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To examine the effects of genetic variation, parental age and BMI on parental allele-specific methylation of imprinted genes in fetal cord blood samples. We have developed SNP genotyping and deep bisulphite sequencing assays for six imprinted genes to determine parental allele-specific methylation patterns in diploid somatic tissues. Multivariate linear regression analyses revealed a negative correlation of paternal age with paternal allele methylation in fetal cord blood. Methylation of the maternal allele showed a positive correlation with maternal age. Paternal BMI was positively correlated with paternal allele methylation. In addition to parental origin, allele-specific methylation of most imprinted genes was largely dependent on the underlying SNP haplotype. Our study supports the idea that parental factors can have an impact, although of small effect size, on the epigenome of the next generation, providing an additional layer of complexity to phenotypic diversity.

Two common polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARG) gene, rs1801282 and rs3856806, may be important candidate gene loci affecting the susceptibility to ischemic stroke. This case-control study sought to identify the relationship between these two single-nucleotide polymorphisms and ischemic stroke risk in a northern Chinese Han population. A total of 910 ischemic stroke participants were recruited from the First Hospital of China Medical University, Shenyang, China as a case group, of whom 895 completed the study. The 883 healthy controls were recruited from the Health Check Center of the First Hospital of China Medical University, Shenyang, China. All participants or family members provided informed consent. The study protocol was approved by the Ethics Committee of the First Hospital of China Medical University, China on February 20, 2012 (approval No. 2012-38-1). The protocol was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559). Plasma genomic DNA was extracted from all participants and analyzed for rs1801282 and rs3856806 single nucleotide polymorphisms using a SNaPshot Multiplex sequencing assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression to estimate the association between ischemic stroke and a particular genotype. Results demonstrated that the G allele frequency of the PPARG gene rs1801282 locus was significantly higher in the case group than in the control group (P < 0.001). Individuals carrying the G allele had a 1.844 fold increased risk of ischemic stroke (OR = 1.844, 95% CI: 1.286-2.645, P < 0.001). Individuals carrying the rs3856806 T allele had a 1.366 fold increased risk of ischemic stroke (OR = 1.366, 95% CI: 1.077-1.733, P = 0.010). The distribution frequencies of the PPARG gene haplotypes rs1801282-rs3856806 in the control and case groups were determined. The frequency of distribution in the G-T haplotype case group was significantly higher than that in the control group. The risk of ischemic stroke increased to 2.953 times in individuals carrying the G-T haplotype (OR = 2.953, 95% CI: 2.082-4.190, P < 0.001). The rs1801282 G allele and rs3856806 T allele had a multiplicative interaction (OR = 3.404, 95% CI: 1.631-7.102, P < 0.001) and additive interaction (RERI = 41.705, 95% CI: 14.586-68.824, AP = 0.860; 95% CI: 0.779-0.940; S = 8.170, 95% CI: 3.772-17.697) on ischemic stroke risk, showing a synergistic effect. Of all ischemic stroke cases, 86% were attributed to the interaction of the G allele of rs1801282 and the T allele of rs3856806. The effect of the PPARG rs1801282 G allele on ischemic stroke risk was enhanced in the presence of the rs3856806 T allele (OR = 8.001 vs. 1.844). The effect of the rs3856806 T allele on ischemic stroke risk was also enhanced in the presence of the rs1801282 G allele (OR = 2.546 vs. 1.366). Our results confirmed that the G allele of the PPARG gene rs1801282 locus and the T allele of the rs3856806 locus may be independent risk factors for ischemic stroke in the Han population of northern China, with a synergistic effect between the two alleles.

Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case–control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least ∼56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson’s disease and other tauopathies, including Alzheimer’s disease.

A meta-analysis of previous genome-wide association studies of Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease, with a combined total of more than 75,000 cases and controls, finds that most loci contribute to both phenotypes and other immune-mediated disorders. Pathogenesis of inflammatory bowel disease Genetic studies have implicated unsuspected mechanisms in the pathogenesis of Crohn's disease and ulcerative colitis, two of the most common forms of inflammatory bowel disease. This paper presents a meta-analysis of published genome-wide association studies, together with validation in more than 75,000 cases and controls. In addition to several new associations, the authors find that most loci contribute to both phenotypes, but also to other immune-mediated disorders. The data reveal an overlap between susceptibility loci for inflammatory bowel disease and mycobacterial infection, and between the pathways that govern host responses to mycobacteria and those predisposing to inflammatory bowel disease. Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations 1 . Genome-wide association studies and subsequent meta-analyses of these two diseases 2 , 3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy 4 , in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Infertility being a multifactorial disorder, both genetic and environmental factors contribute to the etiology of infertile phenotype. Chromosomal anomalies and Y-microdeletion are the established genetic risk factors of male infertility. Y-haplotypes has been found as risk factor for male infertility in certain populations, though in certain others no association has been reported, suggesting a population-specific association of these variations with male infertility. In a case-control study, 165 azoo-/oligospermic patients and 200 controls were haplotyped for certain Y-haplogroups for a possible association with idiopathic male infertility in an Indian population. Analysed Y-haplogroups showed no association with infertile phenotype. Thus this genetic factor is not a risk for infertility in the studied Indian population but that does not rule out the possibility of any of them, to be a risk in other populations.

