Variants Close to NTRK2 Gene Are Associated With Birth Weight in Female Twins

Metrustry, Sarah; Edwards, Mark H.; Medland, Sarah E.; Holloway, John W.; Montgomery, Grant W.; Martin, Nicholas G.; Spector, Tim D.; Cooper, Cyrus; Valdes, Ana M.

doi:10.1017/thg.2014.34

Cited by 17 publications

(15 citation statements)

References 34 publications

(47 reference statements)

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“…Overrepresented gene ontologies (GO) included regulation of protein homooligomerization, actin cytoskeleton reorganization, and GTPase mediated signal transduction ( Table S8 ). We also note that that several of these genes have been associated with weight in human GWAS, including Hmga2, Fto, and Ntrk2 ( Table S6 ) 27–29 .…”

Section: Resultsmentioning

confidence: 83%

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Sandoval-Sierra

Helbing

Williams³

et al. 2019

Preprint

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SummaryDNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and lifespan in 12 inbred mouse strains from the BXD panel that exhibit over two-fold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from mice ranging in age from 6 to 25 months that were maintained on normal chow or high fat diet (HFD). We defined subsets of CpG regions associated with age, BW at young adulthood, and strain-by-diet dependent life expectancy. The age associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites with high CpG density and low average methylation. CpG regions associated with BW were enriched in introns and generally showed lower methylation in mice with higher BW, and inversely correlated with gene expression such that mRNA was higher in mice with higher BW. Lifespan-associated regions featured no distinct genomic characteristics but were linked to genes involved in lifespan regulation, including the telomerase reverse transcriptase gene, Tert, which showed lower methylation and higher gene expression in long-lived strains. An epigenetic clock defined from the age-DMRs conveyed accelerated aging in mice belonging to strains with shorter lifespans. Both higher BW at young adulthood and HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier body weight. Furthermore, the study demonstrates that the measure of epigenetic aging derived from age-DMRs can predict strain and diet-induced differences in lifespan.

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Section: Resultsmentioning

confidence: 83%

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Sandoval-Sierra

Helbing

Williams³

et al. 2019

Preprint

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“…We specifically show that if a standard model, which considers only offspring genotypes, is fit to data generated under an underlying KIR–HLA-C interaction scenario, associations can be missed or identified incorrectly. These simulation results provide an explanation for why neither HLA-C nor KIR loci have been found to be significantly associated with birth weight in standard GWAS [22, 23], which fail to account for the effects of maternal genotypes. Similarly, if a single-locus QMFG test is used when 2 or more polymorphic loci are involved in the MFG interaction, power will likely be reduced.…”

Section: Discussionmentioning

confidence: 90%

“…Human maternal uNK receptors, which are encoded by the killer cell immunoglobulin-like receptor (KIR) gene family, can bind to human leukocyte antigens (HLA) expressed by fetal trophoblast cells thus forming an immune interaction between maternal and fetal cells [21]. Although other genes [22, 23] and environmental factors [24–27] are very likely to influence birth weight, there is evidence that this interaction between uNK KIR and trophoblast HLA influences the balance between restricted and amplified fetal placental cell invasion, transformation of spiral arteries, and, in turn, fetal development.…”

Section: Introductionmentioning

confidence: 99%

Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes

Clark

Chazara²,

Sobel

et al. 2016

Hum Hered

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Background/Aims: Maternal and offspring cell contact at the site of placentation presents a plausible setting for maternal-fetal genotype (MFG) interactions affecting fetal growth. We test hypotheses regarding killer cell immunoglobulin-like receptor (KIR) and HLA-C MFG effects on human birth weight by extending the quantitative MFG (QMFG) test. Methods: Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these interactions, we developed the extended QMFG test, a linear mixed-effect model that can use multi-locus genotype data from families. Results: We demonstrate the extended QMFG test's statistical properties. We also show that if an offspring-only model is fit when MFG effects exist, associations can be missed or misattributed. Furthermore, imprecisely modeling the effects of both KIR and HLA-C could result in a failure to replicate if these loci's allele frequencies differ among populations. To further illustrate the extended QMFG test's advantages, we apply the extended QMFG test to a UK cohort study and the Norwegian Mother and Child Cohort (MoBa) study. Conclusion: We find a significant KIR-HLA-C interaction effect on birth weight. More generally, the QMFG test can detect genetic associations that may be missed by standard genome-wide association studies for quantitative traits.

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“…To explore the genetic variation’s influence on the association between DNA methylation of the target region of FGFR2 and FT-LBW, we identified 156 methylation quantitative trait loci (mQTLs) in relation to CpG 3 (cg22633036) and CpG 7 (cg25052156) through performing a look-up in an online catalog of mQTLs ( http://www.mqtldb.org ) [ 56 ]. None of the 156 identified mQTLs was associated with birth weight according to an online genome-wide association study (GWAS) catalog ( https://www.ebi.ac.uk/gwas ) [ 57 – 60 ], which suggested that the associations of CpG 3 (cg22633036) and CpG 7 (cg25052156) DNA methylation with low birth weight might not be confounded by shared genetic variations. However, it is worth to mention that the mQTLs in the online catalog were identified in cord blood which may not reflect the specific mQTL status in placental tissue; moreover, we cannot identify the mQTLs related to the other CpG sites uncovered by the Illumine 450k methylation array.…”

Section: Discussionmentioning

confidence: 99%

Placental surface area mediates the association between FGFR2 methylation in placenta and full-term low birth weight in girls

et al. 2018

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BackgroundFibroblast growth factor receptor 2 (FGFR2) gene encodes a protein of the fibroblast growth factor receptor family. FGFR2 gene expression is associated with the regulation of implantation process of placenta which plays a vital role in fetal growth. DNA methylation is widely known as a mechanism of fetal growth. However, it is unclear whether and how DNA methylation of FGFR2 gene in the placenta is associated with full-term low birth weight. This case-control study aims to explore the links between FGFR2 methylation in placenta and full-term low birth weight and to further examine the mediation effect of placental surface area on this association.ResultsWe conducted analyses for each of the five valid CpG sites at FGFR2 in 165 mother-baby pairs (86 FT-LBW vs. 79 FT-NBW) and found that per one standard deviation increase in the DNA methylation of CpG 11 at FGFR2 was associated with 1.64-fold higher risk of full-term low birth weight (OR = 1.64, 95% CI = [1.07, 2.52]) and 0.18 standard deviation decrease in placental surface area (β = − 0.18; standard error = 0.08, p = 0.02). The mediation effect of placental surface area on the association between DNA methylation and full-term low birth weight was significant in girls (OR = 1.38, 95% CI = [1.05, 1.80]) but not in boys. The estimated mediation proportion was 48.38%.ConclusionOur findings suggested that placental surface area mediated the association between DNA methylation of FGFR2 in placenta and full-term low birth weight in a sex-specific manner. Our study supported the importance of placental epigenetic changes in placental development and fetal growth.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0472-5) contains supplementary material, which is available to authorized users.

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Variants Close to NTRK2 Gene Are Associated With Birth Weight in Female Twins

Cited by 17 publications

References 34 publications

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Body weight at young adulthood and association with epigenetic aging and lifespan in the BXD murine family

Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring <b><i>KIR</i></b> and <b><i>HLA-C</i></b> Genes

Placental surface area mediates the association between FGFR2 methylation in placenta and full-term low birth weight in girls

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