Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P | 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Montserrat Garcia-Closas and colleagues report a genome-wide association study for bladder cancer. They identify three new susceptibility loci on chromosomes 22q13.1, 19q12 and 2q37.1. We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10−12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10−11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P =...

TY - JOUR. T1 - Identification of a new prostate cancer susceptibility locus on chromosome 8q24. AU - Yeager, Meredith. AU - Chatterjee, Nilanjan. AU - Ciampa, Julia. AU - Jacobs, Kevin B.. AU - Gonzalez-Bosquet, Jesus. AU - Hayes, Richard B.. AU - Kraft, Peter. AU - Wacholder, Sholom. AU - Orr, Nick. AU - Berndt, Sonja. AU - Yu, Kai. AU - Hutchinson, Amy. AU - Wang, Zhaoming. AU - Amundadottir, Laufey. AU - Feigelson, Heather Spencer. AU - Thun, Michael J.. AU - Diver, W. Ryan. AU - Albanes, Demetrius. AU - Virtamo, Jarmo. AU - Weinstein, Stephanie. AU - Schumacher, Fredrick R.. AU - Cancel-Tassin, Geraldine. AU - Cussenot, Olivier. AU - Valeri, Antoine. AU - Andriole, Gerald L.. AU - Crawford, E. David. AU - Haiman, Christopher A.. AU - Henderson, Brian. AU - Kolonel, Laurence. AU - Le Marchand, Loic. AU - Siddiq, Afshan. AU - Riboli, Elio. AU - Key, Timothy J.. AU - Kaaks, Rudolf. AU - Isaacs, William. AU - Isaacs, Sarah. AU - Wiley, Kathleen E.. AU - Gronberg, Henrik. AU - Wiklund, ...

Uncovering common genetic risk factors for Parkinsons disease Introduction. Mutations in the so called PARK genes lead to rare familial forms of Parkinsons disease (PD). However the extent to which common genetic variability around these genes alters risk for common PD remains unclear. The Australian Parkinsons Project is analysing genetic variability around the PARK loci in a large PD case-control sample recruited from three Australian states. The emphasis is on gene-gene and gene-environment interactions between commonly occurring variables. Aim. To report on a pilot PD association analysis of 87 polymorphisms around13 PARK genes in an initial case-control sample recruited during 2006. Methods. PD cases (n=326) and unaffected control subjects (n=298) of white European ancestry were recruited from three specialist clinics in Brisbane and the Australian Electoral Roll. Common genetic variables (86 SNPs genotyped on the TaqMan platform and 1 STR variable genotyped using standard methods) were ...

Novel association of a functional single nucleotide polymorphism in the BTNL2 gene with susceptibility to rheumatoid arthritis and baseline radiographic severity in African-Americans independent of HLA DRB1: Results from the CLEAR registry ...

Breast Cancer Association Consortium (BCAC), Barretts and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkins Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Zhang, Y. D., Hurson, A. ...

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS ...

Introduction Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. Methods European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. Results There were three

Studies on genetic susceptibility for thyroid cancer could have important relevance to understand the etiology of this pathology. Thus, association studies aimed to identify genes for thyroid cancer risk have been recently published (9-12), although no specific genes for thyroid cancer susceptibility have yet been described. Our previous study, using the BAT-40 marker in a case-control study, indicated that the chromosome 1p12-13 is related to thyroid cancer susceptibility (13). Therefore, in the present study, we aimed to map the susceptibility loci on this region. In this context, we have scanned a region of ∼2.4 Mb surrounding the BAT-40 marker by genotyping six single-nucleotide polymorphisms in a Spanish population. This study has allowed us to identify in our population two independent genetic susceptibility loci on chromosome 1p12.. Association analysis using a case-control design showed a strong association between the rs2145418 marker and thyroid cancer incidence, and similar results ...

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six ...

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohns disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two ...

