Susceptibility Susceptibility Single Nucleotide Polymorphisms Research Articles

Genome-wide Meta-analysis for Myopic Macular Neovascularization Identified a Novel Susceptibility Locus and Revealed a Shared Genetic Susceptibility with Age-Related Macular Degeneration

To identify the susceptibility loci for myopic macular neovascularization (mMNV) in patients with high myopia. A genome-wide association study (GWAS) meta-analysis (meta-GWAS). We included 2,783 highly myopic individuals, including 608 patients with mMNV and 2,175 control participants without mMNV. We performed a meta-analysis of three independent GWASs conducted according to genotyping platform (Illumina Asian Screening Array [ASA] dataset, Illumina Human610 BeadChip [610K] dataset, and whole genome sequencing [WGS] dataset), adjusted for age, sex, axial length and the first to third principal components. We used DeltaSVM to evaluate the binding affinity of transcription factors to DNA sequences around the susceptibility single nucleotide polymorphisms (SNPs). In addition, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. The association between SNPs and mMNV in patients with high myopia. The meta-GWAS identified rs56257842 at TEX29 -LINC02337 as a novel susceptibility SNP for mMNV (odds ratio [OR]meta = 0.62, Pmeta = 4.63 × 10-8, I2 = 0.00), which was consistently associated with mMNV in all datasets (ORASA = 0.59, PASA = 1.71 × 10-4; OR610K = 0.63, P610K = 5.53 × 10-4; ORWGS = 0.66, PWGS = 4.38 × 10-2). Transcription factor-wide analysis showed that the transcription factors ZNF740 and EGR1 lost their binding affinity to this locus when rs56257842 had the C allele (alternative allele), and the WNT signaling-related transcription factor ZBTB33 gained binding affinity when rs56257842 had the C allele. When we examined the associations of AMD susceptibility loci, rs12720922 at CETP showed a statistically significant association with mMNV (ORmeta = 0.52, Pmeta = 1.55 × 10-5), while rs61871745 near ARMS2 showed a marginal association (ORmeta = 1.25, Pmeta =7.79 × 10-3). Our study identified a novel locus associated with mMNV in high myopia. Subsequent analyses offered important insights into the molecular biology of mMNV, providing the potential therapeutic targets for mMNV. Furthermore, our findings imply shared genetic susceptibility between mMNV and AMD.

BHMT polymorphism and susceptibility to PTE in Chinese patients.

Pulmonary thromboembolism (PTE) is as a common form of venous thrombosis and a potentially fatal cardiovascular disorder, which has become a severe clinical problem with high incidence and mortality. The PTE has a strong genetic basis, which contributes up to half of the variance in PTE incidence and susceptibility single-nucleotide polymorphisms (SNPs) is associated with PTE. Betaine homocysteine methyltransferase (BHMT) is an essential enzyme that catalyzes the remethylating reaction from homocysteine to methionine and participates in conserving methionine and detoxifying homocysteine. In this work, we aimed to explore BHMT polymorphism and susceptibility to PTE in Chinese patients. Variant loci of the BHMT gene were screened in serum samples of PTE patients, followed by verification using Sanger sequencing. These polymorphic loci were validated in 16 PTE patients and 16 matched normal patients. The frequency differences between the allele and genotypes were compared using the Hardy-Weinberg equilibrium test and Chi-square test. A SNP was identified in PTE patients and a heterozygous transition of G>A (Arg239Gln) in rs3733890 was found. The variance difference at rs3733890 between normal patients (2/16, 0.125) and PTE patients (9/16, 0.5625) was significant (p<0.01). Therefore, we concluded that the BHMT polymorphism, rs3733890 may be a susceptibility SNP for PTE.

Impact of the RNA allosteric effect triggered by single nucleotide polymorphisms on the splicing process.

