Publications by authors named "Tsegaselassie Workalemahu"

45 Publications

Associations of perinatal exposure to PM with gestational weight gain and offspring birth weight.

Environ Res 2021 Sep 22;204(Pt B):112087. Epub 2021 Sep 22.

Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA.

Background: PM have been associated with weight change in animal models and non-pregnant populations. Evidence of associations between PM and gestational weight gain (GWG), an important determinant of course and outcomes of pregnancy, and subsequent birth outcomes is limited.

Methods: The study was conducted among a subset of participants from the Omega Study, a prospective pregnancy cohort. Exposure to PM (μg/m) was ascertained for participants (N = 855) based on their residential address using a validated national spatiotemporal model. Adjusted multivariable linear regression models were used to estimate associations of trimester-specific and pregnancy-month PM exposures with early (<20 weeks gestation), late (≥20 weeks gestation), and total GWG and infant birth weight. Stratified models and product terms were used to examine whether pre-pregnancy BMI (ppBMI) and infant sex modified the associations.

Results: Average monthly PM exposure during the first, second, and third trimesters were 7.3 μg/m, 7.9 μg/m, and 7.7 μg/m, respectively. Higher third trimester PM exposure was associated with higher late (0.40 kg per 5 μg/m (McDowell et al., 2018); 95%CI: 0.12, 0.67) and total (0.35 kg; 95%CI: 0.01, 0.70) GWG among participants with normal ppBMI. Higher second month PM exposure was associated with lower early (-0.70 kg; 95%CI: 1.22, -0.18), late (-0.84 kg; 95% CI: 1.54, -0.14), and total (-1.70 kg; 95%CI: 2.57, -0.82) GWG among participants with overweight/obese ppBMI. Product terms between PM and ppBMI were significant for second month PM exposure and early (p-value = 0.01) and total GWG (p-value<0.01). Higher third trimester PM exposure was associated with higher birth weight, though higher fourth month PM exposure was associated with lower birth weight, particularly among those with normal ppBMI and male infants.

Conclusions: Associations of PM with GWG vary by exposure window and ppBMI, while associations of PM with birth weight potentially vary by exposure window, ppBMI and infant sex. Further exploration of associations between PM and maternal/child health outcomes are needed.
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http://dx.doi.org/10.1016/j.envres.2021.112087DOI Listing
September 2021

Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth.

Hum Genet 2021 Jul 15;140(7):985-997. Epub 2021 Feb 15.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Dr, 6710B-3204, Bethesda, MD, 20892-7004, USA.

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13-40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10 to 4.8 × 10). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10 to 3.71 × 10). At the chr2q23.3-24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (β = 0.44, P = 6.25 × 10 at week 27; β = 0.39, P = 7.72 × 10 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3-24.2 locus and has substantial allele frequency difference between African and European reference samples (F = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan.Clinical trials registration ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1007/s00439-021-02265-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197736PMC
July 2021

Associations of maternal blood pressure-raising polygenic risk scores with fetal weight.

J Hum Hypertens 2021 Feb 3. Epub 2021 Feb 3.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1038/s41371-021-00483-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329099PMC
February 2021

Maternal-fetal genetic interactions, imprinting, and risk of placental abruption.

J Matern Fetal Neonatal Med 2020 09 24:1-10. Epub 2020 Sep 24.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Maternal genetic variations, including variations in mitochondrial biogenesis (MB) and oxidative phosphorylation (OP), are associated with placental abruption (PA). However, the role of maternal-fetal genetic interactions (MFGI) and parent-of-origin (imprinting) effects in PA remain unknown.

Objective: To investigate MFGI in MB-OP, and imprinting effects in relation to risk of PA.

Methods: Among Peruvian mother-infant pairs (503 PA cases and 1052 controls), independent single nucleotide polymorphisms (SNPs), with linkage-disequilibrium coefficient <0.80, were selected to characterize genetic variations in MB-OP (78 SNPs in 24 genes) and imprinted genes (2713 SNPs in 73 genes). For each MB-OP SNP, four multinomial models corresponding to fetal allele effect, maternal allele effect, maternal and fetal allele additive effect, and maternal-fetal allele interaction effect were fit under Hardy-Weinberg equilibrium, random mating, and rare disease assumptions. The Bayesian information criterion (BIC) was used for model selection. For each SNP in imprinted genes, imprinting effect was tested using a likelihood ratio test. Bonferroni corrections were used to determine statistical significance (p-value < 6.4e-4 for MFGI and p-value < 1.8e-5 for imprinting).

