PRENATAL, CHILDHOOD, AND ADOLESCENCE SLEEP AND STRESS : Association with DNA methylation and telomere length

ABSTRACT The Developmental Origins of Health and Disease (DOHaD) hypothesis states that several prenatal, perinatal, childhood, and adolescence factors may program the future health of an individual. These preprograming factors include maternal stress, anxiety, depression, or sleep during pregnancy or adverse life experiences in childhood or stress during adolescence. The programming processes may be changes in deoxyribonucleic acid (DNA) methylation or shortening of leukocyte telomere length (LTL). DNA methylation refers to an epigenetic mechanism that affects gene expression and is modified by external conditions. Telomere shortening is an event where the end of a chromosome shortens slightly in each cell division, ultimately leading to programmed cell death. Therefore, LTL is considered a marker for biological age. We studied this with a large birth cohort of newborns and calculated based on existing literature that our sample size was sufficient to detect previously reported findings. Despite sufficient statistical power, we could not replicate previous findings. Several reasons for this are discussed. Childhood is a phase of rapid brain development, and adverse events in early life are linked to a wide range of adverse health outcomes in adulthood. Several mechanisms behind this association have been proposed, among them LTL shortening. In turn, this shortening is also affected by current mental health disorders, stress, and lifestyle factors. We studied the effect of adverse life events (ACE) during childhood on adult LTL in a large, population-based nationally representative cohort of adults. Current mental disorders, stress, sleep, and various lifestyle and socioeconomic variables were considered. While current stress or mental health did not affect LTL, early adverse experiences had a cumulative effect on adult LTL, even when confounding factors were considered. This suggests that programming of cellular age can occur during childhood and persist into adulthood independent of later health and lifestyle. Adolescence is another phase where rapid brain development occurs and thus the brain is vulnerable to external and internal stressors. We explored this by studying epigenome-wide methylation in a sample of adolescent boys with or without depression and sleep disturbances. Due to the small sample size, we could not identify any significant genome-wide results. However, when the 500 best differentially methylated positions (DMP) were explored, a pathway related to synaptic pruning, the long-term depression (LTD) pathway, was identified as the most significant pathway. In a post-hoc analysis, a flattened slow-wave sleep dissipation, tiredness, and depression correlated with several individual sites in that pathway, suggesting that methylation changes in the LTD pathway may be one potential mechanism behind widespread adverse effects of sleep disturbances. Biological programming may occur in rapid phases of brain development and these effects may last for longer periods of time. However, careful methodological consideration is required to detect these effects.Terveyden ja hyvinvoinnin kehitykselliset juuret- hypoteesi esittää, että useat syntymää edeltävät sekä syntymän jälkeiset sekä lapsuuden ja nuoruuden aikaiset tekijät voivat ohjelmoida yksilön tulevaa terveyttä. Näihin ennalta ohjelmoiviin tekijöihin voivat lukeutua esimerkiksi äidin raskaudenaikainen stressi, ahdistus, masennus tai univaikeudet. Myös lapsuuden epäsuotuisat kokemukset tai nuoruudessa koettu stressi voivat ohjelmoida terveyttä tulevaisuuteen. Näitä ohjelmoivia tapahtumia voivat olla muutokset DNAn metylaatiossa tai valkosoluista mitatun telomeerin lyheneminen. DNA metylaatiomuutokset viittaavat epigeneettiseen säätelymekanismiin, jossa ulkopuoliset tekijät muuttavat perintötekijöiden ilmenemistä. Telomeerien lyheneminen puolestaan viittaa tapahtumaketjuun, jossa jokaisen solujakautumisen yhteydessä kromosomien päässä oleva telomeeri lyhenee hieman, johtaen lopulta ohjattuun solukuolemaan. Tästä syystä telomeerien pituutta on pidetty biologista ikää kuvaavana tekijänä. Tutkimme äidin raskausajan voinnin vaikutusta syntyvän lapsen telomeeripituuksiin suuressa syntymäkohortissa, ja tekemiemme voimalaskelmien perusteella aineistomme koon pitäisi riittää vähintään aiemmin raportoitujen havaintojen toistamiseen. Huolimatta riittävän suuresta aineistosta, emme kyenneet toistamaan aiempia havaintoja. Tälle on useita mahdollisia selityksiä, joita pohdimme työssämme. Lapsuus on aivojen nopean kasvun ja kehityksen vaihe ja siksi lapsuuden epäsuotuisien kokemusten onkin osoitettu olevan yhteydessä erilaisiin terveyden tilan heikkenemisiin aikuisuudessa. Tälle on ehdotettu useita mahdollisia välittäviä tekijöitä tai merkkejä, joista yhtenä on kuvattu valkosolujen telomeerien lyhentyminen. Myös aikuisuuden mielenterveysongelmien ja stressin on osoitettu olevan yhteydessä telomeeripituuteen. Tutkimme lapsuuden vastoinkäymisten merkitystä aikuisiän telomeeripituuteen suurella yleisväestöä edustavalla kohortilla. Ajankohtainen mielenterveys, stressi, uni, sosioekonominen tilanne tai elintavat eivät selittäneet yhteyttä telomeeripituuteen, sen sijaan lapsuuden kokemuksilla oli yhteys, vaikka kaikki em. tekijät huomioitaisiinkin. Lapsuuden epäsuotuisten kokemusten vaikutus näyttääkin yltävän pitkälle aikuisuuteen riippumatta aikuisiän tekijöistä. Nuoruus on vaihe, jossa aivot kehittyvät nopeasti ja ovat siten haavoittuvia sisäisille ja ulkoisille kuormitustekijöille. Tutkimme masennuksen ja univaikeuksien vaikutusta valkosoluista mitattuun koko perimän laajuiseen DNA metylaatioon vertaamalla nuorilla pojilla masennuksesta ja univaikeuksista kärsiviä terveisiin verrokkeihin. Liittyen aineiston pienuuteen emme havainneet perimänlaajuisia eroja, mutta eniten metylaation suhteen eroavat alueet rikastuivat geeneihin, jotka polkuanalyysissä liittyivät synapsien muovautuvuuteen, niin sanottuun Long Term Depression-polkuun. Syväunen määrän muutokset, väsymys ja masennus olivat jälkikäteisanalyysissä yhteydessä moniin tuon polun geenien metylaatiokohtiin viitaten siihen, että metylaatiomuutokset tuon polun geeneissä voisivat olla yksi mahdollinen tekijä masennukseen ja unihäiriöihin liittyvien laaja-alaisten vaikeuksien taustalla. Herkkyytemme biologiamme muovautumiselle saattaa olla lisääntynyt niissä kasvun ja kehityksen vaiheissa, joissa aivojen kehitys on nopeimmillaan ja nämä muovautumiset saattavat vaikuttaa pitkänkin aikaa eteenpäin. Näiden muutosten havaitseminen vaatii kuitenkin menetelmien osalta huolellisuutta ja tarkkuutta.Julkaistu painettuna: Helsinki: Unigrafia, 202