The susceptibility single nucleotide polymorphisms (SNPs) obtained by genome-wide association studies leave some thorny questions, such as prioritization, false positives and unknown pathogenesis. Previous studies suggested that genetic variation may perturb the RNA secondary structure, influence protein recruitment and binding and ultimately affect splicing processes. Therefore, exploring the perturbation of SNPs to structure-function correlations may provide an effective bridge toward understanding the genetic contribution to diseases. Here, aiming to decipher the regulatory mechanism of myopia susceptibility variants, we systematically evaluated the roles of SNP-induced structural changes during splicing. In addition, 7.53% of myopia-related SNPs exhibited significant global structural changes, 19.53% presented noteworthy local structural disturbance and there were wide-ranging structural perturbations in the splice-related motifs. We established a comprehensive evaluation system for structural disturbance in the splicing-related motifs and gave the priority ranking for the SNPs at RNA structural level. These high-priority SNPs were revealed to widely disturb the molecular interaction properties between splicing-related proteins and pre-mRNAs by HDOCK. Moreover, mini-gene assays confirmed that structural perturbation could influence splicing efficiency through structural remodelling. This study deepens our understanding of the potential molecular regulatory mechanisms of susceptible SNPs in myopia and contributes to personalized diagnosis, personalized medicine, disease-risk prediction and functional verification study by guiding the prioritization of the susceptibility SNPs.

Correlation research of susceptibility single nucleotide polymorphisms and the severity of clinical symptoms in attention deficit hyperactivity disorder.

ObjectiveTo analyze the correlation between susceptibility single nucleotide polymorphisms (SNPs) and the severity of clinical symptoms in children with attention deficit hyperactivity disorder (ADHD), so as to supplement the clinical significance of gene polymorphism and increase our understanding of the association between genetic mutations and ADHD phenotypes.Methods193 children with ADHD were included in our study from February 2017 to February 2020 in the Children’s ADHD Clinic of the author’s medical institution. 23 ADHD susceptibility SNPs were selected based on the literature, and multiple polymerase chain reaction (PCR) targeted capture sequencing technology was used for gene analysis. A series of ADHD-related questionnaires were used to reflect the severity of the disease, and the correlation between the SNPs of specific sites and the severity of clinical symptoms was evaluated. R software was used to search for independent risk factors by multivariate logistic regression and the “corplot” package was used for correlation analysis.ResultsAmong the 23 SNP loci of ADHD children, no mutation was detected in 6 loci, and 2 loci did not conform to Hardy-Weinberg equilibrium. Of the remaining 15 loci, there were 9 SNPs, rs2652511 (SLC6A3 locus), rs1410739 (OBI1-AS1 locus), rs3768046 (TIE1 locus), rs223508 (MANBA locus), rs2906457 (ST3GAL3 locus), rs4916723 (LINC00461 locus), rs9677504 (SPAG16 locus), rs1427829 (intron) and rs11210892 (intron), correlated with the severity of clinical symptoms of ADHD. Specifically, rs1410739 (OBI1-AS1 locus) was found to simultaneously affect conduct problems, control ability and abstract thinking ability of children with ADHD.ConclusionThere were 9 SNPs significantly correlated with the severity of clinical symptoms in children with ADHD, and the rs1410739 (OBI1-AS1 locus) may provide a new direction for ADHD research. Our study builds on previous susceptibility research and further investigates the impact of a single SNP on the severity of clinical symptoms of ADHD. This can help improve the diagnosis, prognosis and treatment of ADHD.

Evaluation of polygenic risk scores for ovarian cancer risk prediction in a prospective cohort study

BackgroundGenome-wide association studies have identified >30 common SNPs associated with epithelial ovarian cancer (EOC). We evaluated the combined effects of EOC susceptibility SNPs on predicting EOC risk in an independent...

Comprehensive review and annotation of susceptibility SNPs associated with obesity-related traits.