The recognition that prostate cancer has a strong familial component has led to the search for prostate cancer susceptibility genes. Localization of these genes through linkage studies, however, has become a particularly formidable task. Prostate cancer is the most common cancer affecting American men; this high background rate of sporadic cancer obscures the ability to identify families with true genetic predisposition. Prostate cancer is also a late-onset disease. Thus, it is often difficult to identify and collect samples from individuals in several generations. Despite these problems, linkage studies have identified three autosomal putative prostate cancer susceptibility loci, namely, HPC1, PCAP, and CAPB. The likelihood of locus heterogeneity further complicates prostate cancer linkage studies and necessitates large sample sizes.. To localize HPCX, Xu et al. (16) studied 360 prostate cancer families with an average of 4.3 affected men/family obtained from research studies from two ...

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P | 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast

TY - JOUR. T1 - Multivariate logistic regression for familial aggregation in age at disease onset. AU - Matthews, Abigail G.. AU - Finkelstein, Dianne M.. AU - Betensky, Rebecca. PY - 2007/6/1. Y1 - 2007/6/1. N2 - Familial aggregation studies seek to identify diseases that cluster in families. These studies are often carried out as a first step in the search for hereditary factors affecting the risk of disease. It is necessary to account for age at disease onset to avoid potential misclassification of family members who are disease-free at the time of study participation or who die before developing disease. This is especially true for late-onset diseases, such as prostate cancer or Alzheimers disease. We propose a discrete time model that accounts for the age at disease onset and allows the familial association to vary with age and to be modified by covariates, such as pedigree relationship. The parameters of the model have interpretations as conditional log-odds and log-odds ratios, which can ...

TY - CHAP. T1 - Complex Genetics of Alcoholism. AU - Edenberg, Howard. AU - Foroud, Tatiana. PY - 2014/2. Y1 - 2014/2. N2 - Genetic factors play a significant role in the risk for alcoholism, although environmental influences are also important. Alcohol use disorders are defined by symptomology and are heterogeneous, making the identification of specific genes that affect risk difficult. Several strategies have been applied to identify genes that contribute to alcoholism and alcohol-related phenotypes, including candidate gene studies, family-based linkage studies, and genome-wide association studies. Variants in the alcohol metabolizing genes ALDH2 and ADH1B confer some protection against alcohol dependence. Common variants in other genes, including ADH4, ADH1C, GABRA2, GABRG1, CHRNA5, CHRNA3, CHRM2, PECR, AUTS2, PDYN, OPRK1, and KCNJ6, have been associated with alcohol dependence or other alcohol-related phenotypes. Many of these results await further replication. Meta-analysis of large ...

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic

In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes (INS, PTPN22, IL2RA, CTLA4, IFIH1, SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21, CAPSL, Q7Z4c4(5Q), FOXP3, EFHB) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortiums candidate gene study. The study had approximately 80% power at alpha=0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (-23 HphI) was the most associated

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p ...

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P|5×10(-8)), increasing the number of known susceptibility loci …

The current challenge in biomedical research is to detect genetic risk factors involved in common complex diseases. The power to detect their role is generally poor in populations that have been large for a long time. It has been suggested that the power may be increased by taking advantage of the specificity of founder populations: linkage disequilibrium spanning larger regions and kinship coefficients being stronger than in large populations. A new method is proposed here, the Maximum Identity Length Contrast (MILC) which, in contrast with other existing methods, does not make the assumption of unique ancestry for the genetic risk factors. It is thus appropriate for a search for common genetic risk factors for complex diseases. Statistical properties of the method are discussed in realistic contexts.

Men with an inherited mutation linked to increased risk for prostate cancer may benefit from enhanced cancer screening. The National Cancer Institute opened a clinical trial for prostate cancer screening study looking at MRI to improve prostate cancer detection.

Background: Multiple genome-wide and candidate gene association studies have been performed in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. In order to define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk. Methods: Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo based methods. Results: We identified a three-SNP haplotype across rs3834129, rs6723097 and rs3817578 that was significantly associated with breast cancer (p,5×10-6), with a dominant risk ratio and ...

Objective Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. Methods The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. Results The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 ...