Results: Abruption cases were more likely to experience preeclampsia, have shorter gestational age, and deliver infants with lower birthweight compared with controls. Models with MFGI effects provided improved fit than models with only maternal and fetal genotype main effects for SNP rs12530904 (-value = 1.2e-04) in calcium/calmodulin-dependent protein kinase [CaM kinase] II beta (), and, SNP rs73136795 (-value = 1.9e-04) in peroxisome proliferator-activated receptor-gamma (), both MB genes. We identified 320 SNPs in 45 maternally-imprinted genes (including potassium voltage-gated channel subfamily Q member 1 [], neurotrimin [], and, ATPase phospholipid transporting 10 A []) associated with abruption. Top hits included rs2012323 (-value = 1.6E-16) and rs12221520 (-value1.3e-13) in , rs8036892 (-value = 9.3E-17) and rs188497582 in , rs12589854 (-value = 2.9E-11) and rs80203467 (-value = 4.6e-11) in maternally expressed 8, small nucleolar RNA host (), and rs138281088 in solute carrier family 22 member 2 () (-value = 6.8e-9).

Conclusions: We identified novel PA-related maternal-fetal MB gene interactions and imprinting effects that highlight the role of the fetus in PA risk development. Findings can inform mechanistic investigations to understand the pathogenesis of PA.
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http://dx.doi.org/10.1080/14767058.2020.1822314DOI Listing
September 2020

Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases.

Epigenomics 2020 06 17;12(11):921-934. Epub 2020 Jul 17.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892-7004, USA.

To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 () and decreased expression of in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found -methylation quantitative trait loci for genetic loci in and . Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.2217/epi-2019-0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466909PMC
June 2020

DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.

Clin Epigenetics 2020 06 3;12(1):78. Epub 2020 Jun 3.

Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.

Background: Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life.

Results: We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta.

Conclusion: We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases.

Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1186/s13148-020-00873-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268466PMC
June 2020

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

PLoS Genet 2020 05 14;16(5):e1008747. Epub 2020 May 14.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1371/journal.pgen.1008747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252673PMC
May 2020

Differential DNA Methylation in Placenta Associated With Maternal Blood Pressure During Pregnancy.

Hypertension 2020 04 10;75(4):1117-1124. Epub 2020 Feb 10.

From the Epidemiology Branch (T.W., M.O., D.S., K.L.G., F.T.-A.).

Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate ( values ranging from 6.6×10 to 2.3×10). Several CpGs were enriched in pathways including cardiovascular-metabolic development (=1.0×10). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at , a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912132.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122078PMC
April 2020

Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain.

Int J Obes (Lond) 2020 06 18;44(6):1406-1416. Epub 2020 Feb 18.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: 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).

Method: 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.

Results: Prepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P < 0.05, P ranging from 1.4 × 10 to 1.7 × 10). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (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.

Conclusions: 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.
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http://dx.doi.org/10.1038/s41366-020-0546-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261634PMC
June 2020

Maternal cardiometabolic factors and genetic ancestry influence epigenetic aging of the placenta.

J Dev Orig Health Dis 2021 02 17;12(1):34-41. Epub 2020 Jan 17.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Disruption of physiological aging of the placenta can lead to pregnancy complications and increased risk for cardiometabolic diseases during childhood and adulthood. Maternal metabolic and genetic factors need to operate in concert with placental development for optimal pregnancy outcome. However, it is unknown whether maternal cardiometabolic status and genetic ancestry contribute to differences in placental epigenetic age acceleration (PAA). We investigated whether maternal prepregnancy obesity, gestational weight gain (GWG), blood pressure, and genetic ancestry influence PAA. Among 301 pregnant women from 4 race/ethnic groups who provided placenta samples at delivery as part of the National Institute of Child Health and Human Development Fetal Growth Studies, placental DNA methylation age was estimated using 62 CpGs known to predict placental aging. PAA was defined to be the difference between placental DNA methylation age and gestational age at birth. Percentage of genetic ancestries was estimated using genotype data. We found that a 1 kg/week increase in GWG was associated with up to 1.71 (95% CI: -3.11, -0.32) week lower PAA. Offspring Native American ancestry and African ancestry were associated, respectively, with higher and lower PAA among Hispanics, and maternal East Asian ancestry was associated with lower PAA among Asians (p < 0.05). Among mothers with a male offspring, blood pressure was associated with lower PAA across all three trimesters (p < 0.05), prepregnancy obesity compared to normal weight was associated with 1.24 (95% CI: -2.24, -0.25) week lower PAA. In summary, we observed that maternal cardiometabolic factors and genetic ancestry influence placental epigenetic aging and some of these influences may be male offspring-specific.
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http://dx.doi.org/10.1017/S2040174419000801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365741PMC
February 2021

Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent.

Nat Commun 2019 12 18;10(1):5765. Epub 2019 Dec 18.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.

Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.
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http://dx.doi.org/10.1038/s41467-019-13544-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920448PMC
December 2019

Sex differences in the associations of placental epigenetic aging with fetal growth.

Aging (Albany NY) 2019 08 8;11(15):5412-5432. Epub 2019 Aug 8.

Dean's Office, College of Health and Human Services, George Mason University, Fairfax, VA 22030, USA.

Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.
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http://dx.doi.org/10.18632/aging.102124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710059PMC
August 2019

Race-ethnic differences in the associations of maternal lipid trait genetic risk scores with longitudinal fetal growth.

J Clin Lipidol 2019 Sep - Oct;13(5):821-831. Epub 2019 Jun 29.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors.

Objective: We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial-ethnic populations (Whites, Blacks, Hispanics, and Asians).

Methods: We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRS), low-density lipoprotein cholesterol (GRS), and triglycerides (GRS) and lower high-density lipoprotein cholesterol (GRS).

Results: At 40 weeks' gestation, a unit increase in GRS was associated with 11.4 g higher fetal weight (95% confidence interval [CI] 2.8-20.0 g) among normal-weight Whites, 26.3 g (95% CI 6.0-46.6 g) among obese Blacks, and 30.8 g (95% CI 6.3-55.3 g) among obese Hispanics. Higher GRS was associated with increased fetal weight across 36 to 40 weeks among normal-weight Whites and across 13 to 20 weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40 weeks among normal-weight Hispanics. Higher GRS was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids.

Conclusion: Associations between fetal weight and maternal lipid GRS appear to vary by maternal race-ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth.
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http://dx.doi.org/10.1016/j.jacl.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885118PMC
July 2020

Maternal BMI-Increasing Genetic Risk Score and Fetal Weights among Diverse US Ethnic Groups.

Obesity (Silver Spring) 2019 07;27(7):1150-1160

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

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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http://dx.doi.org/10.1002/oby.22499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592626PMC
July 2019

Maternal dyslipidemia during early pregnancy and epigenetic ageing of the placenta.

Epigenetics 2019 10 14;14(10):1030-1039. Epub 2019 Jun 14.

a Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA.

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.
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http://dx.doi.org/10.1080/15592294.2019.1629234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691987PMC
October 2019

Maternal and Offspring Genetic Risk of Type 2 Diabetes and Offspring Birthweight Among African Ancestry Populations.

J Clin Endocrinol Metab 2019 11;104(11):5032-5042

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Objectives: Maternal genetic risk of type 2 diabetes (T2D) can influence offspring birthweight through shared offspring genetic risk and by altering intrauterine glycemic status. The aim of this study was to estimate the independent effects of maternal and offspring genetic risk scores (GRSs) of T2D on offspring birthweight and the extent to which intrauterine glycemic traits mediate the effect of maternal GRSs on offspring birthweight.

Design: The study involved 949 mother-offspring pairs of African ancestry from the Hyperglycemia Adverse Pregnancy Outcome study. GRSs of T2D were calculated separately for mothers and offspring as the weighted sum of 91 T2D risk alleles identified in a genome-wide association study meta-analysis in African Americans. Linear regression models were fit to estimate changes in birthweight by quartiles of GRSs. Mediation analysis was implemented to estimate the direct and indirect effects of maternal GRS on offspring birthweight through cord blood C-peptide and maternal fasting and postchallenge glucose levels.

