ABSTRACT
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
Subject(s)
Epigenomics , Immune System Diseases/genetics , Monocytes/metabolism , Neutrophils/metabolism , T-Lymphocytes/metabolism , Transcription, Genetic , Adult , Aged , Alternative Splicing , Female , Genetic Predisposition to Disease , Hematopoietic Stem Cells/metabolism , Histone Code , Humans , Male , Middle Aged , Quantitative Trait Loci , Young AdultABSTRACT
Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
Subject(s)
Genetic Predisposition to Disease , Hypertension, Pregnancy-Induced/genetics , Multifactorial Inheritance , Pre-Eclampsia/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Asia, Central/epidemiology , Blood Pressure/genetics , Case-Control Studies , Datasets as Topic , Europe/epidemiology , Female , Fibroblast Growth Factor 5/genetics , Genetic Loci/genetics , Genome-Wide Association Study , Humans , Hypertension, Pregnancy-Induced/epidemiology , MDS1 and EVI1 Complex Locus Protein/genetics , Middle Aged , Pre-Eclampsia/epidemiology , Pregnancy , Prospective StudiesABSTRACT
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (â¼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.