Relief is when you and the right researcher find each other Finding the right clinical trial for Multiple sclerosis susceptibility can be challenging. However, with TrialsFinder (which uses the Reg4ALL database and privacy controls by Private Access), you can permit researchers to let you know opportunities to consider - all without revealing your identity. ...

Using the candidate gene approach (discussed earlier in this chapter), many genes have been associated with asthma or asthma-related traits such as allergy and high concentrations of immunoglobulin E (IgE) in serum (table 2). Not all of these suspected asthma susceptibility genes have been replicated in multiple independent studies. One group of (allergic) asthma susceptibility genes is involved in innate immunity responses, encompassing pattern-recognition receptors, immunoregulatory cytokines and molecules involved in antigen presentation. A second group of asthma susceptibility genes are key players in T-helper type 2 (Th2)-cell differentiation and Th2- cell effector function. Th2 cells are T-lymphocytes that drive the production of allergic immunoglobulins (IgE) and the chronic airway inflammation in (allergic) asthma.. Linkage studies in families have discovered several novel asthma susceptibility genes that are expressed in epithelial cells and/or smooth muscle cells in the airways (table ...

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = ...

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)),

The first edition of Human Genome Epidemiology, published in 2004, discussed how the epidemiologic approach provides an important scientific foundation for studying the continuum from gene discovery to the development, applications and evaluation of human genome information in improving health and preventing disease. Since that time, advances in human genomics have continued to occur at a breathtaking pace.

The first edition of Human Genome Epidemiology, published in 2004, discussed how the epidemiologic approach provides an important scientific foundation for studying the continuum from gene discovery to the development, applications and evaluation of human genome information in improving health and preventing disease. Since that time, advances in human genomics have continued to occur at a breathtaking pace.

NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: Ancillary Studies to the NIDDK Inflammatory Bowel Disease Genetics Consortium (R01- Clinical Trial Optional) RFA-DK-17-017. NIDDK

OLIVEIRA, Martha Maria de et al. Single Nucleotide Polymorphisms (SNPs) of the TNF-a (-238/-308) gene among TB and nom TB patients: susceptibility markers of TB occurrence?. J. bras. pneumol. [online]. 2004, vol.30, n.4, pp.371-377. ISSN 1806-3713. https://doi.org/10.1590/S1806-37132004000400012.. BACKGROUND: Host genetic factors may play a role in the susceptibility to active tuberculosis (TB), and several polymorphisms in different cytokine coding genes have been described and associated with diseases to date. OBJECTIVES: To investigate whether polymorphisms within the promoter region of the TNF-a (-238/-308) coding genes are associated to the occurrence of active TB. METHODS: SNPs within the TNF-a gene were analyzed by PCR-RFLP among two groups of individuals: patients with TB (n = 234, and patients non TB (n = 113). RESULTS: In this study, the presence of the -238A allele was associated with susceptibility to TB disease occurrence and severity (p = 0,00002; OR = 0,15; IC = 0,06-0,36. On the ...

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3 untranslated region at putative microRNA (miRNA)-binding sites represent funct …

This course focuses on the fundamental research methods and applications in the dynamic field of genetic epidemiology. To help students obtain a basic understanding of the field, the course includes topics such as assessing genetic influences on disease; advances in genomics technology; family based study designs for linkage, exome sequencing and case-parent trios; candidate gene and genome-wide association studies of both common and rare genetic variants; gene-environment interactions, epistasis and non-Mendelian genetics; software and web-based data resources; ethical issues in genetic epidemiology; and applications of genetic epidemiology to clinical practice and public health. Students will be exposed to a range of research approaches in genetic epidemiology, to examples of these approaches from the literature and from ongoing studies, and will have an opportunity to apply these methods by writing a grant application or human genome epidemiology review in their area of research ...

