (p = 0.001). Inter-subject variability in CB1R availability was similar in both groups. Voxel-based analyses revealed an inverse association between CB1R availability and visuospatial working memory task performance in both groups (p < 0.001). A CB1R sex difference with a large effect size was observed and should be considered in the design of CB1R-related studies on neuropsychiatric disorders. The behavioural correlates and clinical significance of this difference remain to be further elucidated, but our studies suggest an association between CB1R availability and working memory.

Body mass index trajectories in childhood and adolescence - Risk for non-affective psychosis.

BACKGROUND: Underweight in early adulthood increases risk for schizophrenia, but the effect of early childhood underweight on psychosis risk is not well known. METHODS: We studied whether underweight or overweight in childhood and adolescence increases risk for non-affective psychosis or other psychiatric disorders in a population-based cohort study 'Cardiovascular Risk in Young Finns'. Body mass index (BMI) trajectories were recorded in the years 1980, 1983 and 1986 (in 3-18 years of age), before the first hospitalization due to a psychiatric disorder. BMI was categorized as underweight, normal weight or overweight, using the BMI classification for children and adolescents. We formed DSM-IV based diagnostic groups of non-affective psychosis (n = 69, including a schizophrenia subgroup, n = 41) and affective disorders (i.e. mood and anxiety disorders, n = 112) based on the Care Register for Health Care. Groups were compared with subjects with no psychiatric diagnoses (n = 3310). Sex, age, low birthweight and mother's mental disorders were included in the analyses. RESULTS: Underweight, but not overweight, independently predicted later development of non-affective psychosis. The risk of psychosis was over two-fold (relative risk (RR) [95% CI] 2.31 [1.2-4.4]) and of schizophrenia nearly 2.5-fold (RR 2.44 [1.03-5.8]) after underweight in childhood/adolescence. Underweight or overweight in childhood and adolescence was not associated with mood or anxiety disorders. CONCLUSIONS: These results support the hypothesis of non-affective psychosis as a neurodevelopmental disorder with somatic manifestations throughout childhood and adolescence.

Effects of childhood and adolescence physical activity patterns on psychosis risk-a general population cohort study.

Schizophrenia spectrum disorders are associated with high morbidity and mortality in somatic diseases. The risk factors of this excess mortality include, e.g., obesity, dietary factors, and physical inactivity, especially after the onset of psychosis, but there are limited early developmental data on these factors in individuals who later develop psychosis. A population-based cohort study "Cardiovascular Risk of Young Finns" started in 1980 with 3596 children and adolescents from six different age groups (3, 6, 9, 12, 15, and 18 years). Cardiovascular health parameters, including questionnaire of physical activity before first hospitalization (≤18 years), were studied in 1980, 1983, and 1986. All psychiatric diagnoses of the participants were derived from the Finnish Hospital Discharge Register up to the year 2012. We identified diagnostic groups of non-affective psychosis (n = 68, including a schizophrenia subgroup, n = 41), personality disorders (n = 43), affective disorders (n = 111), and substance-related disorders (n = 49), based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Groups were compared with controls with no psychiatric diagnoses (n = 3325). Sex, age, body mass index, birth weight, non-preterm birth, and mother's mental disorders were included in the statistical model. Low physical activity in childhood and adolescence (9-18 years) independently predicted later development of non-affective psychosis. Lower physical activity index (relative risk 1.26 [1.1-1.5]), lower level of common activity during leisure time (relative risk 1.71 [1.2-2.5]), and non-participation in sports competitions (relative risk 2.58 [1.3-5.3]) were associated with a higher risk for later non-affective psychosis (expressed as increase in relative risk per physical activity unit). The findings were even stronger for schizophrenia, but no such link was observed for other diagnoses. The cause of low physical activity in premorbid/prodromal phase is likely to be multifactorial, including deviant motor and cognitive development. The results provide a rationale for including exercise and physical activity interventions as a part of psychosis prevention programs.