Results: Maternal and offspring GRSs were independently and differentially associated with offspring birthweight. Changes (95% CI) in birthweight across increasing quartiles of maternal GRSs were 0 g (reference), 83.1 g (6.5, 159.6), 103.1 g (26.0, 180.2), and 92.7 g (12.6, 172.8) (P trend = 0.041) and those of offspring GRSs were 0 (reference), -92.0 g (-169.2, -14.9), -64.9 g (-142.4, 12.6), and 2.0 g (-77.8, 81.7) (P trend = 0.032). Cord blood C-peptide mediated the effect of maternal GRS on offspring birthweight, whereas maternal postchallenge glucose levels showed additive effects with maternal GRS on birthweight.

Conclusions: Maternal and offspring GRSs of T2D were independently and differentially associated with offspring birthweight.
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http://dx.doi.org/10.1210/jc.2018-02756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753636PMC
November 2019

Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

Hum Genomics 2019 04 4;13(1):17. Epub 2019 Apr 4.

Laboratorio de Endocrinologia Molecular, Hospital Juárez de México, Mexico City, Mexico.

Background: Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data.

Results: Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10). SNPs associated with both childhood BMI and adult traits were more likely to be functionally deleterious than SNPs associated with neither trait. Genetic variants associated with increased childhood obesity tend to increase risk of cardiometabolic diseases in adulthood. We replicated 39 genetic loci that are known to be associated with childhood BMI and adult traits (coronary artery disease, HDL cholesterol, myocardial infarction, triglycerides, total cholesterol, type 2 diabetes, BMI, waist circumference, and waist-to-hip ratio) in previous genome-wide association studies. We also found a novel association of rs12446632 near GPRC5B, which is highly expressed in adipose tissue and the central nervous system, with adult HDL cholesterol.

Conclusions: This study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases.
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http://dx.doi.org/10.1186/s40246-019-0202-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449964PMC
April 2019

Genetic overlap between birthweight and adult cardiometabolic diseases has implications for genomic medicine.

Sci Rep 2019 03 11;9(1):4076. Epub 2019 Mar 11.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Before implementing therapeutic genomic interventions for optimizing health in early life, comprehensive understanding of their effect on several traits across the life course is warranted. Abnorml  birthweight is associated with cardiometabolic disease risk in adulthood; however, the extent of genetic pleiotropy in the association has not been comprehensively investigated. We tested for pleiotropy and enrichment of functional loci between birthweight and 15 cardiometabolic disease traits (CMD). We found significantly abundant genetic pleiotropy (P < 3.3 × 10) and enrichment of functional annotations (P < 3.3 × 10) in loci influencing both birthweight and CMD. We did not observe consistent effect directions of pleiotropic loci on the traits. A total of 67 genetic loci, of which 65 loci have been reported in previous genome-wide association studies, were associated with both birthweight and CMD at a false discovery rate of 5%. Two novel loci were associated with birthweight and adult coronary artery disease (rs2870463 in CTRB1) and with birthweight and adult waist circumference (rs12704673 in CALCR). Both loci are known to have regulatory effects on expression of nearby genes. In all, our findings revealed pervasive genetic pleiotropy in early growth and adulthood cardiometabolic diseases, implying the need for caution when considering genetic loci as therapeutic targets.
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http://dx.doi.org/10.1038/s41598-019-40834-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411883PMC
March 2019

Genomics of body fat percentage may contribute to sex bias in anorexia nervosa.

Am J Med Genet B Neuropsychiatr Genet 2019 09 28;180(6):428-438. Epub 2018 Dec 28.

Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Anorexia nervosa (AN) occurs nine times more often in females than in males. Although environmental factors likely play a role, the reasons for this imbalanced sex ratio remain unresolved. AN displays high genetic correlations with anthropometric and metabolic traits. Given sex differences in body composition, we investigated the possible metabolic underpinnings of female propensity for AN. We conducted sex-specific GWAS in a healthy and medication-free subsample of the UK Biobank (n = 155,961), identifying 77 genome-wide significant loci associated with body fat percentage (BF%) and 174 with fat-free mass (FFM). Partitioned heritability analysis showed an enrichment for central nervous tissue-associated genes for BF%, which was more prominent in females than males. Genetic correlations of BF% and FFM with the largest GWAS of AN by the Psychiatric Genomics Consortium were estimated to explore shared genomics. The genetic correlations of BF% and BF% with AN differed significantly from each other (p < .0001, δ = -0.17), suggesting that the female preponderance in AN may, in part, be explained by sex-specific anthropometric and metabolic genetic factors increasing liability to AN.
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http://dx.doi.org/10.1002/ajmg.b.32709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751355PMC
September 2019

Influence of Fetal and Maternal Genetic Susceptibility to Obesity on Birthweight in African Ancestry Populations.

