Human Molecular Genetics (HUM MOL GENET )

Publisher: Oxford University Press

Description

Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics neurogenetics chromosome structure and function molecular aspects of cancer genetics gene therapy biochemical genetics major advances in gene mapping understanding of genome organisation In addition the journal also publishes research on other model systems for the analysis of genes especially when there is an obvious relevance to human genetics. Key features of the journal include: Articles - comprehensive reports and definitive research findings of interest to a broad audience of human molecular geneticists. We encourage inclusion of full experimental details with as many display items (figures and tables) as required to tell the complete story. Reports - descriptions of novel results of biological and genetic importance in the field. Commentaries - these discuss recent papers in the journal or review areas of particular interest in the field. Now in its eighth year of publication Human Molecular Genetics has clearly become one of the leading journals in this exciting frontier of scientific research. With the enthusiastic support of the executive editors and editorial board we intend to ensure that the journal's reputation for quality is reinforced in the years to come.

  • Impact factor
    7.69
    Show impact factor history
     
    Impact factor
  • 5-year impact
    7.54
  • Cited half-life
    6.60
  • Immediacy index
    1.55
  • Eigenfactor
    0.11
  • Article influence
    3.08
  • Website
    Human Molecular Genetics website
  • Other titles
    Human molecular genetics
  • ISSN
    0964-6906
  • OCLC
    25594670
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

