Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie ...these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3).
Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m
increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P < 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta.
Prepregnancy BMI was associated with DNA methylation at cg14568196EGFL7, cg15339142VETZ, and cg02301019AC092377.1 (FDR P < 0.05, P ranging from 1.4 × 10
to 1.7 × 10
). GWG1 or GWG2 was associated with DNA methylation at cg17918270MYT1L, cg20735365DLX5, and cg17451688SLC35F3 (FDR P < 0.05, P ranging from 6.4 × 10
to 1.2 × 10
). Both prepregnancy BMI and DNA methylation at cg1456819 EGFL7 were negatively correlated with EGFL7 expression in placenta (P < 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood.
We identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.
The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the ...Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.
Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected ...tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%).
We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls.
We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval CI, 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis.
Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).
Abnormal birthweight is associated with increased risk for cardiometabolic diseases in later life. Although the placenta is critical to fetal development and later life health, it has not been ...integrated into largescale functional genomics initiatives, and mechanisms of birthweight-associated variants identified by genome wide association studies (GWAS) are unclear. The goal of this study is to provide functional mechanistic insight into the causal pathway from a genetic variant to birthweight by integrating placental methylation and gene expression with established GWAS loci for birthweight. We identify placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. We find that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in placenta. Multi-trait colocalization identifies PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. These findings reveal candidate functional pathways that underpin the genetic regulation of birthweight via placental epigenetic and transcriptomic mechanisms. Clinical trial registration; ClinicalTrials.gov, NCT00912132.
Podoconiosis is an environmental lymphoedema affecting people living and working barefoot on irritant red clay soil. Podoconiosis is relatively well described in southern Ethiopia, but remains ...neglected in other parts of the Ethiopian highlands. This study aimed to assess the burden of podoconiosis in rural communities in western Ethiopia.
A cross-sectional study was conducted in Gulliso woreda (district), west Ethiopia. A household survey in the 26 rural kebeles (villages) of this district was conducted to identify podoconiosis patients and to measure disease prevalence. A more detailed study was done in six randomly selected kebeles to describe clinical features of the disease, patients' experiences of foot hygiene, and shoe wearing practice. 1,935 cases of podoconiosis were registered, giving a prevalence of 2.8%. The prevalence was higher in those aged 15-64 years (5.2%) and in females than males (prevalence ratio 2.6∶1). 90.3% of patients were in the 15-64 year age group. In the detailed study, 335 cases were interviewed and their feet assessed. The majority of patients were farmers, uneducated, and poor. Two-third of patients developed the disease before the age of thirty. Almost all patients (97.0%) had experienced adenolymphangitis (ALA - red, hot legs, swollen and painful groin) at least once during the previous year. Patients experienced an average of 5.5 ALA episodes annually, each of average 4.4 days, thus 24 working days were lost annually. The incidence of ALA in podoconiosis patients was higher than that reported for filariasis in other countries. Shoe wearing was limited mainly due to financial problems.
We have documented high podoconiosis prevalence, frequent adenolymphangitis and high disease-related morbidity in west Ethiopia. Interventions must be developed to prevent, treat and control podoconiosis, one of the core neglected tropical diseases in Ethiopia.
Objective
To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees.
Design
State‐wide matched case–control study.
Setting
Utah, United States.
...Population
Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019.
Methods
Using the Utah Population Database, a population‐based genealogical resource linked with state fetal death and birth records, we identified high‐risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first‐degree relatives (FDR), second‐degree relatives (SDR) and third‐degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models.
Main outcome measures
Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models.
Results
We identified 390 high‐risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P‐value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14‐fold (95% confidence interval CI: 1.04–1.26), 1.22‐fold (95% CI 1.11–1.33) and 1.15‐fold (95% CI 1.08–1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex‐specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22‐fold (95% CI 1.02–1.47), 1.38‐fold (95% CI 1.17–1.62) and 1.17‐fold (95% CI 1.05–1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12‐fold (95% CI 0.98–1.28), 1.09‐fold (95% CI 0.96–1.24) and 1.15‐fold (95% CI 1.06–1.24) higher stillbirth odds compared with those of unaffected mothers, respectively.
Conclusions
We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large‐scale studies to determine the genetic architecture of stillbirth.
