Job-related exhaustion risk variant in UST is associated with dementia and DNA methylation.

Previous genome-wide association and replication study for job-related exhaustion indicated a risk variant, rs13219957 in the UST gene. Epidemiological studies suggest connection of stress-related conditions and dementia risk. Therefore, we first studied association of rs13219957 and register-based incident dementia using survival models in the Finnish National FINRISK study surveys (N = 26,693). The AA genotype of rs13219957 was significantly associated with 40% increased risk of all-cause dementia. Then we analysed the UST locus association with brain pathology in the Vantaa 85+ cohort and found association with tau pathology (Braak stage) but not with amyloid pathology. Finally, in the functional analyses, rs13219957 showed a highly significant association with two DNA methylation sites of UST, and UST expression. Thus, the results suggest a common risk variant for a stress-related condition and dementia. Mechanisms to mediate the connection may include differential DNA methylation and transcriptional regulation of UST.

Nightmares share genetic risk factors with sleep and psychiatric traits.

Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e-06), depressive (rg = 0.562, p = 1.282e-07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e-07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual's liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts.

Association of cumulative prenatal adversity with infant subcortical structure volumes and child problem behavior and its moderation by a coexpression polygenic risk score of the serotonin system.

Prenatal adversity has been linked to later psychopathology. Yet, research on cumulative prenatal adversity, as well as its interaction with offspring genotype, on brain and behavioral development is scarce. With this study, we aimed to address this gap. In Finnish mother-infant dyads, we investigated the association of a cumulative prenatal adversity sum score (PRE-AS) with (a) child emotional and behavioral problems assessed with the Strengths and Difficulties Questionnaire at 4 and 5 years (N = 1568, 45.3% female), (b) infant amygdalar and hippocampal volumes (subsample N = 122), and (c) its moderation by a hippocampal-specific coexpression polygenic risk score based on the serotonin transporter (SLC6A4) gene. We found that higher PRE-AS was linked to greater child emotional and behavioral problems at both time points, with partly stronger associations in boys than in girls. Higher PRE-AS was associated with larger bilateral infant amygdalar volumes in girls compared to boys, while no associations were found for hippocampal volumes. Further, hyperactivity/inattention in 4-year-old girls was related to both genotype and PRE-AS, the latter partially mediated by right amygdalar volumes as preliminary evidence suggests. Our study is the first to demonstrate a dose-dependent sexually dimorphic relationship between cumulative prenatal adversity and infant amygdalar volumes.

Genetic background to attention deficit and hyperactivity disorder and attention deficit and hyperactivity disorder symptoms at the age of 5 years: the role of sleep duration.

STUDY OBJECTIVES: We studied the associations between polygenic risk score (PRS) for attention deficit and hyperactivity disorder (ADHD) and (1) ADHD symptoms in 5-year-old children, (2) sleep duration throughout childhood, and (3) the interaction between PRS for ADHD and short sleep duration relative to ADHD symptoms at 5 years. METHODS: This study is based on the population-based CHILD-SLEEP birth cohort (N = 1420 children). PRS was used to quantitate the genetic risk for ADHD. Parent-reported ADHD symptoms at 5 years were obtained from 714 children, using the Strengths and Difficulties Questionnaire (SDQ) and the Five-to-Fifteen (FTF). Our primary outcomes were SDQ-hyperactivity and FTF-ADHD total scores. Parent-reported sleep duration was measured at 3, 8, 18, 24 months, and 5 years in the whole sample and actigraphy-based sleep duration at 2 and 24 months in a subsample. RESULTS: PRS for ADHD associated with SDQ-hyperactivity (ß = 0.214, p = .012) and FTF-ADHD total (ß = 0.639, p = .011), and FTF-inattention and hyperactivity subscale scores (ß = 0.315, p = .017 and ß = 0.324, p = .030), but not with sleep duration at any time point. Significant interactions were found between high PRS for ADHD and parent-reported short sleep throughout childhood in FTF-ADHD total score (F = 4.28, p = .039) and FTF-inattention subscale (F = 4.66, p = .031). We did not find any significant interaction between high PRS for ADHD and actigraphy-based short sleep. CONCLUSIONS: Parent-reported short sleep moderates the association between genetic risk of ADHD and ADHD symptoms in early childhood in the general population, so that children with short sleep, in combination with high genetic risk for ADHD, could be at highest risk for ADHD symptoms.