We aimed to summarize the results of genetic association studies for obesity and provide a comprehensive annotation of all susceptibility single nucleotide polymorphisms (SNPs). A total of 72 studies were summarized, resulting in 90,361 susceptibility SNPs (738 index SNPs and 89,623 linkage disequilibrium SNPs). Over 90% of the susceptibility SNPs are located in non-coding regions, and it is challenging to understand their functional significance. Therefore, we annotated these SNPs by using various functional databases. We identified 24,623 functional SNPs, including 4 nonsense SNPs, 479 missense SNPs, 399 untranslated region SNPs which might affect microRNA binding, 262 promoter and 5,492 enhancer SNPs which might affect transcription factor binding, 7 splicing sites, 76 SNPs which might affect gene methylation levels, 1,839 SNPs under natural selection and 17,351 SNPs which might modify histone binding. Expression quantitative trait loci analyses for functional SNPs identified 98 target genes, including 69 protein coding genes, 27 long non-coding RNAs and 3 processed transcripts. The percentage of protein coding genes that could be correlated with obesity-related pathways directly or through gene-gene interaction is 75.36 (52/69). Our results may serve as an encyclopaedia of obesity susceptibility SNPs and offer guide for functional experiments.

EPB41, a novel hepatoma susceptibility gene dysregulated by c-Myc: an integrative functional genomics study

BackgroundGenome-wide association studies (GWAS) have provided insight into cancer genetics. However, molecular mechanisms whereby many susceptibility single nucleotide polymorphisms (SNPs) identified by GWAS promote cancer heritability and risk are unknown. New research strategies to evaluate functionality are needed to systematically study causal genetic variants. MethodsIn this study, we developed an integrative functional genomics method to identify cancer susceptibility SNPs in transcription factor binding sites across the whole genome. By integration of functional genomic data from c-Myc cistromics, 1000 Genomes and the TRANSFAC matrix databases, we identified SNPs in the c-Myc cistrome that might modulate c-Myc binding affinity in hepatocellular carcinoma. We took blood samples from patients with hepatitis B-related hepatocellular carcinoma who were admitted to Shandong Cancer Hospital, Jinan, Shandong Province. China, or Huaian No. 2 Hospital, Huaian, Jiangsu Province, China. We extracted genomic DNA from these samples and did genotype analyses. Written informed consent was obtained from all participants and the study was ethically approved by the institutional review boards. FindingsWe identified 12 SNPs in 1806 people with hepatitis B-related hepatocellular carcinoma, we genotyped these SNPs and 1708 controls. We identified a novel hepatocellular carcinoma susceptibility SNP, EPB41 rs157224 G>T (OR of T allele 1·64 [95% CI 1·32–2·02]; p<0·00001), in Chinese patients with hepatocellular carcinoma. This SNP in EPB41 predisposes individuals to hepatocellular carcinoma through modification of c-Myc-mediated transcriptional regulation; the risk allele has decreased gene expression. EPB41 is a novel hepatocellular carcinoma susceptibility gene. Consistent with this notion, a EPB41 expression is decreased tissue samples from patients with hepatocellular carcinoma, especially portal vein metastasis or intrahepatic metastasis. InterpretationOur results show that SNP EPB41 rs157224 G>T could be associated with increased susceptibility to hepatocellular carcinoma and show that insight into malignancy pathology can be made using a genome-wide approach. FundingNational Natural Science Foundation of China (81201586 and 31271382), National High-Tech Research and Development Program of China (2015AA020950), State Key Laboratory of Molecular Oncology (SKL-KF-2015-05).

