117 research outputs found
Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP
A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 x 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 x 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic
variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary
arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial
hypertension. These GWAS used data from four international case-control studies across 11744 individuals with
European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and
the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching
genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants
at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and
tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.
Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10–
¹⁵) and a second locus in
HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71],
p=7·65×10–
²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus
had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48],
p=1·69×10–
¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene
regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined
haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The
HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in
patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI
12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity.
Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in
HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more
common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed
to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA
typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA,
ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and
RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR
Germline selection shapes human mitochondrial DNA diversity.
Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan
GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility
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