Depressiooni ja ärevusega seotud geenivariandid: mõju isiksuseomadustele ja tervistmõjustavale käitumisele

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Varasemate uuringute põhjal on teada, et mõned isiksuseomadused suurendavad depressiooni tekkimise riski. Nii isiksuseomadustel kui ka depressioonil on aga tugev pärilik taust ja osa geneetilisest alusest arvatakse neil olevat ühine. Kummagi fenotüübi geneetilist ülesehitust ei ole veel suudetud tuvastada. Käesoleva väitekirja eesmärgiks oli uurida suurel rahvastiku suhtes representatiivsel valimil, kuidas on seotud neurotransmissiooni mõjustavad depressiooni kandidaatgeenide variandid 5-HTTLPR, BDNF Val66Met, COMT Val158Met ja TPH2 G-703T isiksuseomadustega. Lisaks uurisime ka geenidevahelisi interaktsioone, vanuse ja soo mõju ning seoseid teiste tervise ja heaolu teguritega. Leidsime, et kõik nimetatud kandidaatgeenid tõepoolest mõjutavad isiksuseomadusi rahvastikus. COMT genotüüp avaldab mõju Neurootilisusele, ehk kalduvusele liigselt muretseda ja ärevust tunda. BDNF ja TPH2 mõjutavad aga Meelekindlust, inimese kalduvust olla kohusetundlik, täpne ja distsipliineeritud. Ilmnes ka 5-HTTLPR polümorfismi moduleeriv roll genotüübi ja Meelekindluse seostes. Samuti leidsime, et nii TPH2 kui COMT genotüüpide mõju Neurootilisusele oli sõltuv uuritavate vanusest. Kuigi me ei leidnud nimetatud geenivariantide seoseid ärevus- ja meeleoluhäiretega, peegeldub mõju isiksusele ka teistes inimese tervise ja heaoluga seotud tegurites. Näiteks BDNF polümorfism avaldab mõju söömishäirete sümptomaatika tekkimisel ning COMT mõjutab depressiivsuse taset, haridusteed ja hinnanguid sotsiaalmajanduslikule staatusele. Käitumisgeneetika valdkonna ummikseis isiksuseomaduste geneetiliste aluste tuvastamisel viitab erinevatele moduleerivatele mõjuteguritele geeniefektide avaldumisel. Väitekirjas käsitletud suure rahvastikupõhise uuringu tulemuste põhjal rõhutame soo, vanuse ja geenidevahelise interaktsiooni arvestamise olulisust genotüüpide mõju uurimisel väga mitmetahulistele fenotüüpidele.Previous findings have indicated that some personality traits are increasing the risk for depression. Personality traits and depression are both to a significant extent heritable and are considered to share some of the genetic components. Unraveling the genetic basis of these phenotypes has proven to be difficult. The purpose of this dissertation was to study the effects of several depression-related gene variants, 5-HTTLPR, BDNF Val66Met, COMT Val158Met and TPH2 G-703T, on personality traits in a large population representative sample. In addition, we aimed to study gene × gene interactions, time and sex as possible modulators, and furthermore, to assess if there are any genotype effects on other health-related behaviours. Indeed, we found that all candidate genes under investigation had influence on personality traits. The COMT genotype was affecting Neuroticism, a trait for excessive worrying and anxiety. The main effects of BDNF and TPH2 gene variants were on Conscientiousness, a trait for dutifulness, precision and self-discipline. In addition, these genotype effects on Conscientiousness were modulated by the 5-HTTLPR polymorphism. Also we found the effects of TPH2 and COMT on Neuroticism to be age-dependent. Although we did not find any genotype effects on the history of mood and anxiety disorders, there were associations with health-related behaviour. We found the BDNF polymorphism to affect the emergence of eating disorder symptoms and COMT polymorphism to influence depressiveness, educational attainment, and also socioeconomic status assessment. The difficulties in unraveling the genetic foundations of personality traits suggest a large number of additional factors, which may modulate the emergence of genotype effects. With these results on a large population representative study, we highlight the significance of considering time, sex and gene × gene interactions as possible modulators of genotype effects

Acute COVID-19 severity and mental health morbidity trajectories in patient populations of six nations: an observational study