Front Genet 2018 2;9:511. Epub 2018 Nov 2.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.

Fetal and maternal genetic propensity to obesity can influence birthweight. We investigated the effects of fetal and maternal genetic risk of obesity on birthweight and evaluated whether these genetic influences modify the well-known association between maternal pre-pregnancy body mass index (BMI) and birthweight. In 950 mother-baby pairs of African ancestry, a genetic risk score for adulthood obesity was generated for mothers (mGRS) and their babies (bGRS) as the weighted sum of BMI-increasing alleles of 97 single nucleotide polymorphisms known to be associated with BMI. The median GRS value was used as a cut-off to define high or low bGRS and mGRS. High bGRS was significantly associated with 70 g lower birthweight (95% Confidence Interval [CI] = -127.4 to -12.4) compared to low bGRS. mGRS was positively correlated with birthweight but the association was not significant. mGRS modified the significant birthweight-increasing effect of maternal pre-pregnancy BMI ( = 0.03); among mothers with low mGRS, those who were overweight or obese had 127.7 g heavier babies (95% CI = 27.1 to 228.2) compared to those who had normal weight. In summary, fetal obesity genetic risk loci exert direct influence on birthweight, and maternal loci modify the effect of pre-pregnancy BMI on birthweight.
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http://dx.doi.org/10.3389/fgene.2018.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224338PMC
November 2018

Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.

Am J Obstet Gynecol 2018 12 5;219(6):617.e1-617.e17. Epub 2018 Sep 5.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae.

Objective: The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated.

Study Design: The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex.

Results: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×10) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48-10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11-2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex.

Conclusion: In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.
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http://dx.doi.org/10.1016/j.ajog.2018.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497388PMC
December 2018

Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies.

Placenta 2018 06 16;66:8-16. Epub 2018 Apr 16.

Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA.

Introduction: Accumulating epidemiological evidence points to strong genetic susceptibility to placental abruption (PA). However, characterization of genes associated with PA remains incomplete. We conducted a genome-wide association study (GWAS) of PA and a meta-analysis of GWAS.

Methods: Participants of the Placental Abruption Genetic Epidemiology (PAGE) study, a population based case-control study of PA conducted in Lima, Peru, were genotyped using the Illumina HumanCore-24 BeadChip platform. Genotypes were imputed using the 1000 genomes reference panel, and >4.9 million SNPs that passed quality control were analyzed. We performed a GWAS in PAGE participants (507 PA cases and 1090 controls) and a GWAS meta-analysis in 2512 participants (959 PA cases and 1553 controls) that included PAGE and the previously reported Peruvian Abruptio Placentae Epidemiology (PAPE) study. We fitted population stratification-adjusted logistic regression models and fixed-effects meta-analyses using inverse-variance weighting.

Results: Independent loci (linkage-disequilibrium<0.80) suggestively associated with PA (P-value<5e-5) included rs4148646 and rs2074311 in ABCC8, rs7249210, rs7250184, rs7249100 and rs10401828 in ZNF28, rs11133659 in CTNND2, and rs2074314 and rs35271178 near KCNJ11 in the PAGE GWAS. Similarly, independent loci suggestively associated with PA in the GWAS meta-analysis included rs76258369 near IRX1, and rs7094759 and rs12264492 in ADAM12. Functional analyses of these genes showed trophoblast-like cell interaction, as well as networks involved in endocrine system disorders, cardiovascular diseases, and cellular function.

Conclusions: We identified several genetic loci and related functions that may play a role in PA risk. Understanding genetic factors underlying pathophysiological mechanisms of PA may facilitate prevention and early diagnostic efforts.
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http://dx.doi.org/10.1016/j.placenta.2018.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995331PMC
June 2018

High burden of birthweight-lowering genetic variants in Africans and Asians.

BMC Med 2018 05 24;16(1):70. Epub 2018 May 24.

School of Medicine, University of Adelaide, Adelaide, SA, Australia.