Linked article:This article is commented on by Matthew A. Shear, pp. 463 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471-0528.17365
Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) ...conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N = 1892) collected from the Wolaita and two other Ethiopian populations, the Amhara and the Oromo, also affected by podoconiosis. Fourteen SNPs in the HLA class II region showed significant genome-wide association (P < 5.0 × 10
) with podoconiosis. The lead SNP was rs9270911 (P = 5.51 × 10
; OR 1.53; 95% CI 1.34-1.74), located near HLA-DRB1. Inclusion of data from the first GWAS (combined N = 2289) identified 47 SNPs in the class II HLA region that were significantly associated with podoconiosis (lead SNP also rs9270911 (P = 2.25 × 10
). No new loci outside of the HLA class II region were identified in this more highly-powered second GWAS. Our findings confirm the HLA class II association with podoconiosis suggesting HLA-mediated abnormal induction and regulation of immune responses may have a direct role in its pathogenesis.
Disruption of physiological ageing of the placenta is associated with obstetric complications. Altered lipid metabolism is a known trigger of tissue ageing, but the effect of maternal dyslipidemia on ...placental ageing is not clearly understood. We examined the relationship between maternal dyslipidemia and placental age acceleration (PAA), an epigenetic ageing measure derived from the difference between DNA methylation age and chronological gestational age. We also assessed whether the association varies by maternal pre-pregnancy obesity status and fetal sex. Placental data were obtained as part of the NICHD Fetal Growth Studies that involved participants from four race/ethnic groups. Placental DNA methylation age was estimated using 62 CpGs that have previously been found to have high placental age prediction accuracy. We used multivariable linear regression to test associations between maternal dyslipidemia during early gestation (i.e., high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), total cholesterol (TChol), and triglycerides) and PAA adjusting for fetal sex and socio-demographic factors. Among normal-weight women, low HDLc, compared to high HDLc, was associated with 0.82 (95% CI: 0.00, 1.64) weeks higher PAA. Among women with female neonates, low HDLc, compared to high HDLc, was associated with 1.20 (95% CI: 0.17, 2.24) weeks higher PAA. High TChol was associated with 1.28 (95% CI: 0.12, 2.45) weeks higher PAA among Whites. In all, the study found that maternal dyslipidemia due to low HDLc was associated with accelerated epigenetic ageing of the placenta among mothers with normal pre-pregnancy weight and a female fetus.
Maternal blood pressure (BP) is associated with variations in fetal weight, an important determinant of neonatal and adult health. However, the association of BP-raising genetic risk with fetal ...weight is unknown. We tested the associations of maternal BP-raising polygenic risk scores (PRS) with estimated fetal weights (EFWs) at 13, 20, 27, and 40 weeks of gestation. This study included 622 White, 637 Black, 568 Hispanic, and 238 Asian pregnant women with genotype data from the NICHD Fetal Growth Studies. PRS of systolic (SBP) and diastolic BP (DBP) were calculated for each participant based on summary statistics from a recent genome-wide association study. Linear regression models were used to compare mean EFW differences between the highest versus lowest tertile of PRS, adjusting for maternal age, education, parity, genetic principal components and fetal sex. Hispanics in the highest DBP PRS tertile, compared to those in the lowest, had 8.1 g (95% CI: -15.1, -1.1), 32.4 g (-58.4, -6.4) and 119.4 g (-218.1, -20.7) lower EFW at 20, 27 and 40 weeks, respectively. Similarly, Asians in the highest DBP PRS tertile had 137.2 g (-263.5, -10.8) lower EFW at week 40, and those in the highest tertile of SBP PRS had 3.2 g (-5.8, -0.7), 12.9 g (-23.5, -2.4), and 39.8 g (-76.9, -2.7) lower EFWs at 13, 20, and 27 weeks. The findings showed that pregnant women's genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.
Objective
Associations between maternal genetic risk for obesity and fetal weight were examined at the end of the first (13 weeks 6 days), second (27 weeks 6 days), and third (40 weeks 0 days) ...trimesters of pregnancy among four race/ethnic groups in the US.
Methods
For 603 white, 591 black, 535 Hispanic, and 216 Asian women, maternal genetic risk score (GRS) was calculated as the sum of 189 BMI‐increasing alleles and was categorized into high or low GRS. Associations between GRS (continuous and categorical) and estimated fetal weight were tested overall and stratified by prepregnancy BMI, gestational weight gain (GWG), and fetal sex.
Results
High GRS compared with low GRS was associated with increased fetal weight at the end of the second (β: 22.7 g; 95% CI: 2.4‐43.1; P = 0.03) and third trimesters (β: 88.3 g; 95% CI: 9.0‐167.6; P = 0.03) among Hispanic women. The effect of GRS was stronger among Hispanic women with normal prepregnancy weight, adequate first trimester GWG, or inadequate second trimester GWG (P < 0.05). Among Asian women, high GRS was associated with increased weight among male fetuses but decreased weight among female fetuses (P < 0.05).
Conclusions
Maternal obesity genetic risk was associated with fetal weight with potential effect modifications by maternal prepregnancy BMI, GWG, and fetal sex.
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