ZNF365 promotes stalled replication forks recovery to maintain genome stability

Zhang, Yuqing; Park, Eunmi; Kim, Christopher S.; Paik, Jihye

doi:10.4161/cc.25882

Cited by 18 publications

(22 citation statements)

References 47 publications

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“…However, seven SNPs, meeting the threshold for suggestive association (p <5 × 10 -7 ) look promising (Table 3). Among these, 6 SNPs are either located in, or have been shown to affect the expression of four genes involved in DNA integrity maintenance: CTU2 , CUEDC2 , ZNF365 , TOPBP1 (44, 45, 46, 47, 48). Moreover, one of these SNPs (rs1409313) was shown to regulate cerebellum expression of C10orf26 (49), a gene associated with schizophrenia (50).…”

Section: Resultsmentioning

confidence: 99%

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

Chaste

Klei

Sanders

et al. 2015

Biological Psychiatry

136

113

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Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD.

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Section: Resultsmentioning

confidence: 99%

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

Chaste

Klei

Sanders

et al. 2015

Biological Psychiatry

136

113

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“…46 Genetic variation in ZNF365 was associated with atopic dermatitis in Japanese and Chinese populations, 47,48 but not in Europeans. 49 Atopic dermatitis is an allergic disease modulated through IgE, and therefore our association with IgE reinforces the role of ZNF365 in atopic phenotypes.…”

Section: Discussionmentioning

confidence: 95%

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Pino-Yanes

Gignoux

Galanter

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Immunoglobulin E (IgE) is a key mediator of allergic inflammation and is frequently elevated in allergic disorders. Objective To identify genetic variants associated with IgE levels in Latinos. Methods We performed a genome-wide association study (GWAS) and admixture mapping of total IgE levels in 3,334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1,564 European Americans, and 3,187 African Americans from independent studies. Results We confirmed associations of six genes identified by previous GWAS and identified a novel genome-wide significant association of a polymorphism in ZNF365 with total IgE (rs200076616, p=2.3x10−8). We next identified four admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) where local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower levels of IgE (p=4.95x10−8). All but 22q13.1 were replicated in an independent sample of Latinos, and two of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified six genome-wide significant single nucleotide polymorphisms in Latinos, two of which replicated in European Americans. Another SNP was peak-wide significant within 14q23.2 in African Americans (rs1741099, p=3.7x10−6), and replicated in non-African American samples (p=0.011). Conclusion We confirmed genetic associations at six genes, and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse, multi-ethnic populations to uncover novel loci associated with total IgE levels.

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“…Our results suggest that the haplotype in iCHAV2 associated with reduced risk of breast cancer is associated with silencing of the NRBF2 promoter. ZNF365 encodes the zinc finger protein 365, which plays a critical role in stabilizing fragile sites within the genome and telomeres 37 and maintaining genome stability, 38 and is therefore a good candidate for a breast cancer Both haplotypes of the iCHAV2 PRE2 were cloned upstream of NRBF2-and ZNF365-promoter-driven luciferase reporters. Cells were transiently transfected with the common (PRE2) and the protective (Prot Hap) haplotype constructs and assayed for luciferase activity 24 hr later.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Darabi

McCue

Beesley

et al. 2015

The American Journal of Human Genetics

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Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

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ZNF365 promotes stalled replication forks recovery to maintain genome stability

Cited by 18 publications

References 47 publications

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

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