Epigenetic dysregulation of genes related to synaptic long-term depression among adolescents with depressive disorder and sleep symptoms

Funding Information: Financial support for the study includes a special federal grant ( TYH 2013342 ) to T.P. and funding from the Academy of Finland (grant number 276612 to A.S.U. and number 290039 to T.P.), Emil Aaltonen Foundation , Finnish Medical Foundation , Finnish Brain Foundation , Orion-Farmos Research Foundation , Päivikki and Sakari Sohlberg Foundation , and the Foundation for Psychocultural Research . We also wish to thank Auli Toivola for her valuable contribution regarding laboratory work. Publisher Copyright: © 2019 Elsevier B.V.Objectives: This study aimed to test the hypothesis that sleep and depression have independent effects on brain development and plasticity in adolescents, and that these changes are reflected in changes in the epigenome. Methods: Participants were 17 medication-free adolescent boys (age 16.05 +/- 0.80 years, mean +/- standard deviation (SD); eight cases with depression and sleep symptoms, nine healthy controls). Sleep was assessed by polysomnography recordings and the Pediatric Daytime Sleepiness Scale (PDSS) and Athens Insomnia Scale (AIS). Participants underwent a clinical evaluation. DNA methylation of blood leukocytes was measured by Illumina 450K array, and Ingenuity Pathway analysis was applied to identify the most significant pathways with differentially methylated positions (DMPs). Secondary analysis of the identified loci included linear correlations between methylation and the subjectively rated scales of sleep, depression and sleep microarchitecture. Results: Due to small sample size, we found no genome-wide significant differences in methylation between cases and controls. However, pathway analysis identified the synaptic long-term depression (LTD) canonical pathway (p = 0.00045) when the best 500 DMPs from the original case-control design were included. A flattened dissipation of slow wave sleep, tiredness and depression severity values correlated with five of 10 sites from the LTD pathway (IGF1R, PLAG16, PLA2R1, PPP2C5 and ERK12) in the secondary analysis when the case-control status was controlled for. Conclusion: Among adolescents, depressive disorder with sleep symptoms is associated with a distinctive epigenetic pattern of DNA methylation in blood leukocytes. The enrichment of DMPs on genes related to synaptic LTD emphasizes the role of sleep in synaptic plasticity and the widespread physiological consequences of disturbed sleep. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Chronotype as self-regulation: morning preference is associated with better working memory strategy independent of sleep