Oxford University Press

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 month embargo on science, technology, medicine articles
    • 24 month embargo on arts and humanities articles
    • Some titles may have different embargoes
  • Conditions
    • Pre-print can only be posted prior to acceptance
    • Pre-print must be accompanied by set statement (see link)
    • Pre-print must not be replaced with post-print, instead a link to published version with amended set statement should be made
    • Pre-print on personal website, employer website, free public server or pre-prints in subject area
    • Post-print on Institutional or Central repositories
    • Publisher version cannot be used except for Nucleic Acids Research articles
    • Published source must be acknowledged
    • Must link to publisher version
    • Set phrase to accompany archived copy (see policy)
    • Articles in some journals can be made Open Access on payment of additional charge
    • Eligible UK authors may deposit in OpenDepot
    • Publisher will deposit on behalf of NIH funded authors to PubMed Central, Nucleic Acids Research authors must pay their fee first
    • Some titles may use different policies
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia, the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of Friedreich's ataxia. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15 -HETE and 11-HETE in cerebellar samples of KIKO mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased cyclooxygenase activity. While constitutive cyclooxygenase 1 was unchanged, inducible cyclooxygenase 2 (COX2) expression was elevated over 1.35 fold (p<0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 (AP1) and cAMP response element-binding protein (CREB), both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in Friedreich's ataxia, which has both pathomechanistic and therapeutic implications.
    Human Molecular Genetics 08/2014;
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    ABSTRACT: Pathological modifications in the microtubule-associated protein Tau is a common characteristic observed in different neurological diseases, suggesting that analogous metabolic pathways might be similarly affected during neurodegeneration. To identify these molecules and mechanisms, we utilized Drosophila models of human Tau-mediated neurodegeneration to perform a RNA interference functional screening against genes considered to be implicated in the pathogenesis of different neurodegenerative disorders. We found that the down regulation of the Drosophila REEP1 homolog protein enhanced Tau toxicity with increased formation of insoluble aggregates. On the contrary the overexpression of either the Drosophila or the human REEP1 protein was able to revert these phenotypes and promote neuronal resistance to ER stress. These studies identify a new function for the REEP1 protein in vivo and a novel cellular mechanism to prevent Tau toxicity.
    Human Molecular Genetics 08/2014;
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    ABSTRACT: The Protein Kinase C Alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P=0.033), and a risk haplotype in intron 3 (P=7.7*10(-4); meta-analysis with previously-published data: P=4.01*10(-8)). Expression experiments demonstrated that the protective signal is associated with alleles conferring higher PRKCA expression levels, well fitting our observation that MS patients have significantly lower PRKCA mRNA levels in blood. The risk haplotype was shown to be driven by a GGTG ins/del polymorphism influencing the hnRNP-H-dependent inclusion/skipping of a PRKCA alternative exon (3*). Indeed, exon 3* can be present in two different versions in PRKCA mRNAs (out-of-frame 61-bp or in-frame 66-bp long), and is preferentially included in transcripts generated through a premature polyadenylation event. The GGTG insertion downregulates 3* inclusion and shifts splicing towards the 66-bp isoform. Both events reduce the nonsense-mediated mRNA-decay-induced degradation of exon 3*-containing mRNAs. Since we demonstrated that the protein isoform produced through premature polyadenylation aberrantly localizes to the plasma membrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility.
    Human Molecular Genetics 07/2014;
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    ABSTRACT: Hearing function is known to be heritable but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in 8 population samples of Northern and Southern European ancestry (n=4591) and the Silk Road (n=348) was measured using pure-tone audiometry, and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (p=3.7x10(-8)) and further supported by whole genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for maintenance of adult auditory function.
    Human Molecular Genetics 07/2014;
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    ABSTRACT: Lethal Congenital Contracture Syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenital (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci, and combined autozygome analysis and whole exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.
    Human Molecular Genetics 07/2014;
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    ABSTRACT: During postnatal development neuronal activity controls the remodeling of initially imprecise neuronal connections through the regulation of gene expression. MeCP2 binds to methylated DNA and modulates gene expression during neuronal development and MECP2 mutation causes the autistic disorder Rett syndrome. To investigate a role for MeCP2 in neuronal circuit refinement and to identify activity-dependent MeCP2 transcription regulations, we leveraged the precise organization and accessibility of olfactory sensory axons to manipulation of neuronal activity through odorant exposure in vivo. We demonstrate that olfactory sensory axons failed to develop complete convergence when Mecp2 is deficient in olfactory sensory neurons in an otherwise wild-type animal. Furthermore, we demonstrate that expression of selected adhesion genes were elevated in Mecp2-deficient glomeruli, while acute odor stimulation in control mice resulted in significantly reduced MeCP2 binding to these gene loci, correlating with increased expression. Thus, MeCP2 is required for both circuitry refinement and activity-dependent transcriptional responses in olfactory sensory neurons.
    Human Molecular Genetics 07/2014;
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    ABSTRACT: Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood. To understand the genetic-epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co-segregating with cerebellar ataxia in a five generation family. We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island. This induced hypermethylation is maintained in somatic cells of carriers across several generations in a t(8;20) dependent-manner however, is erased in the germ cells of the translocation carriers. Subsequently, chromatin remodelling of the locus perturbed monoallelic expression of DLGAP4 mRNAs and non-coding RNAs in haploid cells having the translocation. Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus.