Polygenic risk for neuroticism is associated with externalizing symptoms in 2-year-old boys.

Recent advances in genome-wide association studies have enabled the estimation of genetic risk of complex traits, including neuroticism, with polygenic risk scores (PRS). Neuroticism PRS has been associated with psychiatric disorders and symptoms in adults, but studies in children are scarce. We studied whether neuroticism PRS, and its subscales, worry PRS and depressive affect PRS, were associated with externalizing and internalizing symptoms in 2-year-olds. We also examined parental neuroticism PRSs' association with children's externalizing and internalizing symptoms and whether parental depressive symptoms mediated the effect. Participants from two Finnish birth cohorts, CHILD-SLEEP and FinnBrain Birth Cohort Study, who had DNA and data on Brief Infant-Toddler Social and Emotional Assessment (BITSEA) available were included in the study (N = 806 and N = 987, respectively). PRSs were calculated based on GWAS data from UK Biobank. Child's neuroticism PRS, and its subscale worry PRS, were positively associated with externalizing symptoms in 2-year-old boys, but not in girls. Mother's depressive symptoms mediated the association between maternal neuroticism PRS and externalizing and internalizing symptoms in boys, but not in girls. Our results suggest that neuroticism PRS, and its subscale worry PRS, are associated with externalizing symptoms in already as young as 2-year-old boys, and, that subclinical symptoms of maternal depression that are based on genetic disposition, have an effect on boy's internalizing and externalizing symptoms. As we did not find any associations in girls, our study supports the suggestion that girls and boys may differ in how genetic and environmental factors contribute to their development.

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-O-methyltransferase (COMT) Val158Met and brain-derived neurotrophic factor (BDNF) Val66Met. Both COMT and BDNF polymorphisms influenced local oscillation amplitudes and their long-range temporal correlations (LRTCs), while only BDNF polymorphism affected the strength of large-scale synchronization. Our findings demonstrate that COMT and BDNF 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 COMT and BDNF polymorphisms influenced local oscillations by modulating the excitation-inhibition balance according to the brain criticality framework.

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.

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.

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.

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.

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.

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.

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. RESULTS: In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.

Sex-specific association between infant caudate volumes and a polygenic risk score for major depressive disorder.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54 days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

The role of TPH2 variant rs4570625 in shaping infant attention to social signals.

TPH2, the rate-limiting enzyme in the synthesis of serotonin, has been connected to several psychiatric outcomes. Its allelic variant, rs4570625, has been found to relate to individual differences in cognitive and emotion regulation during infancy with T-carriers of rs4570625 showing a relatively heightened attention bias for fearful faces. A significant gene-environment interaction was also reported with the T-carriers of mothers with depressive symptoms showing the highest fear bias. We investigated these associations in a sample of 8-month old infants (N = 330), whose mothers were prescreened for low/high levels of prenatal depressive and/or anxiety symptoms. Attention disengagement from emotional faces (neutral, happy, fearful, and phase-scrambled control faces) to distractors was assessed with eye tracking and an overlap paradigm. Maternal depressive symptoms were assessed at several time points during pregnancy and postpartum. The mean levels of symptoms at six months postpartum and the trajectories of symptoms from early pregnancy until six months postpartum were used in the analyses (N = 274). No main effect of the rs4570625 genotype on attention disengagement was found. The difference in fear bias between the genotypes was significant but in an opposite direction compared to a previous study. The results regarding the interaction of the genotype and maternal depression were not in accordance with the previous studies. These results show inconsistencies in the effects of the rs4570625 genotype on attention biases in separate samples of infants from the same population with only slight differences in age.

Variation near MTNR1A associates with early development and interacts with seasons.

Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift-work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8-month-old infants from the Finnish CHILD-SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p = .025) and communication (p = .0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development.

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

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.

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.

Identification of NCAN as a candidate gene for developmental dyslexia.

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.

Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C) are associated with sleep latency in infants.

Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly) with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys) from the Finnish CHILD-SLEEP birth cohort (genotyped by Illumina Infinium PsychArray BeadChip). Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted P<0.05). There was no significant association between studied variants and night awakenings or sleep duration. CACNA1C variants for psychiatric disorders were found to be associated with long sleep latency among 8-month-old infants. It remains to be clarified whether the findings refer to defective regulation of sleep, or to distractibility of sleep under external influences.