An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved

Pre-Readers at the Alien Zoo: A Preregistered Study of the Predictors of Dyslexia and Linguistic Sound Symbolism in 6-year-olds

Recent studies suggest that multisensory linkages betweenspeech and vision are implicated in the development ofdyslexia. Current data only address a relationship in adultswith existing diagnoses, but do not inform us about thedevelopmental trajectory of the association. We conducted apre-registered study of multisensory matching in 388 pre-readers in Singapore (Age: 5y 10m) using an adaptation of thebouba-kiki task (the Alien Zoo), and compared children’sperformance on this task to their earlier scores on measuresknown to predict dyslexia: phonological awareness,vocabulary size and letter knowledge. As reported elsewhere,children’s Alien Zoo scores were lower than adults’(Woon &Styles, 2017a). The language measures were strongly inter-correlated, suggesting persistent language skills acrossmultiple domains, However we found no significantrelationship between performance on the Alien Zoo task andany of the predictors of dyslexia. This may mean that therelationship is yet to emerge in this population. The childrenin this cohort will be tracked and tested at a later time point toestablish the developmental trajectory of this relationship

The Effect of Older Sibling, Postnatal Maternal Stress, and Household Factors on Language Development in Two-to Four-Year-Old Children

Previous literature has shown that family structure affects language development. Here, factors relating to older siblings (their presence in the house, sex and age gap), mothers (maternal stress) and household size and residential crowding were examined to systematically examine the different role of these factors. Data from mother-child dyads in a Singaporean birth cohort, (677-855 dyads; 52% males; 58-61% Chinese, 20-24% Malay, 17-19% Indian) collected when children were 24-, 48-, and 54-months old, were analysed. There was a negative effect of having an older sibling, moderated by the siblings’ age gap, but not by the older sibling’s sex, nor household size or residential crowding. Maternal stress affected language outcomes in some analyses but not others. Implications for understanding the effect of family structure on language development are discussed

The Effect of Older Sibling, Postnatal Maternal Stress, and Household Factors on Language Development in Two- to Four-Year-Old Children

Previous literature has shown that family structure affects language development. Here, factors relating to older siblings (their presence in the house, sex and age gap), mothers (maternal stress) and household size and residential crowding were examined to systematically examine the different role of these factors. Data from mother-child dyads in a Singaporean birth cohort, (677-855 dyads; 52% males; 58-61% Chinese, 20-24% Malay, 17-19% Indian) collected when children were 24-, 48-, and 54-months old, were analysed. There was a negative effect of having an older sibling, moderated by the siblings’ age gap, but not by the older sibling’s sex, nor household size or residential crowding. Maternal stress affected language outcomes in some analyses but not others. Implications for understanding the effect of family structure on language development are discussed

The association between chronotype and sleep problems in preschool children

Objective Adolescents and adults who are evening-types exhibit shorter sleep duration and more sleep problems than individuals with an earlier chronotype. We hypothesized that already at a preschool age, evening-types would exhibit more sleep problems relative to children who are morning or intermediate chronotypes. The aim of this study was to examine the association between chronotype and sleep problems among preschool children. Methods We studied a subset of typically-developing 4.5-year-olds taking part in the Growing Up in Singapore Towards healthy Outcomes birth cohort study (n = 244). The Children's Chronotype Questionnaire (CCTQ) was used to categorize children into morning-, intermediate-, and evening-types. Sleep problems were measured using the Children's Sleep Habits Questionnaire (CSHQ), with higher scores corresponding to greater sleep problems. The relation between chronotype, sleep–wake timing, and nocturnal sleep time was also evaluated in a subsample of 117 children using actigraphy recordings with parent-reported sleep diaries. Results After controlling for potential confounders (maternal education, child's sex, birth order, and ethnicity), a significant main effect of chronotype on sleep problems was observed, in which evening-types exhibited greater CSHQ scores compared to morning- and intermediate-types (all p <0.001). Actigraphy data in the subsample confirmed that evening-types had later bedtimes (p <0.001) and get-up times (p = 0.02) during weekdays and weekends, but shorter nocturnal sleep time (p = 0.034) only during weekdays, compared to children who had earlier chronotypes. Conclusions In preschool children, sleep problems were greater in evening-types compared to morning- and intermediate-types, suggesting that chronotype could be a contributing factor to sleep disturbances in early childhood

Cultural differences in mirror self-recognition in 18 month-old Singaporean toddlers

Western societies put emphasis on the development of the individual self, while Asian societies prioritize the sense of the self in relation to social groups. In Western populations roughly 60% of 18-month-old toddlers show self-referential behavior upon viewing themselves reflected in a mirror. Self-referential behavior has been used as a measure of self-recognition and development of the self. The aim of the current study was to investigate possible cultural differences in toddler's self-referential behavior while looking at themselves in a mirror. The current study involved 329 18-months-old Southeast Asian, multi-ethnic Singaporean toddlers taking part in a larger prospective mother-offspring birth cohort study GUSTO. In contrast to Western results, only 31.3 % of Singaporean toddlers showed mirror self-recognition behavior. However, rates significantly differed by ethnicity, with Singaporean Indian toddlers showing more self-referential behavior than Singaporean Malay and Chinese toddlers. Thus, collectivistic values could explain differences in self-referential behavior and expression of self-recognition. We propose that the sense of the self might have developed similarly across different cultures but that other variables, such as parenting styles, might influence self-referential behavior

Do intrinsic brain functional networks predict working memory from childhood to adulthood?