Peer reviewe

The Helsinki approach to face transplantation

Aim: We herein describe the establishment of the Helsinki Vascularized Composite Allotransplantation (VCA) program and its execution in the first two face transplant cases. Methods & patients: The Helsinki VCA program initially required the fulfillment of legal, hospital, financial, and ethical requirements. Thereafter, the assembling of a multidisciplinary team commenced. A team of Plastic, maxillofacial and ENT surgeons comprise the facial VCA team. The protocol involves collaboration with the Solid Organ Transplant (SOT) team, transplant immunology, immunosuppression, microbiology, psychiatric evaluation, well-defined VCA indications and informed consent. Between 2011 and 2017 two patients were selected for transplantation. Both patients had a severe composite facial deformity involving the maxilla and mandible following earlier ballistic injury. Results: Patient 1 was a 35 year-old male who underwent successful near total face transplantation in February 2016 and at 30 months he has a good aesthetic outcome with symmetrical restoration of the central face and good sensory and symmetrical motor functional outcomes. Patient 2 was a 58 year-old male who underwent full face transplantation in March 2018 and at 5 months he has recovered without major problems. Conclusion: A successful facial VCA program requires a well-prepared research protocol, experts from multiple specialties and careful patient selection. The establishment of the Helsinki VCA program required long and thorough planning and resulted in the first two Nordic face transplantation cases. This protocol now forms the platform (as a proof of concept) for other types of vascularized composite allotransplantations. (C) 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Maternal stress or sleep during pregnancy are not reflected on telomere length of newborns

Telomeres play an important role in maintaining chromosomal integrity.With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health‑related outcomes. Transgenerationaleffects have been implicated in newborns, with maternal stress, depression,and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using aqPCR‑based method.In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self‑reported sleep quality were evaluated with self‑reported questionnaires.Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature,we were unable to replicate the previous correlation between maternal stress, anxiety, depression,or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.Peer reviewe

Prenatal, childhood, and adolescence sleep and stress : Association with DNA methylation and telomere length

Painettu väitöskirja 2021

Childhood adversities are associated with shorter leukocyte telomere length at adult age in a population-based study

Correction: vol. 153 DOI: 10.1016/j.psyneuen.2023.106286 Article Number: 06286 Published: JUL 2023Telomeres are repeat sequences and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and are regarded markers for cellular aging. Shorter leukocyte telomere length (LTL) has been observed in many complex diseases, including psychiatric disorders. However, analyses focusing on psychiatric disorders are mainly based on clinical samples and the significance of shorter LTL on the population level remains uncertain. We addressed this question in a population-based sample from Finland (N = 7142). The survey was performed and the blood samples were collected in 2000-2001 to assess major public health problems and their determinants. DSM-IV diagnoses of major psychiatric illnesses were obtained by interview using the Composite International Diagnostic Interview. Information regarding their risk factors, including the number of self-reported childhood adversities, recent psychological distress, and sleep difficulties was collected by questionnaires. LTL was measured by qPCR. None of the studied psychiatric illnesses, sleep difficulties, or recent psychological distress associated with LTL. However, individuals with three or more childhood adversities had shorter LTL at adult age (13 = -0.006, P = 0.005). Also, current occupational status was associated with LTL (13 = -0.03, P = 0.04). These effects remained significant after adjusting for known LTLassociated lifestyle or sociodemographic factors. In conclusion, relatively common childhood adversities were associated with shorter LTL at adult age in a nationally representative population-based cohort, implying that childhood adversities may cause accelerated telomere shortening. Our finding has potentially important implications as it supports the view that childhood adversities have an impact on psychological and somatic wellbeing later in life.Peer reviewe