    Human Molecular Genetics 07/2014;
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    ABSTRACT: Dopamine beta-hydroxylase (DBH) is the biosynthetic enzyme catalyzing formation of norepinephrine. Changes in DBH expression or activity have been implicated in the pathogenesis of cardiovascular and neuropsychiatric disorders. Genetic determination of DBH enzymatic activity and its secretion are only incompletely understood. We began with a genome-wide association search for loci contributing to DBH activity in human plasma. Initially, in a population sample of European ancestry, we identified the proximal DBH promoter as a region harboring 3 common trait-determining variants (top hit rs1611115, p=7.2 x 10(-51)). We confirmed their effects on transcription and showed that the 3 variants each acted additively on gene expression. Results were replicated in a population sample of Native American descent (top hit rs1611115, p=4.1 x 10(-15)). Jointly, DBH variants accounted for 57% of DBH trait variation. We further identified a genome-wide significant SNP at the LOC338797 locus on chromosome 12 as trans-quantitative trait locus (QTL) (rs4255618, p=4.62 x 10(-8)). Conditional analyses on DBH identified a third genomic region contributing to DBH variation: a likely cis-QTL adjacent to DBH in SARDH (rs7040170, p=1.31x10(-14)) on chromosome 9q. We conclude that 3 common SNPs in the DBH promoter act additively to control phenotypic variation in DBH levels, and that two additional novel loci (SARDH and LOC338797) may also contribute to the expression of this catecholamine biosynthetic trait. Identification of DBH variants with strong effects makes it possible to take advantage of Mendelian randomization (MR) approaches to test causal effects of this intermediate trait on disease.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53Mb on chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single nucleotide polymorphism or exome sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephaly.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Golgi fragmentation is an early hallmark of many neurodegenerative diseases but its pathophysiological relevance and molecular mechanisms are unclear. We here demonstrate severe and progressive Golgi fragmentation in motor neurons of progressive motor neuronopathy (pmn) mice due to loss of the Golgi-localized tubulin-binding cofactor E (TBCE). Loss of TBCE in mutant pmn and TBCE-depleted motor neuron cultures causes defects in Golgi-derived microtubules, as expected, but surprisingly also reduced levels of COPI subunits, decreased recruitment of tethering factors p115/GM130 and impaired Golgi SNARE-mediated vesicle fusion. Conversely, ARF1, which stimulates COPI vesicle formation, enhances the recruitment of TBCE to the Golgi, increases polymerization of Golgi-derived microtubules and rescues TBCE-linked Golgi fragmentation. These data indicate an ARF1/TBCE-mediated cross talk that coordinates COPI formation and tubulin polymerization at the Golgi. We conclude that interruption of this cross talk causes Golgi fragmentation in pmn mice and hypothesize that similar mechanisms operate in human amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Common cancers have been demarcated into 'hereditary' or 'sporadic' ('non-hereditary') types historically. Such distinctions initially arose from work identifying rare, highly penetrant germline mutations causing 'hereditary' cancer. While rare mutations are important in particular families, most cases in the general population are 'sporadic'. Twin studies have suggested that many 'sporadic' cancers show little or no heritability. To quantify the role of germline mutations in cancer susceptibility, we applied a method for estimating the importance of common genetic variants (array heritability, h(2) g) to twelve cancer types. The following cancers showed a significant (P<0.05) array heritability: melanoma USA set h(2) g =0.19 (95% CI=0.01-0.37) and Australian set h(2) g =0.30 (0.10-0.50); pancreatic h(2) g =0.18 (0.06-0.30); prostate h(2) g =0.81 (0.32-1); kidney h(2) g =0.18 (0.04-0.32); ovarian h(2) g=0.30 (0.18-0.42); esophageal adenocarcinoma h(2) g=0.24 (0.14-0.34); esophageal squamous cell carcinoma h(2) g=0.19 (0.07-0.31); endometrial UK set h(2) g =0.23 (0.01-0.45) and Australian set h(2) g =0.39 (0.02-0.76). Three cancers showed a positive but non-significant effect: breast h(2) g=0.13 (0-0.56); gastric h(2) g =0.11 (0-0.27); lung h(2) g=0.10 (0-0.24). One cancer showed a small effect: bladder h(2) g=0.01 (0-0.11). Amongst these cancers, previous twin studies were only able to show heritability for prostate and breast cancer but we can now make much stronger statements for several common cancers which emphasize the important role of genetic variants in cancer susceptibility. We have demonstrated that several 'sporadic' cancers have a significant inherited component. Larger genome-wide association studies in these cancers will continue to find more loci which explain part of the remaining polygenic component.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Proper localization and anchorage of nuclei within skeletal muscle is critical for cellular function. Alterations in nuclear anchoring proteins modify a number of cellular functions including mechanotransduction, nuclear localization, chromatin positioning/compaction and overall organ function. In skeletal muscle, nesprin 1 and desmin are thought to link the nucleus to the cytoskeletal network. Thus, we hypothesize that both of these factors play a key role in skeletal muscle function. To examine this question we utilized global ablation murine models of nesprin 1, desmin or both nesprin 1 and desmin. Herein, we have created the nesprin-desmin double knockout (DKO) mouse, eliminating a major fraction of nuclear-cytoskeletal connections and enabling understanding of the importance of nuclear anchorage in skeletal muscle. Globally, DKO mice are marked by decreased lifespan, body weight, and muscle strength. With regard to skeletal muscle, DKO myonuclear anchorage was dramatically decreased compared to wild type, nesprin 1(-/-) and desmin(-/-) mice. Additionally, nuclear-cytoskeletal strain transmission was decreased in DKO skeletal muscle. Finally, loss of nuclear anchorage in DKO mice coincided with a fibrotic response as indicated by increased collagen and extracellular matrix deposition, and increased passive mechanical properties of muscle bundles. Overall, our data demonstrate that nesprin 1 and desmin serve redundant roles in nuclear anchorage, and that the loss of nuclear anchorage in skeletal muscle results in a pathological response characterized by increased tissue fibrosis and mechanical stiffness.