Objective White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample). Interpretation This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
The importance of real-time polymerase chain reaction (PCR) has increased steadily in clinical applications over the last decade. Many applications utilize SYBR Green I dye to follow the accumulation of amplicons in real time. SYBR Green I has, however, a number of limitations that include the inhibition of PCR, preferential binding to GC-rich sequences and effects on melting curve analysis. Although a few alternative dyes without some of these limitations have been recently proposed, no large-scale investigation into the properties of intercalating dyes has been performed. In this study, we investigate 15 different intercalating DNA dyes for their inhibitory effects on PCR, effects on DNA melting temperature and possible preferential binding to GC-rich sequences. Our results demonstrated that in contrast to the results of SYBR Green I, two intercalating dyes SYTO-13 and SYTO-82 do not inhibit PCR, show no preferential binding to GC rich sequences and do not influence melting temperature, Tm, even at high concentrations. In addition, SYTO-82 demonstrated a 50-fold lower detection limit in a dilution series assay. In conclusion, the properties of SYTO-82 and SYTO-13 will simplify the development of multiplex assays and increase the sensitivity of real-time PCR.
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50–179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4–15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
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