SNPs and breast cancer risk prediction for African American and Hispanic women

For African American or Hispanic women, the extent to which clinical breast cancer risk prediction models are improved by including information on susceptibility single nucleotide polymorphisms (SNPs) is unknown, even though these women comprise increasing proportions of the US population and represent a large proportion of the world’s population. We studied 7539 African American and 3363 Hispanic women from the Women’s Health Initiative. The age-adjusted 5-year risks from the BCRAT and IBIS risk prediction models were measured and combined with a risk score based on >70 independent susceptibility SNPs. Logistic regression, adjusting for age group, was used to estimate risk associations with log-transformed age-adjusted 5-year risks. Discrimination was measured by the odds ratio (OR) per standard deviation (SD) and the area under the receiver operator curve (AUC). When considered alone, the ORs for African American women were 1.28 for BCRAT, and 1.04 for IBIS. When combined with the SNP risk score (OR 1.23), the corresponding ORs were 1.39 and 1.22. For Hispanic women the corresponding ORs were 1.25 for BCRAT, and 1.15 for IBIS. When combined with the SNP risk score (OR 1.39), the corresponding ORs were 1.48 and 1.42. There was no evidence that any of the combined models were not well calibrated. Including information on known breast cancer susceptibility loci provides approximately 10 and 19 % improvement in risk prediction using BCRAT for African Americans and Hispanics, respectively. The corresponding figures for IBIS are approximately 18 and 26 %, respectively.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3641-7) contains supplementary material, which is available to authorized users.

Abstract 4604: DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk

Abstract Chromosome 8q24 has emerged as an important region for the genetic susceptibility to several cancers, including prostate cancer; however, little is known about the contribution of DNA methylation in this region to risk. To evaluate DNA methylation levels at 8q24 in relation to the risk of prostate cancer, we conducted a nested case-control study using pre-diagnostic peripheral blood samples from 694 prostate cancer cases and 703 controls in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We quantified DNA methylation levels at 63 specific CpG sites nearby cancer susceptibility single nucleotide polymorphisms (SNPs) at 8q24 or the MYC oncogene using pyrosequencing with bisulfite-treated DNA. For each of the 50 CpG sites meeting our quality control requirements, we used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the risk of prostate cancer associated with each unit increase in percent DNA methylation. We identified 7 CpG sites whose DNA methylation levels were associated with prostate cancer risk (p less than 0.05), including 5 CpG sites in POU5F1B that were moderately correlated with one another (Spearman rho: 0.20-0.52), as well as 2 intergenic CpG sites (Chr8:128081593 and Chr8:128513944). The most significant association was observed for Chr8:128498079 in POU5F1B (OR = 0.97, 95% CI: 0.95-0.99, p-value = 0.01). The five POU5F1B CpG sites found to be associated with prostate cancer risk were significantly correlated with several established cancer susceptibility SNPs at 8q24 from genome-wide association studies, including rs6983267 (rho: 0.14-0.36), which has been previously associated with prostate cancer, among other cancers. Rs6983267 was only marginally associated with prostate cancer risk in this study (p = 0.10). When rs6983267 was included in the models for the five correlated CpG sites at POU5F1B, the associations for these CpG sites with prostate cancer were attenuated, suggesting that the POU5F1B CpG sites may be part of the same biological pathway conferring increased prostate cancer risk. Our findings suggest that DNA methylation at 8q24 may contribute to the risk of prostate cancer, and epigenetic mechanisms may help explain some of the SNP-associated risk in this important cancer susceptibility region. Citation Format: Kathryn Hughes Barry, Lee E. Moore, Joshua Sampson, Stella Koutros, Liying Yan, Ann Meyer, Mahitha Reddy, Michael B. Cook, Joseph F. Fraumeni, Meredith Yeager, Laufey Amundadottir, Sonja I. Berndt. DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4604. doi:10.1158/1538-7445.AM2015-4604

Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature.

What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome? Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS. PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature. Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period. All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls. After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively). The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed. This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.

Genetic and clinical risk prediction model for postoperative atrial fibrillation.

Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model. We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001). We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.

DNA methylation levels at chromosome 8q24 in peripheral blood are associated with 8q24 cancer susceptibility loci.