Background Long-term mental and physical health consequences of COVID-19 (long COVID) are a persistent public health concern. Little is still known about the long-term mental health of non-hospitalised patients with COVID-19 with varying illness severities. Our aim was to assess the prevalence of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis. Methods This observational follow-up study included seven prospectively planned cohorts across six countries (Denmark, Estonia, Iceland, Norway, Sweden, and the UK). Participants were recruited from March 27, 2020, to Aug 13, 2021. Individuals aged 18 years or older were eligible to participate. In a cross-sectional analysis, we contrasted symptom prevalence of depression, anxiety, COVID-19-related distress, and poor sleep quality (screened with validated mental health instruments) among individuals with and without a diagnosis of COVID-19 at entry, 0–16 months from diagnosis. In a cohort analysis, we further used repeated measures to estimate the change in mental health symptoms before and after COVID-19 diagnosis. Findings The analytical cohort consisted of 247 249 individuals, 9979 (4·0%) of whom were diagnosed with COVID-19 during the study period. Mean follow-up was 5·65 months (SD 4·26). Participants diagnosed with COVID-19 presented overall with a higher prevalence of symptoms of depression (prevalence ratio [PR] 1·18 [95% CI 1·03–1·36]) and poorer sleep quality (1·13 [1·03–1·24]) but not symptoms of anxiety (0·97 [0·91–1·03]) or COVID-19-related distress (1·05 [0·93–1·20]) compared with individuals without a COVID-19 diagnosis. Although the prevalence of depression and COVID-19-related distress attenuated with time, individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risk of depression (PR 0·83 [95% CI 0·75–0·91]) and anxiety (0·77 [0·63–0·94]) than those not diagnosed with COVID-19, whereas patients who were bedridden for more than 7 days were persistently at higher risk of symptoms of depression (PR 1·61 [95% CI 1·27–2·05]) and anxiety (1·43 [1·26–1·63]) than those not diagnosed throughout the study period. Interpretation Severe acute COVID-19 illness—indicated by extended time bedridden—is associated with long-term mental morbidity among recovering individuals in the general population. These findings call for increased vigilance of adverse mental health development among patients with a severe acute disease phase of COVID-19.Funding Nordforsk, Horizon2020, Wellcome Trust, and Estonian Research Council

True Correlations Between Personality and Psychopathology

A comprehensive multi-rater assessment of the empirical overlap of personality traits and psychopathology

Age-dependent effects of body mass index across the adult life span on the risk of dementia : A cohort study with a genetic approach

Background: While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox. Methods: We used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGSBMI) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGSBMI. Results: At age 35-49, 5 units higher BMI was associated with 15% (95% CI 7-24%) higher risk of dementia in the STR. There was a significant interaction (p = 0.04) between BMI and the PGSBMI, and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08-1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10-11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGSBMI in the STR (p = 0.01), but not the HRS, with the inverse association present only among those with a high PGSBMI (HR 0.70, 95% CI 0.52-0.94). No genetic influences were evident from co-twin control models of late-life BMI. Conclusions: Not only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable. © 2020 The Author(s).CC BY 4.0CC0 1.0The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.</p

The role of ADHD genetic risk in mid-to-late life somatic health conditions

Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors

Physical activity, suicidal ideation, suicide attempt and death among individuals with mental or other medical disorders: A systematic review of observational studies

A growing body of research has demonstrated the potential role for physical activity as an intervention across mental and other medical disorders. However, the association between physical activity and suicidal ideation, attempts, and deaths has not been systematically appraised in clinical samples. We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, EMBASE, and PsycINFO for observational studies investigating the influence of physical activity on suicidal behavior up to December 6, 2023. Of 116 eligible full-text studies, seven (n = 141691) were included. Depression was the most frequently studied mental condition (43%, k = 3), followed by chronic pain as the most common other medical condition (29%, k = 2). Two case-control studies examined suicide attempts and found an association between physical activity and a reduced frequency of such attempts. However, in studies examining suicidal ideation (k = 3) or suicide deaths (k = 2), no consistent associations with physical activity were observed. Overall, our systematic review found that physical activity may be linked to a lower frequency of suicide attempts in non-prospective studies involving individuals with mental disorders.</p