Background: Birthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations.

Methods: Genotype data were extracted from phase 3 of the 1000 Genomes Project for 2504 participants from 26 global populations grouped into five super-populations. GRB was calculated in offspring as the weighted sum of the number of birthweight-lowering genetic variants of 59 autosomal single-nucleotide polymorphisms associated with birthweight, and comparisons were made between Europeans and non-Europeans.

Results: GRB was significantly higher in Africans (mean difference 3.15; 95% confidence interval 2.64, 3.66), admixed Americans (3.02; 2.34, 3.70), East Asians (2.85; 2.29, 3.41), and South Asians (1.07; 0.49, 1.65) compared to Europeans. Birthweight-lowering genetic variants in Africans and East Asians were enriched for rare and frequency-fixed alleles (P < 0.001). African and Asian populations had the greatest deviation from the expectation of the common disease-common variant hyothesis. Compared to Europeans, the GRB of ancestral alleles was significantly higher and that of derived alleles was significantly lower in non-Europeans (P < 0.001).

Conclusions: The burden of birthweight-lowering genetic variants is higher in Africans and East Asians. This finding is consistent with the high incidence of low birthweight in the two populations. The genetic variants we studied may not be causal and the extent to which they tag the causal variants in non-Europeans is unknown; however, our findings highlight that genetic variations contribute to population differences in birthweight.
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http://dx.doi.org/10.1186/s12916-018-1061-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967042PMC
May 2018

Genetic and Environmental Influences on Fetal Growth Vary during Sensitive Periods in Pregnancy.

Sci Rep 2018 05 8;8(1):7274. Epub 2018 May 8.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Aberrant fetal growth is associated with morbidities and mortality during childhood and adult life. Although genetic and environmental factors are known to influence in utero growth, their relative contributions over pregnancy is unknown. We estimated, across gestation, the genetic heritability, contribution of shared environment, and genetic correlations of fetal growth measures (abdominal circumference (AC), humerus length (HL), femur length (FL), and estimated fetal weight (EFW)) in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies. Structural equation models were fit at the end of first trimester, during mid-gestation, late second trimester, and third trimester of pregnancy. The contribution of fetal genetics on fetal size increased with gestational age, peaking in late second trimester (AC = 53%, HL = 57%, FL = 72%, EFW = 71%; p < 0.05). In contrast, shared environment explained most of phenotypic variations in fetal growth in the first trimester (AC = 50%, HL = 54%, FL = 47%, EFW = 54%; p < 0.05), suggesting that the first trimester presents an intervention opportunity for a more optimal early fetal growth. Genetic correlations between growth traits (range 0.34-1.00; p < 0.05) were strongest at the end of first trimester and declined with gestation, suggesting that different fetal growth measures are more likely to be influenced by the same genes in early pregnancy.
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http://dx.doi.org/10.1038/s41598-018-25706-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940684PMC
May 2018

Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

PLoS Genet 2017 Apr 27;13(4):e1006528. Epub 2017 Apr 27.

Estonian Genome Center, University of Tartu, Tartu, Estonia.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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http://dx.doi.org/10.1371/journal.pgen.1006528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407576PMC
April 2017

Placental genetic variations in vitamin D metabolism and birthweight.

Placenta 2017 02 27;50:78-83. Epub 2016 Dec 27.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, United States; Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, United States.

Introduction: Vitamin D has pleiotropic functions that regulate fetal growth and development. We investigated associations of common placental genetic variations in vitamin D metabolism with birthweight.

Methods: The study was conducted among participants (506 maternal-infant pairs) of a pregnancy cohort study. Data were collected using interviewer-administered questionnaires and post-delivery medical record abstraction. DNA, extracted from placental samples collected at delivery, was genotyped for eight single nucleotide polymorphisms (SNPs) in five vitamin D metabolism genes (CUBN, LRP2, VDR, GC, and CYP2R1). Linear and logistic regression models were used to evaluate associations of SNPs with birthweight and risk of low birthweight, respectively. Effect modification of associations by infant sex was examined using stratified analyses and interaction terms in regression models.