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Inter-individual variation in cytosine modifications could contribute to heterogeneity in disease risks and other complex traits. We assessed the genetic architecture of cytosine modifications at 283540 CpG sites in lymphoblastoid cell lines (LCLs) derived from independent samples of European and African descent. Our study suggests that cytosine modification variation was primarily controlled in local by single major modification quantitative trait locus (mQTL) and additional minor loci. Local genetic epistasis was detectable for a small proportion of CpG sites, which were enriched by more than nine-fold for CpG sites mapped to population-specific mQTL. Genetically dependent CpG sites whose modification levels negatively (repressive sites) or positively (facilitative sites) correlated with gene expression levels significantly co-localized with transcription factor binding, with the repressive sites predominantly associated with active promoters whereas the facilitative sites rarely at active promoters. Genetically independent repressive or facilitative sites preferentially modulated gene expression variation by influencing local chromatin accessibility, with the facilitative sites primarily antagonizing H3K27me3 and H3K9me3 deposition. In comparison with expression quantitative trait loci (eQTL), mQTL detected from LCLs were enriched in associations for a broader range of disease categories including chronic inflammatory, autoimmune and psychiatric disorders, suggesting that cytosine modification variation, while possesses a degree of cell linage specificity, is more stably inherited over development than gene expression variation. About 11% of unique SNPs reported in the Genome-Wide Association Study Catalog were annotated, 78% as mQTL and 31% as eQTL in LCLs, which covered 37% of the investigated diseases/traits and provided insights to the biological mechanisms.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Bardet Biedl syndrome (BBS) and autosomal dominant polycystic kidney disease (ADPKD) are two genetically distinct ciliopathies but share common phenotypes such as renal cysts. Seven BBS proteins form a complex called the BBSome which is localized at the basal body or ciliary axoneme and regulates the ciliary entry or flagellar exit of several signaling molecules. Here we demonstrate that, unlike the seven-span somatostatin receptor 3 (SSTR3) or the leptin receptor that interacts with all subunits of the BBSome, the ADPKD protein polycystin-1 (PC1) interacts with BBS1, BBS4, BBS5, and BBS8, four out of the seven components of the BBSome. Only depletion or mutation of BBS1, but not depletion of BBS5 and BBS8, or knockout of BBS4, impairs ciliary trafficking of PC1 in kidney epithelial cells. Depletion of these BBS proteins affects neither the ciliary length nor the plasma membrane targeting of PC1. Expression of a pathogenic BBS3/Arl6 mutant (T31R) that locks Arl6 in the GDP form leads to stunted cilia and inhibition of PC1 on primary cilia. We propose that the eleven-span membrane protein PC1 is a BBSome cargo and that the components of the BBSome may possess subunit-specific functions. Moreover, physical interactions between the BBS and ADPKD proteins may underline the overlapping renal phenotypes in these two diseases.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Cervical cancer is caused by infection with human papillomavirus (HPV). A genome-wide association study (GWAS) has identified several susceptibility loci for cervical cancer, but they explain only a small fraction of cervical cancer heritability. Other variants with weaker effect may be missed due to the stringent significance threshold. To identify important pathways in cervical carcinogenesis, we performed a two-stage pathway analysis in two independent GWASs in the Swedish population, using the single-nucleotide polymorphism (SNP) ratio test. The 565 predefined pathways from KEGG and BioCarta databases were systematically evaluated in the discovery stage (1034 cases and 3948 controls with 632 668 SNPs) and the suggestive pathways were further validated in the replication stage (616 cases and 506 controls with 341 358 SNPs). We found 12 pathways that were significant in both stages, and these were further validated using set-based analysis. For 10 of these pathways the effect was mainly due to genetic variation within the major histocompatibility complex (MHC) region. In addition, we identified a set of novel candidate genes outside the MHC region in the pathways denoted 'Staphylococcus aureus infection' and 'Herpes simplex infection' that influenced susceptibility to cervical cancer (empirical P=4.99×10(-5) and 4.99×10(-5) in the discovery study; empirical P=8.98×10(-5) and 0.009 in the replication study, respectively). Staphylococcus aureus infection may evoke an inflammatory response that inadvertently enhances malignant progression caused by HPV infection, and Herpes simplex virus-2 (HSV-2) infection may act in conjunction with HPV infection to increase the risk of cervical carcinoma development. These findings provide new insights into the etiology of cervical cancer.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Positive predictions were made in the aftermath of the development of induced pluripotent stem cell technology for the use of patient-specific iPSCs to model neurological diseases, including dementia. Here we review the current state of the field, and explore how close we are to the goal of in vitro models that capture all aspects of the cell and molecular biology of dementia.
    Human Molecular Genetics 06/2014;
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    ABSTRACT: Platform technologies for measurement of CpG methylation at multiple loci across the genome have made ambitious epigenome-wide association studies affordable and practicable. In contrast to genetic studies which estimate the effects of structural changes in DNA, and transcriptomic studies which measure genomic outputs, epigenetic studies can access states of regulation of genome function in particular cells and in response to specific stimuli. Although many factors complicate the interpretation of epigenetic variation in human disease, cell-specific methylation patterns and the cellular heterogeneity present in peripheral blood and tissue biopsies are anticipated to cause the most problems. In this review we suggest that the difficulties may be exaggerated, and we explore how cellular heterogeneity may be embraced with appropriate study designs and analytical tools. We further suggest that systematic mapping of the loci influenced by age, sex, and genetic polymorphisms will bring important biological insights as well as improved control of epigenome-wide association studies.
    Human Molecular Genetics 06/2014;

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