Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry.

Background: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts. Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

Consistent cord blood DNA methylation signatures of gestational age between South Asian and white European cohorts.

BACKGROUND: Epigenetic modifications, particularly DNA methylation (DNAm) in cord blood, are an important biological marker of how external exposures during gestation can influence the in-utero environment and subsequent offspring development. Despite the recognized importance of DNAm during gestation, comparative studies to determine the consistency of these epigenetic signals across different ethnic groups are largely absent. To address this gap, we first performed epigenome-wide association studies (EWAS) of gestational age (GA) using newborn cord blood DNAm comparatively in a white European (n = 342) and a South Asian (n = 490) birth cohort living in Canada. Then, we capitalized on established cord blood epigenetic GA clocks to examine the associations between maternal exposures, offspring characteristics and epigenetic GA, as well as GA acceleration, defined as the residual difference between epigenetic and chronological GA at birth. RESULTS: Individual EWASs confirmed 1,211 and 1,543 differentially methylated CpGs previously reported to be associated with GA, in white European and South Asian cohorts, respectively, with a similar distribution of effects. We confirmed that Bohlin's cord blood GA clock was robustly correlated with GA in white Europeans (r = 0.71; p = 6.0 × 10-54) and South Asians (r = 0.66; p = 6.9 × 10-64). In both cohorts, Bohlin's clock was positively associated with newborn weight and length and negatively associated with parity, newborn female sex, and gestational diabetes. Exclusive to South Asians, the GA clock was positively associated with the newborn ponderal index, while pre-pregnancy weight and gestational weight gain were strongly predictive of increased epigenetic GA in white Europeans. Important predictors of GA acceleration included gestational diabetes mellitus, newborn sex, and parity in both cohorts. CONCLUSIONS: These results demonstrate the consistent DNAm signatures of GA and the utility of Bohlin's GA clock across the two populations. Although the overall pattern of DNAm is similar, its connections with the mother's environment and the baby's anthropometrics can differ between the two groups. Further research is needed to understand these unique relationships.

A method to estimate the contribution of rare coding variants to complex trait heritability.

It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the "missing" heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h2RV) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h2RV. Using unaggregated variants, 27 traits had h2RV > 5%, with height having the highest h2RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h2RV, enabling the assessment of gene-level characteristics and revealing 11, previously unreported, gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, innovative methods are needed to predict RV functionality.

A high-resolution PheWAS approach to alcohol-related polygenic risk scores reveals mechanistic influences of alcohol reinforcing value and drinking motives.

AIMS: This study uses a high-resolution phenome-wide approach to evaluate the motivational mechanisms of polygenic risk scores (PRSs) that have been robustly associated with coarse alcohol phenotypes in large-scale studies. METHODS: In a community-based sample of 1534 Europeans, we examined genome-wide PRSs for the Alcohol Use Disorders Identification Test (AUDIT), drinks per week, alcohol use disorder (AUD), problematic alcohol use (PAU), and general addiction, in relation to 42 curated phenotypes. The curated phenotypes were in seven categories: alcohol consumption, alcohol reinforcing value, drinking motives, other addictive behaviors, commonly comorbid psychiatric syndromes, impulsivity, and personality traits. RESULTS: The PRS for each alcohol phenotype was validated via its within-sample association with the corresponding phenotype (adjusted R2s = 0.35-1.68%, Ps = 0.012-3.6 × 10-7) with the exception of AUD. All PRSs were positively associated with alcohol reinforcing value and drinking motives, with the strongest effects from AUDIT-consumption (adjusted R2s = 0.45-1.33%, Ps = 0.006-3.6 × 10-5) and drinks per week PRSs (adjusted R2s = 0.52-2.28%, Ps = 0.004-6.6 × 10-9). Furthermore, the PAU and drinks per week PRSs were positively associated with adverse childhood experiences (adjusted R2s = 0.6-0.7%, Ps = 0.0001-4.8 × 10-4). CONCLUSIONS: These results implicate alcohol reinforcing value and drinking motives as genetically-influenced mechanisms using PRSs for the first time. The findings also highlight the value of dissecting genetic influence on alcohol involvement through diverse phenotypic risk pathways but also the need for future studies with both phenotypic richness and larger samples.