Chromosome 8q24 has emerged as an important region for genetic susceptibility to various cancers, but little is known about the contribution of DNA methylation at 8q24. To evaluate variability in DNA methylation levels at 8q24 and the relationship with cancer susceptibility single nucleotide polymorphisms (SNPs) in this region, we quantified DNA methylation levels in peripheral blood at 145 CpG sites nearby 8q24 cancer susceptibility SNPs or MYC using pyrosequencing among 80 Caucasian men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. For the 60 CpG sites meeting quality control, which also demonstrated temporal stability over a 5-year period, we calculated pairwise Spearman correlations for DNA methylation levels at each CpG site with 42 8q24 cancer susceptibility SNPs. To account for multiple testing, we adjusted P values into q values reflecting the false discovery rate (FDR). In contrast to the MYC CpG sites, most sites nearby the SNPs demonstrated good reproducibility, high methylation levels, and moderate-high between-individual variation. We observed 10 statistically significant (FDR < 0.05) CpG site-SNP correlations. These included correlations between an intergenic CpG site at Chr8:128393157 and the prostate cancer SNP rs16902094 (ρ = -0.54; P = 9.7 × 10(-7); q = 0.002), a PRNCR1 CpG site at Chr8:128167809 and the prostate cancer SNP rs1456315 (ρ = 0.52; P = 1.4 × 10(-6); q = 0.002), and two POU5F1B CpG sites and several prostate/colorectal cancer SNPs (for Chr8:128498051 and rs6983267, ρ = 0.46; P = 2.0 × 10(-5); q = 0.01). This is the first report of correlations between blood DNA methylation levels and cancer susceptibility SNPs at 8q24, suggesting that DNA methylation at this important susceptibility locus may contribute to cancer risk.

Abstract 288: DNA methylation patterns in peripheral blood and the relationship with cancer susceptibility loci at chromosome 8q24

Abstract Chromosome 8q24 has emerged as an important region for genetic susceptibility to several cancers, but little is known about the contribution of DNA methylation in this region. To explore the extent of variation in DNA methylation at 8q24 in peripheral blood and its relationship with genetic variation in the region, we conducted a cross-sectional study using blood samples from 80 non-Hispanic Caucasian males in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Specifically, we aimed to evaluate between-individual variation in DNA methylation levels at specific CpG sites at 8q24 and to investigate the underlying genetic structure in the region by examining correlations for DNA methylation levels with each other and with the established cancer susceptibility SNPs at 8q24. We quantified DNA methylation levels at 145 CpG sites nearby cancer susceptibility single nucleotide polymorphisms (SNPs) at 8q24 or the MYC oncogene using pyrosequencing of bisulfite-treated DNA, which is considered a highly sensitive method to detect differences in DNA methylation levels between individuals. We calculated pairwise Spearman correlations (rho), adjusting for multiple testing using the False Discovery Rate (FDR) method. We identified a large number of CpG sites that were reproducible and demonstrated moderate to high between-individual variation in our study population. Among these CpG sites, some sites within or nearby MYC and POU5F1B were strongly correlated with one another (highest rho=0.74), suggesting a coordination of DNA methylation levels in gene regions. Moreover, we observed strong correlations between several CpG sites and some of the known cancer susceptibility SNPs at 8q24. Some of the correlations remained statistically significant after adjustment for multiple comparisons, including a CpG site and an established prostate cancer SNP in the long non-coding RNA PRNCR1 (Chr8:128167809 and rs1456315, rho=0.52; p-value=1.4x10-6; FDR-adjusted p-value=0.002) and a CpG site (Chr8:128498051) in POU5F1B and the known prostate/colorectal cancer SNP rs6983267 (rho=0.46; p-value=2.0x10-5; FDR-adjusted p-value=0.01). This is the first study to report associations between DNA methylation levels at 8q24 in peripheral blood and 8q24 cancer susceptibility SNPs, suggesting that DNA methylation at this important susceptibility locus may contribute to risk. Additional studies are needed to clarify the relationship between genetic and epigenetic variation at 8q24 and cancer risk. Citation Format: Kathryn Hughes Barry, Lee Moore, Joshua Sampson, Liying Yan, Ann Meyer, Charles C. Chung, Meredith Yeager, Laufey Amundadottir, Sonja I. Berndt. DNA methylation patterns in peripheral blood and the relationship with cancer susceptibility loci at chromosome 8q24. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 288. doi:10.1158/1538-7445.AM2014-288

Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium.

Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.

Genotype–phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women

Are there any correlations between the phenotypes of polycystic ovary syndrome (PCOS) and the genotypes of the PCOS susceptibility single nucleotide polymorphisms (SNPs) in THADA, DENND1A and LHCGR? The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in patients with PCOS. PCOS is a heterogeneous endocrinopathy characterized by oligo-anovulation, hyperandrogenism and polycystic ovaries. In a previous genome-wide association study, the SNP variants rs13429458, rs12478601, rs2479106, rs10818854 and rs13405728 in the THADA, DENND1A and LHCGR genes were identified as being independently associated with PCOS. The aim of this study was to identify any additional correlations between the phenotypes of PCOS and genotypes of the five SNPs described in the previous study. In the present cross-sectional study, a total of 1731 PCOS patients and 4964 controls were enrolled. Patients were diagnosed according to Rotterdam criteria. Clinical information was collected from the patients and controls. Endocrine and metabolic parameters were evaluated for phenotype-genotype correlation analyses. Using a recessive model, the AA group for rs13429458 in THADA was associated with increased luteinizing hormone (LH) (P < 0.01) and testosterone (T) (P = 0.02) levels in subjects with PCOS; the LH/follicle-stimulating hormone ratio was also higher in the AA group (P < 0.01). Also using a recessive model, the CC genotype of rs12478601, also in THADA, was associated with increased levels of low-density lipoprotein (P = 0.02). Using a dominant model, the GG + AG group for rs2479106 in DENND1A was associated with elevated serum insulin levels 2 h after a glucose load in the patients with PCOS (P = 0.02). All of the comparisons were adjusted for age and BMI. The relatively younger age of the participants may represent a considerable bias when evaluating metabolic alterations as a function of different genotypes, as significant metabolic disturbances may emerge later in life. Furthermore, the sample sizes of several sub-genotype groups were relatively small; to some extent this limited the statistical power of the analysis. The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in PCOS patients of Han Chinese descent. The findings have shown genuine heterogeneity, stratified on the basis of both clinical findings and genotypes. Replication of these results is expected in other ethnic groups.

Mutual information and linkage disequilibrium based SNP association study by grouping case-control

Two main reasons for the difficulties to search for susceptibility single-nucleotide polymorphisms (SNPs) underlying genetic diseases are that the findings are not easy to be confirmed and the interactions between potential susceptibility SNPs are not clear. Many available association studies usually presented results with significance levels but did not illustrate the stability of the results. In some sense, their performances might be unclear in real practice. In this paper, we develop a novel method based on mutual information theory and linkage disequilibrium by grouping case-control. Mutual information (MI) is used to test multiple SNPs in combining with disease status. Those SNPs contributing the maximum MI are selected as potential susceptibility SNPs. Linkage disequilibrium (LD) analysis is used to extend MI detected result so that both direct and indirect factors can be included in the final result. The purpose of case-control grouping is to generate a number of data groups by randomly sampling from target samples. Each group is assumed to have almost the same number of individuals (cases and controls), and overlap is allowed among the groups. We apply the method to each data group, and then make comparisons and intersections between the results obtained from each of the groups so as to give the final result. We implement the method by continuously grouping until the final result reaches a stable state and a highly significance level. The experimental results indicate that our method to detect susceptibility SNPs in simulated and real data sets has shown remarkable success.

Autism risk assessment in siblings of affected children using sex-specific genetic scores

BackgroundThe inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system.MethodsSNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism.ResultsWe identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively).ConclusionsOur results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism.