Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.(Extended Data Fig. 5). These results show the value of large sample sizes in blood to detect trans-mQTLs regardless of the tissue. Trans-mQTL SNPs and DNAm exhibit patterned TF binding.Recent studies have uncovered multiple types of transcription factor (TF)-DNA interactions influenced by DNAm, including the binding of DNAm-sensitive TFs [26][27][28] and cooperativity between TFs 27,29 . To gain insights into how SNPs induce long-range DNAm changes, we mapped enrichments for DNAm sites and SNPs across binding sites for 171 TFs in 27 cell types 30,31 . We found strong enrichments for most TFs and cell types among DNAm sites with a trans association (cis + trans: 55%; trans only: 80%; cis only: 18%) and among cis-acting SNPs (cis only: 96%, cis + trans: 91%, trans only: 1%; Fig. 2b, Supplementary Tables 7 and 8, and Supplementary Figs. 22 and 23). Consistent with the observation that trans-only DNAm sites are enriched for CpG islands (Supplementary Fig. 13), DNAm sites that overlap TF-binding sites (TFBSs) were relatively hypomethylated (weighted mean DNAm levels = 21% versus 52%, P < 2.2 × 10 −16 ; Supplementary Fig. 24).Next, we hypothesized that, if a trans-mQTL is driven by TF activity 8,10 , then particular TF-TF pairs may exhibit preferential enrichment 32 . An mQTL has a pair of TFBS annotations 31 , one for the SNP and one for the DNAm site. We evaluated whether the annotation pairs among 18,584 interchromosomal trans-mQTLs were associated with TF binding in a nonrandom pattern (Supplementary Note and Extended Data Fig. 6a,b). We found that 6.1% (22,962 of 378,225) of possible pairwise combinations of SNP-DNAm site annotations were more over-or underrepresented than expected by chance after strict multiple testing correction (Supplementary Note, Supplementary Table 9 and Extended Data Fig. 6c).After accounting for abundance and other characteristics, the strongest pairwise enrichments involved sites close to TFBSs for proteins in the cohesin complex, ...
Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium. (J Allergy Clin Immunol 2019;143:2062-74.)
Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (P Bonferroni < 1.06 x 10 −7 ). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10 −74 ) and BMI in pregnancy (3/914, p = 1.13x10 −3 ), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10−7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a6causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.
Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10−15 for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.
BackgroundThe Asian origin of Native Americans is largely accepted. However uncertainties persist regarding the source population(s) within Asia, the divergence and arrival time(s) of the founder groups, the number of expansion events, and migration routes into the New World. mtDNA data, presented over the past two decades, have been used to suggest a single-migration model for which the Beringian land mass plays an important role.ResultsIn our analysis of 568 mitochondrial genomes, the coalescent age estimates of shared roots between Native American and Siberian-Asian lineages, calculated using two different mutation rates, are A4 (27.5 ± 6.8 kya/22.7 ± 7.4 kya), C1 (21.4 ± 2.7 kya/16.4 ± 1.5 kya), C4 (21.0 ± 4.6 kya/20.0 ± 6.4 kya), and D4e1 (24.1 ± 9.0 kya/17.9 ± 10.0 kya). The coalescent age estimates of pan-American haplogroups calculated using the same two mutation rates (A2:19.5 ± 1.3 kya/16.1 ± 1.5 kya, B2:20.8 ± 2.0 kya/18.1 ± 2.4 kya, C1:21.4 ± 2.7 kya/16.4 ± 1.5 kya and D1:17.2 ± 2.0 kya/14.9 ± 2.2 kya) and estimates of population expansions within America (~21-16 kya), support the pre-Clovis occupation of the New World. The phylogeography of sublineages within American haplogroups A2, B2, D1 and the C1b, C1c andC1d subhaplogroups of C1 are complex and largely specific to geographical North, Central and South America. However some sub-branches (B2b, C1b, C1c, C1d and D1f) already existed in American founder haplogroups before expansion into the America.ConclusionsOur results suggest that Native American founders diverged from their Siberian-Asian progenitors sometime during the last glacial maximum (LGM) and expanded into America soon after the LGM peak (~20-16 kya). The phylogeography of haplogroup C1 suggest that this American founder haplogroup differentiated in Siberia-Asia. The situation is less clear for haplogroup B2, however haplogroups A2 and D1 may have differentiated soon after the Native American founders divergence. A moderate population bottle neck in American founder populations just before the expansion most plausibly resulted in few founder types in America. The similar estimates of the diversity indices and Bayesian skyline analysis in North America, Central America and South America suggest almost simultaneous (~ 2.0 ky from South to North America) colonization of these geographical regions with rapid population expansion differentiating into more or less regional branches across the pan-American haplogroups.
We examined mitochondrial DNA (mtDNA) haplogroup and haplotype diversity in 188 individuals from three Chibchan (Kogi, Arsario, and Ijka) populations and one Arawak (Wayuú) group from northeast Colombia to determine the biological relationship between lower Central American and northern South American Chibchan speakers. mtDNA haplogroups were obtained for all individuals and mtDNA HVS-I sequence data were obtained for 110 samples. Resulting sequence data were compared to 16 other Caribbean, South, and Central American populations using diversity measures, neutrality test statistics, sudden and spatial mismatch models, intermatch distributions, phylogenetic networks, and a multidimensional scaling plot. Our results demonstrate the existence of a shared maternal genetic structure between Central American Chibchan, Mayan populations and northern South American Chibchan-speakers. Additionally, these results suggest an expansion of Chibchan-speakers into South America associated with a shift in subsistence strategies because of changing ecological conditions that occurred in the region between 10,000-14,000 years before present.
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