Exploring Genetic Susceptibility to Autism Spectrum Disorders

Abstract.pdfTiivistelmä.pd

Genetic variants for morningness in relation to habitual sleep-wake behavior and diurnal preference in a population-based sample of 17,243 adults

Objective Associations of eveningness with health hazards benefit from analyzing to what extent the polygenic score for morningness correlates with the assessments of the behavioral trait of morningness-eveningness and chronotype. Methods With a population-based sample of 17,243 Finnish adults, aged 25–74 years, this study examines the associations of four feasible assessment methods of chronotype, a) biological the genetic liability based on the polygenic score for morningness (PGSmorn), b) the widely-used single item for self-assessed morningness/eveningness (MEQi19) of the original Morningness-Eveningness Questionnaire (MEQ), c) the behavioral trait of morningness-eveningness as assessed with the score on the shortened version (sMEQ) of the original MEQ, and d) the phase of entrainment as assessed with the habitual midpoint of sleep based on the self-reported sleep-wake schedule during weekend (Sleepmid-wknd) as well as the sleep debt corrected midpoint of sleep (Sleepmid-corr). Results All self-report measures correlated with each other, but very weakly with the PGSmorn, which explained 1–2% of the variation in diurnal preference or habitual sleep-wake schedule. The influence of age was greater on Sleepmid-wknd and Sleepmid-corr than on the sMEQ or MEQi19, indicating that the diurnal preference might be a more stable indicator for morningness-eveningness than the sleep-wake schedule. Analyses of the discrepancies between sMEQ and MEQi19 indicated that eveningness can be over-estimated when relying on only the single-item self-assessment. Conclusions The current polygenic score for morningness explains only a small proportion of the variation in diurnal preference or habitual sleep-wake schedule. The molecular genetic basis for morningness-eveningness needs further elucidation.Peer reviewe

Oxytocin receptor genotype moderates the association between maternal prenatal stress and infant early self-regulation

Introduction: Maternal prenatal stress may have long-term adverse consequences for child development. Accumulating evidence shows that the oxytocin-receptor genotype may play a role in differential susceptibility to early-life adversity, but no studies have examined whether this moderation extends to the prenatal stress exposures. Methods: In the FinnBrain Birth Cohort Study, a sample of 1173 mother-child dyads were examined. We studied the possible moderating effect of the cumulative effect of infant oxytocin-receptor risk genotypes (rs53576GG and rs2254298A) in the association between maternal prenatal stress, and infant negative reactivity and emerging self-regulation at 6 months of age. Results: The number of OTr risk genotypes moderated the association between maternal prenatal anxiety and infant self-regulation, implying a cumulative effect of genotype, although effects sizes were small. In infants with two risk genotypes, a negative association between prenatal anxiety and self-regulation was observed, whereas in infants with one or no risk genotypes, the association between maternal prenatal anxiety and temperament was non-significant. Conclusion: Oxytocin-receptor genotype may moderate the association of maternal stress during pregnancy and child social-emotional development. Possible mechanisms for this moderation effect are discussed. Further studies with a more comprehensive polygenic approach are needed to confirm these results.Peer reviewe

Interactions of genetic variants and prenatal stress in relation to the risk for recurrent respiratory infections in children

Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n=96) were identified by the age of 24 months and compared with the remaining cohort children (n=894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14-2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04-3.67). Our study didn't find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.Peer reviewe

Portability of Polygenic Risk Scores for Sleep Duration, Insomnia and Chronotype in 33,493 Individuals

Polygenic risk scores (PRSs) estimate genetic liability for diseases and traits. However, the portability of PRSs in sleep traits has remained elusive. We generated PRSs for self-reported insomnia, chronotype and sleep duration using summary data from genome-wide association studies (GWASs) performed in 350,000 to 697,000 European-ancestry individuals. We then projected the scores in two independent Finnish population cohorts (N = 33,493) and tested whether the PRSs were associated with their respective sleep traits. We observed that all the generated PRSs were associated with their corresponding traits (p < 0.05 in all cases). Furthermore, we found that there was a 22.2 min difference in reported sleep between the 5% tails of the PRS for sleep duration (p < 0.001). Our findings indicate that sleep-related PRSs show portability across cohorts. The findings also demonstrate that sleep measures using PRSs for sleep behaviors may provide useful instruments for testing disease and trait associations in cohorts where direct sleep parameters have not yet been measured

Oxytocin receptor genotype moderates the association between maternal prenatal stress and infant early self-regulation