Finally, a risk score consisting of 47 T2D susceptibility gene variants showed a strong association with fasting glucose, T2D and HOMA-B. Interaction analysis suggested that its effect on fasting glucose levels might be modulated by BMI. The score was associated with greater increase in fasting glucose in obese individuals compared to overweight or normal individuals. The same effect was not observed for T2D risk, possibly because of reduced statistical power. When the variants were partitioned by their proposed physiologic mechanism in the disease, a strong association was found with decreased HOMA-B for one set of SNPs and with increased HOMA-IR for another. The genetic risk score associated with IR, but not the other genetic risk scores, showed a strong association with chronic kidney disease (CKD). Mendelian randomization analysis suggested a causal effect of IR on impaired glomerular filtration rate. The association was statistically significant after the exclusion of diabetic individuals ...

Psoriasis is really a physically, emotionally, and socially invalidating multifactorial disorder, with a substantial effect on the individuals standard of living. the most essential improvements in psoriasis biomarker finding, directing out those biomarkers that have also been analyzed in additional stress-related conditions, therefore emphasizing the partnership between psoriasis and tension. 1. Intro Psoriasis is really a chronic, immune-mediated, polygenic skin condition with a common occurrence affecting around 2% from the Caucasian human buy 139110-80-8 population [1, 2]. It really is a physically, psychologically, and socially invalidating condition with an excellent effect on the individuals standard of living [3]. Individuals with psoriasis frequently experience sociable stigma. Psoriasis can show up at any age group, but two peaks in age group starting point have already been reported: the very first between 20 and 30 years and the next between 50 and 60 years [4]. Men and women are ...

Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. A number of studies have conducted on the association of TP53 codon 72 polymorphisms with susceptibility to breast carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship. We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. A total of seventeen case-control studies, including 12226 cases and 10782 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta-analyses. Overall, no associations of TP53 codon 72 polymorphisms with breast carcinoma were observed

To explore the readiness of living, untested first-degree relatives (FDRs) to have cascade genetic testing (CGT) for a hereditary predisposition to cancer. Adults with a hereditary predisposition to cancer completed an anonymous, online survey about their genetic testing and their FDRs vital status, awareness of the variant, uptake of CGT, and readiness for CGT among living, untested FDRs using transtheoretical model stages of change. One hundred fifty participants completed the survey and reported 825 FDRs. Overall, 70.3% of FDRs were reportedly aware of the variant and 30.5% had completed CGT. Siblings had higher rates of awareness and CGT than parents or children (p | 0.001). Relatives sex was associated with awareness and CGT; mothers were aware and had CGT at higher rates than fathers (p = 0.049 and p | 0.001), sisters were aware and had CGT at higher rates than brothers (p = 0.041 and p = 0.002), and daughters had higher rates of awareness than sons (p = 0.038). Of 340 living, untested FDRs, 79

Alzheimers Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.

Academy of Finland Centre of Excellence in Complex Disease Genetics (CoECDG), Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki.

The purpose of the Alzheimers Disease Genetics Study is to help identify the genes that may be responsible for causing Alzheimers Disease (AD) by collecting genetic material from families with multiple members diagnosed with AD. Qualifying families will have two living blood-related individuals who have been diagnosed with or are showing symptoms of AD or dementia. Local study sites are located all over the United States, and arrangements may be made for eligible families who do not live near a participating site. The biological samples and data from these families will be made available to qualified researchers, who must sign a Materials Transfer Agreement (MTA) in order to protect the privacy rights of study participants before receiving DNA and data ...

BACKGROUND: Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair. METHODS: We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were ...

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P , 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P , 10(-4)) were selected for ...

Objective: Schizophrenia is a complex genetic disorder which likely involves many genes each producing a slight increase in risk. Finding weak-acting genes in complex genetic disorders has been challenging and will likely require a number of approaches and large clinical samples. Several strategies have emerged recently that appear to markedly improve the power of genetic studies for detecting such genes. These include using association (rather than linkage) and using intermediate phenotypes in addition to DMS-IV diagnosis.. Study Population: We propose to take advantage of these techniques by studying quantitative traits related to schizophrenia in patients, siblings, and controls.. Design: We will employ an association design, rather than linkage. Traits will include quantifiable neurobiological variables that have been implicated previously as possible phenotypes related to schizophrenia. These include tests of attention and cognition, and a variety of parameters using brain imaging and ...