Working memory (WM) is defined as the ability to maintain a representation online to guide goal-directed behavior. Its capacity in early childhood predicts academic achievements in late childhood and its deficits are found in various neurodevelopmental disorders. We employed resting-state fMRI (rs-fMRI) of 468 participants aged from 4 to 55 years and connectome-based predictive modeling (CPM) to explore the potential predictive power of intrinsic functional networks to WM in preschoolers, early and late school-age children, adolescents, and adults. We defined intrinsic functional networks among brain regions identified by activation likelihood estimation (ALE) meta-analysis on existing WM functional studies (ALE-based intrinsic functional networks) and intrinsic functional networks generated based on the whole brain (whole-brain intrinsic functional networks). We employed the CPM on these networks to predict WM in each age group. The CPM using the ALE-based and whole-brain intrinsic functional networks predicted WM of individual adults, while the prediction power of the ALE-based intrinsic functional networks was superior to that of the whole-brain intrinsic functional networks. Nevertheless, the CPM using the whole-brain but not the ALE-based intrinsic functional networks predicted WM in adolescents. And, the CPM using neither the ALE-based nor whole-brain networks predicted WM in any of the children groups. Our findings showed the trend of the prediction power of the intrinsic functional networks to cognition in individuals from early childhood to adulthood

Inflammatory modulation of the associations between prenatal maternal depression and neonatal brain

Inflammatory signaling has a role in sensing intrauterine environment, which may be moderators in altering fetal brain development upon maternal environment. This study integrated cytokine transcriptome of post-mortem fetal brains, neonatal brain imaging and genetic variants (n = 161) to examine whether cytokines are candidates for modulating the relationship between prenatal maternal depression and fetal brain development. This study obtained the transcriptome data of 208 cytokine genes in 12 fetal brain regions from the BrainSpan database. We also included 161 mother–child dyads with prenatal maternal depressive symptoms assessed at 26 weeks of gestation, cytokine genotype data extracted from umbilical cord specimens, and neonatal brain images from a longitudinal prospective birth cohort. We revealed that 22 cytokine genes are expressed in specific brain regions in utero, whose variants have roles in modulating the effects of the prenatal environment on the accelerated fetal development of the hippocampus, auditory, parietal, orbitofrontal, and dorsal prefrontal cortex. Neonates high in the genetic expression score (GES) of TNFRSF19 and IL17RB showed a larger right hippocampal volume, high in the GES of BMPR1B showed the thicker thickness of the sensorimotor cortex, and high in the GES of IL1RAP and CXCR4 demonstrated the thicker thickness of the dorsal and orbital prefrontal cortex in relation with greater prenatal maternal depressive symptoms. Our findings suggest that in humans, the cytokine genes are expressed in a brain region-specific manner in utero and may have potential roles in modulating the fetal development of the corresponding brain regions in response to the maternal environment

Associations of maternal zinc and magnesium with offspring learning abilities and cognitive development at 4 years in GUSTO

Objectives: Minerals deficiencies during pregnancy have been shown to be associated with poorer cognitive outcomes in offspring. This study aimed to investigate associations of maternal plasma zinc and magnesium concentrations with cognitive development in 4-year old children from the Growing Up in Singapore Towards healthy Outcome cohort.Methods: Maternal plasma zinc and magnesium concentrations were measured at 26–28 weeks’ gestation. The Lollipop test of school readiness, tests of working memory, number knowledge, receptive vocabulary, and phonological awareness were performed in children at 4 years. Associations were examined in 715 mother-offspring pairs using linear regressions adjusted for key confounders.Results: Maternal plasma zinc and magnesium concentrations were 812 ± 144 µg/L and 19.9 ± 1.8 mg/L (mean±SD); 19% and 71% of mothers were zinc deficient and magnesium insufficient, respectively. After adjustment for multiple testing, higher maternal zinc concentrations (per SD increment) were associated with 0.35 higher scores in Lollipop subtest 2 of picture description and spatial identification (95% CI: 0.13, 0.58); higher maternal magnesium concentrations (per SD increment) were associated with 0.65 higher scores in Lollipop subtest 4 of letters and writing identification (95% CI: 0.23, 1.07).Discussion: No significant associations were observed for other tests, suggesting little long term influences of maternal zinc and magnesium on child's cognitive development

Sleep and dietary patterns in pregnancy: Findings from the gusto cohort

Evidence on the association between sleep, diet, and eating behaviors in pregnant women is lacking. We examine this in a cohort of apparently healthy pregnant women. At 26–28 weeks gestation, 497 participants completed the Pittsburgh Sleep Quality Index to assess sleep and a 24-h recall to assess dietary intake. Diet quality was assessed by the Healthy Eating Index for pregnant women in Singapore (HEI-SGP) score and previously derived dietary patterns (vegetables-fruit-rice, seafood-noodles, and pasta-cheese-meat pattern). Eating behaviors studied included the longest night-time fasting interval, frequency of consumption occasions, energy from discretionary foods, and night-time eating. Adjusted means were estimated between poor/good quality and short/normal sleepers using linear regressions, including covariates. Good sleep quality versus poor sleep quality, was associated with better diet quality (mean HEI‐SGP 54.6 vs. 52.0; p = 0.032), greater adherence to the vegetables-fruit-rice pattern (mean 0.03 vs. −0.15; p = 0.039), lesser adherence to the seafood-noodle pattern (mean −0.14 vs. 0.03; p = 0.024), and a trending lower calories from discretionary foods (mean 330.5 vs. 382.6 kcal; p = 0.073), after adjusting for covariates. After additional adjustment for anxiety, only sleep quality and the seafood‐noodle pattern remained significantly associated (p = 0.018). Short sleep was not associated with any diet or eating behavior. In conclusion, good sleep quality is associated with a better diet quality and a greater adherence to the vegetable-fruit-rice pattern, but with lesser adherence to the seafood-noodle diets in pregnant women