Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic ...loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility ...alleles for one disease provide protection for the other.
Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (
IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (
CTLA4, PTPN22, IL2RA).
As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling.
We obtained evidence of association between
IL13 variants and total serum IgE levels (
P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes
CTLA4 and
PTPN22 and the candidate gene
IL2RA with IgE levels.
Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes.
Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.
Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic ...architecture of this phenotype.
We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364).
Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009 <P-replication ≤0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027).
Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
SUMMARY
Haptoglobin binds free haemoglobin that prevents oxidative damage produced by haemolysis. There is a copy number variant (CNV) in the haptoglobin gene (HP) consisting of two alleles, Hp1 (no ...duplication), and Hp2 (1.7kb duplication involving two exons). The spread of the Hp2 allele is believed to have taken place under selective pressures conferred by malaria resistance. However, molecular evidence is lacking and Hp did not emerge in genomewide SNPs surveys for evidence of selection. In Europe, there is geographical constancy of Hp2 frequency, indicative of absence of clinal pressures and that modern day European alleles represent a “snapshot” of their out‐of‐Africa migrations. In this work we test for signatures of natural selection acting on the Hp CNV in a sample from the UK population (Avon Longitudinal Study of Parents and Children, ALSPAC). We present here heterozygosity decay, pairwise FST values observed between ALSPAC and 301 populations from all five populated continents, extended haplotype homozygosity analyses involving the CNV and 80 SNPs surrounding the CNV ∼500kb in each direction, and linkage disequilibrium and pairwise haplotypic analyses involving 160 SNPs on chromosome 16q22.1. Taken together, our results represent the first molecular analysis of natural selection in the Hp CNV genetic region.
We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an ...independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of ...variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study ...(GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
OBJECTIVE--Glycated hemoglobin (HbA.sub.1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and ...abnormal glycation of hemoglobin could also be associated with increased levels of HbA.sub.1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA.sub.1c levels. RESEARCH DESIGN AND METHODS--We studied associations with HbA.sub.1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA.sub.1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS--Ten loci reached genome-wide significant association with HbA.sub.1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10.sup.-26), HFE (rs1800562/P = 2.6 x 10.sup.-20), TMPRSS6 (rs855791/P = 2.7 x 10.sup.-14), ANK1 (rs4737009/ P = 6.1 x 10.sup.-12 ), SPTA1 (rs2779116/P = 2.8 x 10.sup.-9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10.sup.-9), and four known HbA.sub.1c loci: HK1 (rs16926246/P = 3.1 x 10.sup.-54), MTNRIB (rs1387153/P = 4.0 x 10-n), GCK (rs1799884/P = 1.5 x 10.sup.-20) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10.sup.-18). We show that associations with HbA.sub.1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA.sub.1c) difference between the extreme 10% tails of the risk score, and would reclassify ~2% of a general white population screened for diabetes with HbA.sub.1c. CONCLUSIONS--GWAS identified 10 genetic loci reproducibly associated with HbA.sub.1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA.sub.1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA.sub.1c. Diabetes 59: 3229-3239, 2010
Attempts to identify susceptibility loci that, on their own, have marginal main effects by use of gene-gene interaction tests have increased in popularity. The results obtained from analyses of ...epistasis are, however, difficult to interpret. Gene-gene interaction, albeit only marginally significant, has recently been reported for the interleukin-4 and interleukin-13 genes (
IL4 and
IL13) with the interleukin-4 receptor A gene (
IL4RA), contributing to the susceptibility of type 1 diabetes (T1D). We aimed to replicate these findings by genotyping both large family and case-control data sets and by using previously published data. Gene-gene interaction tests were performed using linear regression models in cases only. We did not find any single-locus associations with T1D and did not obtain evidence of gene-gene interaction. Additional support from independent samples will be even more important in the study of gene-gene interactions and other subgroup analyses.
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