The G-protein-coupled purinergic receptor P2Y2 (P2RY2) plays an important role in the mechanism of atherosclerosis, which is relevant to ischemic stroke. This retrospective case-control study aimed to assess the relationship between P2RY2 gene polymorphisms and ischemic stroke risk in the northern Han Chinese population. In this study, clinical data and peripheral blood specimens were collected from 378 ischemic stroke patients and 344 controls. The ischemic stroke participants were recruited from the First Affiliated Hospital of China Medical University and the First Affiliated Hospital of Liaoning Medical University. The controls were recruited from the Health Check Center at the First Affiliated Hospital of China Medical University. Ischemic stroke patients were divided into two subgroups according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification: large-artery atherosclerosis (n = 178) and small-artery occlusion (n = 200) strokes. All subjects were genotyped for three single nucleotide polymorphisms (rs4944831, rs1783596, and rs4944832) in the P2RY2 gene using peripheral venous blood samples. The distribution of the dominant rs4944832 phenotype (GG vs. GA+AA) differed significantly between small-artery occlusion patients and control subjects (odds ratio (OR) = 1.720, 95% confidence interval (CI): 1.203-2.458, P < 0.01). Multivariable logistic regression analysis revealed that the GG genotype of rs4944832 was significantly more prevalent in small-artery occlusion patients than in control subjects (OR = 1.807, 95% CI: 1.215-2.687, P < 0.01). The overall distribution of the haplotype established by rs4944831-rs1783596-rs4944832 was significantly different between ischemic stroke patients and controls (P < 0.01). In ischemic stroke patients, the frequency of the G-C-G haplotype was significantly higher than in control subjects (P = 0.028), whereas the frequency of the T-C-A haplotype was lower than in control subjects (P = 0.047). These results indicate that the G-C-G haplotype of P2RY2 is a susceptibility haplotype for ischemic stroke. In addition, the GG genotype of rs4944832 may be associated with the development of small-artery occlusion in the northern Han Chinese population. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of China Medical University on February 20, 2012 (No. 2012-38-1) and the First Affiliated Hospital of Liaoning Medical University, China, on March 1, 2013 (No. 2013-03-1). All participants gave their informed consent. This trial was registered with the ISRCTN Registry (ISRCTN11439124) on October 24, 2018. Protocol version (1.0).

Variants at the GTF2I repeat domain containing 1 (GTF2IRD1)-GTF2I locus are associated with primary Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Numerous studies have indicated that this susceptibility locus is shared by multiple autoimmune diseases. However, until now there were no studies of the correlation between GTF2IRD1-GTF2I polymorphisms and neuromyelitis optica spectrum disorders (NMOSD). This case control study assessed this association by recruiting 305 participants with neuromyelitis optica spectrum disorders and 487 healthy controls at the Department of Neurology, from September 2014 to April 2017. Peripheral blood was collected, DNA extracteds and the genetic association between GTF2IRD1-GTF2I polymorphisms and neuromyelitis optica spectrum disorders in the Chinese Han population was analyzed by genotyping. We found that the T allele of rs117026326 was associated with an increased risk of neuromyelitis optica spectrum disorders (odds ratio (OR) = 1.364, 95% confidence interval (CI) 1.019-1.828; P = 0.037). This association persisted after stratification analysis for aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) positivity (OR = 1.397, 95% CI 1.021-1.912; P = 0.036) and stratification according to coexisting autoimmune diseases (OR = 1.446, 95% CI 1.072-1.952; P = 0.015). Furthermore, the CC genotype of rs73366469 was frequent in AQP4-IgG-seropositive patients (OR = 3.15, 95% CI 1.183-8.393, P = 0.022). In conclusion, the T allele of rs117026326 was associated with susceptibility to neuromyelitis optica spectrum disorders, and the CC genotype of rs73366469 conferred susceptibility to AQP4-IgG-seropositivity in Han Chinese patients. The protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China (approval number: 2016-31) on March 2, 2016.

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. The Structural Variation Analysis Group of The 1000 Genomes Project reports an integrated structural variation map based on discovery and genotyping of eight major structural variation classes in 2,504 unrelated individuals from across 26 populations; structural variation is compared within and between populations and its functional impact is quantified. Structural variation mapped in over 2,500 human genomes The Structural Variation Analysis Group of The 1000 Genomes Project reports an integrated structural variation map based on discovery and genotyping of eight major structural variation classes in genomes for 2,504 unrelated individuals from across 26 populations. They characterize structural variation within and between populations and quantify its functional effect. The authors further create a phased reference panel that will be valuable for population genetic and disease association studies.

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data 1 , 2 . Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank 3 . This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation. To measure selection on variants, whole-genome sequencing of approximately 150,000 individuals from the UK Biobank is used to rank sequence variants by their level of depletion.

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data 1 , 2 . Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions 3 , 4 . We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have ‘relocated’ on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences 5 , 6 . A study comparing the pattern of single-nucleotide variation between unique and duplicated regions of the human genome shows that mutation rate and interlocus gene conversion are elevated in duplicated regions.