Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Development and internal validation of a non-invasive clinical tool to predict sufficient omega-3 levels in early pregnancy.

BACKGROUND: Complications from preterm birth (PTB) are the leading cause of death and disability in those under five years. Whilst the role of omega-3 (n-3) supplementation in reducing PTB is well-established, growing evidence suggests supplementation use in those replete may increase the risk of early PTB. AIM: To develop a non-invasive tool to identify individuals with total n-3 serum levels above 4.3% of total fatty acids in early pregnancy. METHODS: We conducted a prospective observational study recruiting 331 participants from three clinical sites in Newcastle, Australia. Eligible participants (n = 307) had a singleton pregnancy between 8 and 20 weeks' gestation at recruitment. Data on factors associated with n-3 serum levels were collected using an electronic questionnaire; these included estimated intake of n-3 (including food type, portion size, frequency of consumption), n-3 supplementation, and sociodemographic factors. The optimal cut-point of estimated n-3 intake that predicted mothers with total serum n-3 levels likely above 4.3% was developed using multivariate logistic regression, adjusting for maternal age, body mass index, socioeconomic status, and n-3 supplementation use. Total serum n-3 levels above 4.3% was selected as previous research has demonstrated that mothers with these levels are at increased risk of early PTB if they take additional n-3 supplementation during pregnancy. Models were evaluated using various performance metrics including sensitivity, specificity, area under receiver operator characteristic (AUROC) curve, true positive rate (TPR) at 10% false positive rate (FPR), Youden Index, Closest to (0,1) Criteria, Concordance Probability, and Index of Union. Internal validation was performed using 1000-bootstraps to generate 95% confidence intervals for performance metrics generated. RESULTS: Of 307 eligible participants included for analysis, 58.6% had total n-3 serum levels above 4.3%. The optimal model had a moderate discriminative ability (AUROC 0.744, 95% CI 0.742-0.746) with 84.7% sensitivity, 54.7% specificity and 37.6% TPR at 10% FPR. CONCLUSIONS: Our non-invasive tool was a moderate predictor of pregnant women with total serum n-3 levels above 4.3%; however, its performance is not yet adequate for clinical use. TRIAL REGISTRATION: This trial was approved by the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (Reference 2020/ETH00498 on 07/05/2020 and 2020/ETH02881 on 08/12/2020).

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Preterm labor is a distinct process from term labor following computational analysis of human myometrium.

BACKGROUND: The onset of the term human parturition involves myometrial gene expression changes to transform the uterus from a quiescent to a contractile phenotype. It is uncertain whether the same changes occur in the uterus during preterm labor. OBJECTIVE: This study aimed to compare the myometrial gene expression between term and preterm labor and to determine whether the presence of acute clinical chorioamnionitis or twin gestation affects these signatures. STUDY DESIGN: Myometrial specimens were collected during cesarean delivery from the following 7 different groups of patients: term not in labor (n=31), term labor (n=13), preterm not in labor (n=21), preterm labor with acute clinical chorioamnionitis (n=6), preterm labor with no acute clinical chorioamnionitis (n=9), twin preterm not in labor (n=8), and twin preterm labor with no acute clinical chorioamnionitis (n=5). RNA was extracted, reverse transcribed and quantitative polymerase chain reactions were performed on 44 candidate genes (with evidence for differential expression in human term labor) using the Fluidigm platform. Computational analysis was performed using 2-class unpaired Wilcoxon tests and principal component analysis. RESULTS: Computational analysis revealed that gene expression in the preterm myometrium, irrespective of whether in labor or not in labor, clustered tightly and is clearly different from the term labor and term not-in-labor groups. This was true for both singleton and twin pregnancies. Principal component analysis showed that 57% of the variation was explained by 3 principal components. These 44 genes interact in themes of prostaglandin activity and inflammatory signaling known to be important during term labor, but are not a full representation of the myometrium transcriptional activity. CONCLUSION: The myometrial contractions associated with preterm labor are associated with a pattern of gene expression that is distinct from term labor. Therefore, preterm labor may be initiated by a different myometrial process or processes outside the myometrium.

Genome-wide associations for birth weight and correlations with adult disease.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (ß = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (ß ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the ß-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits.

BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months), and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism-based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08-0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = -0.74), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.

Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Combined vaginal progesterone and cervical cerclage in the prevention of preterm birth: a systematic review and meta-analysis.

OBJECTIVE: Vaginal progesterone and cervical cerclage are both effective interventions for reducing preterm birth. It is currently unclear whether combined therapy offers superior effectiveness than single therapy. This study aimed to determine the efficacy of combining cervical cerclage and vaginal progesterone in the prevention of preterm birth. DATA SOURCES: We searched Medline (Ovid), EMBASE (Ovid), PsycINFO (Ovid), CINAHL (EBSCOhost), Cochrane Library (Wiley), and Scopus (from their inception to 2020). STUDY ELIGIBILITY CRITERIA: The review accepted randomized and pseudorandomized control trials, nonrandomized experimental control trials, and cohort studies. High risk patients (shortened cervical length <25mm or previous preterm birth) who were assigned cervical cerclage, vaginal progesterone, or both for the prevention of preterm birth were included. Only singleton pregnancies were assessed. METHODS: The primary outcome was birth <37 weeks. Secondary outcomes included birth <28 weeks, <32 weeks and <34 weeks, gestational age at delivery, days between intervention and delivery, preterm premature rupture of membranes, cesarean delivery, neonatal mortality, neonatal intensive care unit admission, intubation, and birthweight. Following title and full-text screening, 11 studies were included in the final analysis. Risk of bias was assessed using the Cochrane Collaboration tool for assessing the risk of bias (ROBINS-I and RoB-2). Quality of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) tool. RESULTS: Combined therapy was associated with lower risk of preterm birth at <37 weeks than cerclage alone (risk ratio, 0.51; 95% confidence interval, 0.37-0.79) or progesterone alone (risk ratio, 0.75; 95% confidence interval, 0.58-0.96). Compared with cerclage only, combined therapy was associated with preterm birth at <34 weeks, <32 weeks, or <28 weeks, decreased neonatal mortality, increased birthweight, increased gestational age, and a longer interval between intervention and delivery. Compared with progesterone alone, combined therapy was associated with preterm birth at <32 weeks, <28 weeks, decreased neonatal mortality, increased birthweight, and increased gestational age. There were no differences in any other secondary outcomes. CONCLUSION: Combined treatment of cervical cerclage and vaginal progesterone could potentially result in a greater reduction in preterm birth than in single therapy. Further, well-conducted and adequately powered randomized controlled trials are needed to assess these promising findings.

The Role of Genetics in Preterm Birth.

Preterm birth (PTB), defined as the birth of a child before 37 completed weeks gestation, affects approximately 11% of live births and is the leading cause of death in children under 5 years. PTB is a complex disease with multiple risk factors including genetic variation. Much research has aimed to establish the biological mechanisms underlying PTB often through identification of genetic markers for PTB risk. The objective of this review is to present a comprehensive and updated summary of the published data relating to the field of PTB genetics. A literature search in PubMed was conducted and English studies related to PTB genetics were included. Genetic studies have identified genes within inflammatory, immunological, tissue remodeling, endocrine, metabolic, and vascular pathways that may be involved in PTB. However, a substantial proportion of published data have been largely inconclusive and multiple studies had limited power to detect associations. On the contrary, a few large hypothesis-free approaches have identified and replicated multiple novel variants associated with PTB in different cohorts. Overall, attempts to predict PTB using single "-omics" datasets including genomic, transcriptomic, and epigenomic biomarkers have been mostly unsuccessful and have failed to translate to the clinical setting. Integration of data from multiple "-omics" datasets has yielded the most promising results.

Changes in Refractive Error During Young Adulthood: The Effects of Longitudinal Screen Time, Ocular Sun Exposure, and Genetic Predisposition.

Purpose: Changes in refractive error during young adulthood is common yet risk factors at this age are largely unexplored. This study explored risk factors for these changes, including gene-environmental interactions. Methods: Spherical equivalent refraction (SER) and axial length (AL) for 624 community-based adults were measured at 20 (baseline) and 28 years old. Participants were genotyped and their polygenic scores (PGS) for refractive error calculated. Self-reported screen time (computer, television, and mobile devices) from 20 to 28 years old were collected prospectively and longitudinal trajectories were generated. Past sun exposure was quantified using conjunctival ultraviolet autofluorescence (CUVAF) area. Results: Median change in SER and AL were -0.023 diopters (D)/year (interquartile range [IQR] = -0.062 to -0.008) and +0.01 mm/year (IQR = 0.000 to 0.026), respectively. Sex, baseline myopia, parental myopia, screen time, CUVAF, and PGS were significantly associated with myopic shift. Collectively, these factors accounted for approximately 20% of the variance in refractive error change, with screen time, CUVAF, and PGS each explaining approximately 1% of the variance. Four trajectories for total screen time were found: "consistently low" (n = 148), "consistently high" (n = 250), "consistently very high" (n = 76), and "increasing" (n = 150). Myopic shift was faster in those with "consistently high" or "consistently very high" screen time compared to "consistently-low" (P ≤ 0.031). For each z-score increase in PGS, changes in SER and AL increased by -0.005 D/year and 0.002 mm/year (P ≤ 0.045). Of the three types of screen time, only computer time was associated with myopic shift (P ≤ 0.040). There was no two- or three-way interaction effect between PGS, CUVAF, or screen time (P ≥ 0.26). Conclusions: Higher total or computer screen time, less sun exposure, and genetic predisposition are each independently associated with greater myopic shifts during young adulthood. Given that these factors explained only a small amount of the variance, there are likely other factors driving refractive error change during young adulthood.

Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.