IntroductionMaternal prenatal stress may have long-term adverse consequences for child development. Accumulating evidence shows that the oxytocin-receptor genotype may play a role in differential susceptibility to early-life adversity, but no studies have examined whether this moderation extends to the prenatal stress exposures.MethodsIn the FinnBrain Birth Cohort Study, a sample of 1173 mother-child dyads were examined. We studied the possible moderating effect of the cumulative effect of infant oxytocin-receptor risk genotypes (rs53576GG and rs2254298A) in the association between maternal prenatal stress, and infant negative reactivity and emerging self-regulation at 6 months of age.ResultsThe number of OTr risk genotypes moderated the association between maternal prenatal anxiety and infant self-regulation, implying a cumulative effect of genotype, although effects sizes were small. In infants with two risk genotypes, a negative association between prenatal anxiety and self-regulation was observed, whereas in infants with one or no risk genotypes, the association between maternal prenatal anxiety and temperament was non-significant.ConclusionOxytocin-receptor genotype may moderate the association of maternal stress during pregnancy and child social-emotional development. Possible mechanisms for this moderation effect are discussed. Further studies with a more comprehensive polygenic approach are needed to confirm these results.</p

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

Association between arterial hypertension and liver outcomes using polygenic risk scores : a population-based study

Arterial hypertension (HTA) is associated with liver disease, but causality remains unclear. We investigated whether genetic predisposition to HTA is associated with liver disease in the population, and if antihypertensive medication modifies this association. Participants of the Finnish health-examination surveys, FINRISK 1992-2012 and Health 2000 (n = 33,770), were linked with national electronic healthcare registers for liver-related outcomes (K70-K77, C22.0) and with the drug reimbursement registry for new initiation of antihypertensive medication during follow-up. Genetic predisposition to HTA was defined by polygenic risk scores (PRSs). During a median 12.9-year follow-up (409,268.9 person-years), 441 liver-related outcomes occurred. In the fully-adjusted Cox-regression models, both measured systolic blood pressure and clinically defined HTA were associated with liver-related outcomes. PRSs for systolic and diastolic blood pressure were significantly associated with liver-related outcomes (HR/SD 1.19, 95% CI 1.01-1.24, and 1.12, 95% CI 1.01-1.25, respectively). In the highest quintile of the systolic blood pressure PRS, new initiation of antihypertensive medication was associated with reduced rates of liver-related outcomes (HR 0.55, 95% CI 0.31-0.97). HTA and a genetic predisposition for HTA are associated with liver-related outcomes in the population. New initiation of antihypertensive medication attenuates this association in persons with high genetic risk for HTA.Peer reviewe

Genetic polymorphisms in COMT and BDNF influence synchronization dynamics of human neuronal oscillations

Neuronal oscillations, their inter-areal synchronization, and scale-free dynamics constitute fundamental mechanisms for cognition by regulating communication in neuronal networks. These oscillatory dynamics have large inter-individual variability that is partly heritable. We hypothesized that this variability could be partially explained by genetic polymorphisms in neuromodulatory genes. We recorded resting-state magnetoencephalography (MEG) from 82 healthy participants and investigated whether oscillation dynamics were influenced by genetic polymorphisms in catechol- -methyltransferase ( ) Val Met and brain-derived neurotrophic factor ( ) Val Met. Both and polymorphisms influenced local oscillation amplitudes and their long-range temporal correlations (LRTCs), while only polymorphism affected the strength of large-scale synchronization. Our findings demonstrate that and genetic polymorphisms contribute to inter-individual variability in neuronal oscillation dynamics. Comparison of these results to computational modeling of near-critical synchronization dynamics further suggested that and polymorphisms influenced local oscillations by modulating the excitation-inhibition balance according to the brain criticality framework

The Effects of Genetic Background for Diurnal Preference on Sleep Development in Early Childhood

Purpose: No previous research has examined the impact of the genetic background of diurnal preference on children´s sleep. Here, we examined the effects of genetic risk score for the liability of diurnal preference on sleep development in early childhood in two population-based cohorts from Finland. Participants and methods: The primary sample (CHILD-SLEEP, CS) comprised 1420 infants (695 girls), and the replication sample (FinnBrain, FB; 962 girls) 2063 infants. Parent-reported sleep duration, sleep-onset latency and bedtime were assessed at three, eight, 18 and 24 months in CS, and at six, 12 and 24 months in FB. Actigraphy-based sleep latency and efficiency were measured in CS in 365 infants at eight months (168 girls), and in 197 infants at 24 months (82 girls). Mean standard scores for each sleep domain were calculated in both samples. Polygenic risk scores (PRS) were used to quantitate the genetic risk for eveningness (PRSBestFit) and morningness (PRS10kBest). Results: PRSBestFit associated with longer sleep-onset latency and later bedtime, and PRS10kBest related to shorter sleep-onset latency in CS. The link between genetic risk for diurnal preference and sleep-onset latency was replicated in FB, and meta-analysis resulted in associations (P<0.0005) with both PRS-values (PRSBestFit: Z=3.55; and PRS10kBest: Z=-3.68). Finally, PRSBestFit was related to actigraphy-based lower sleep efficiency and longer sleep latency at eight months. Conclusion: Genetic liability to diurnal preference for eveningness relates to longer sleep-onset during the first two years of life, and to objectively measured lowered sleep efficiency. These findings enhance our understanding on the biological factors affecting sleep development, and contribute to clarify the physiological sleep architecture in early childhood.Peer reviewe