Results: Mean (standard-deviation) birthweight among all, male, and female infants was 3482.1 (549.9), 3544.6 (579.0) and 3419.2 (512.5) grams, respectively. Each copy of the minor allele of rs2282679 (GC) was associated with a 68.6 g (95%CI:3.1134.7 g) increase in birthweight overall. Sex-specific associations were observed for SNP rs4667591 (LRP2) (p-value for interaction < 0.001). Each copy of the minor allele of rs4667591 was associated with a 124.7 g (95%CI:20.1229.0 g) increase in birthweight among female infants, and a suggested 81.6 g decrease in birthweight among male infants (95%CI:-183.7,20.5 g).

Discussion: Our study identified overall and sex-specific associations between placental genetic variations in vitamin D metabolism and birthweight. If confirmed by larger replication studies, observed associations may provide insight into mechanistic underpinnings of the relationships between placental vitamin D metabolism and birth size.
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http://dx.doi.org/10.1016/j.placenta.2016.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319727PMC
February 2017

Genetic variations related to maternal whole blood mitochondrial DNA copy number: a genome-wide and candidate gene study.

J Matern Fetal Neonatal Med 2017 Oct 4;30(20):2433-2439. Epub 2017 Apr 4.

d Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA , USA.

We conducted genome-wide (GWAS) and candidate gene association studies of maternal mitochondrial DNA copy number. Maternal peripheral blood was collected during labor and delivery admission from 471 participants of a placental abruption case-control study conducted in Lima, Peru. Single nucleotide polymorphism (SNP) genotyping was performed using the Illumina Cardio-Metabo Chip. Whole blood mitochondrial DNA (mtDNA) copy number was measured using qRT-PCR techniques. We evaluated 119,629 SNPs in the GWAS and 161 SNPs (in 29 mitochondrial biogenesis and oxidative phosphorylation genes) in the candidate association study. Top hits from GWAS and the candidate gene study were selected to compute weighted genetic risk scores (wGRS). Linear regression models were used to calculate effect size estimates and related nominal p values. The top hit in our GWAS was chr19:51063065 in FOXA3 (empirical p values = 2.20e - 6). A total of 134 SNPs had p values < 0.001 including rs17111633 in CNNM1 (p values = 6.32e - 6) and chr19:51083059 in MYPOP (p values = 3.23e - 5). In the candidate association study, several SNPs in PPARG, PRKCA, SP1 and THRB were associated with mtDNA copy number (p values < 0.05). mtDNA copy number was significantly associated with wGRS based on top GWAS hits (β = 0.49, 95% CI:0.38-0.60, p < 0.001). Variations in nuclear DNA are potentially associated with maternal mtDNA copy number.
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http://dx.doi.org/10.1080/14767058.2016.1252747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681349PMC
October 2017

Placental telomere length and risk of placental abruption.

J Matern Fetal Neonatal Med 2016 Sep 26;29(17):2767-72. Epub 2015 Nov 26.

d Department of Epidemiology , Harvard T.H. Chan School of Public Health , Boston , MA , USA.

Objective: To investigate the associations of placental telomere length with placental abruption (PA) risk and interactions between placental telomere length and placental mitochondrial DNA (mtDNA) copy number on PA risk.

Materials And Methods: Relative telomere length and mtDNA copy number in placental samples collected from 105 cases and 73 controls were measured in two batches using qRT-PCR. Mean differences in relative telomere length between PA cases and controls were examined. After creating batch-specific median cutoffs for relative telomere length (84.92 and 102.53) and mtDNA copy number (2.32 and 1.42), interaction between the two variables was examined using stratified logistic regression models.

Results: Adjusted mean difference in relative telomere length between PA cases and controls was -0.07 (p > 0.05). Among participants with low mtDNA copy number, participants with short relative telomere length had a 3.07-fold higher odds (95% CI: 1.13-8.38) of PA as compared with participants with long relative telomere length (the reference group). Among participants with high mtDNA copy number, participants with short relative telomere length had a 0.71-fold lower odds (95% CI: 0.28-1.83) of PA as compared with the reference group (interaction p values = 0.03).

Conclusion: Findings suggest complex relationships between placental telomere length, mtDNA copy number and PA risk which warrant further larger studies.
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http://dx.doi.org/10.3109/14767058.2015.1103224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984533PMC
September 2016

Genetic studies of body mass index yield new insights for obesity biology.

Nature 2015 Feb;518(7538):197-206

Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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http://dx.doi.org/10.1038/nature14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382211PMC
February 2015
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