Three common mutations in the CARD15 (NOD2) gene are known to be associated with susceptibility to Crohn disease (CD), and genetic data suggest a gene dosage model with an increased risk of 2-4-fold in heterozygotes and 20-40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicates that some heterozygotes for the common mutations have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. We addressed this issue by screening CARD15 for mutations in 100 CD patients who were heterozygous for one of the three common mutations. We also developed a strategy for evaluating potential disease susceptibility alleles (DSAs) that involves assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in three primates (chimp, gibbon, and ...

Pulmonary emphysema is defined as a nonuniform pattern of abnormal, permanent distention of the air spaces with destruction of the alveolar walls and eventually a reduced pulmonary capillary bed. It appears to be the end stage of a process that has progressed slowly for many years. Smoking is the major cause. In a few patients, there is familial predisposition associated with a plasma protein abnormality ( deficiency in alpha-1 antitrypsin), making the person sensitive to environmental factors ( air pollution, infectious agents, allergens). Emphysema manifests commonly in the fifth decade of life and is classified as follows:. ...

Other research groups also have found the G2385R mutation is at a higher frequency in Asian patients with Parkinsons disease, than in matched control subjects. These types of case and control genetic studies provide a powerful tool for researchers to find disease genes and risk factors in homogeneous or isolated populations where there has been little immigration. Interestingly, the present papers authors found evidence to suggest G2385R carriers share a common ancestor. They performed a genetic analysis looking at the inheritance pattern of a specific DNA sequence along chromosome 12 that includes the LRRK2 gene. Examining known genetic markers, which are short stretches of repeated DNA subject to variation in the number of times they repeat, their analysis showed a unique pattern of these DNA sequence markers is almost always passed from generation to generation along with the G2385R variant. Researchers used genetic theory to estimate the level of variation at these genetic markers between ...

Rare variants as low-penetrance alleles Rare variants will not be detectable by population association studies based on the use of linked polymorphic markers, even with very large case/control cohort studies. This is because of low allelic frequency and individually small contributions to the overall inherited susceptibility of a disease. These variants are less common…

TY - JOUR. T1 - Effect of docosahexaenoic acid supplementation on inflammatory cytokine levels in infants at high genetic risk for type 1 diabetes. AU - The Type 1 Diabetes TrialNet Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Study Group. AU - Chase, H. Peter. AU - Boulware, David. AU - Rodriguez, Henry. AU - Donaldson, David. AU - Chritton, Sonia. AU - Rafkin, Lisa. AU - Krischer, Jeffrey. AU - Skyler, Jay S. AU - Clare-Salzler, Michael. AU - Lescheck, E.. AU - Krause Steinrauf, H.. AU - Azare, S. M.. AU - Adams, S.. PY - 2015/6/1. Y1 - 2015/6/1. N2 - Objective: Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic β-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D. Research design and methods: This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, ...

TY - JOUR. T1 - Correction to. T2 - Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci (Nature Genetics, (2018), 50, 7, (928-936), 10.1038/s41588-018-0142-8). AU - Breast and Prostate Cancer Cohort Consortium (BPC3). AU - The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium. AU - Cancer of the Prostate in Sweden (CAPS). AU - Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS). AU - The Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium. AU - The Profile Study. AU - Australian Prostate Cancer BioResource (APCB). AU - The IMPACT Study. AU - Canary PASS Investigators. AU - Schumacher, Fredrick R.. AU - Olama, Ali Amin Al. AU - Berndt, Sonja I.. AU - Benlloch, Sara. AU - Ahmed, Mahbubl. AU - Saunders, Edward J.. AU - Dadaev, Tokhir. AU - Leongamornlert, ...

Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium.

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P | 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa

YAKUBU, A.; DE DONATO, M. e IMUMORIN, I. G.. Modelling functional and structural impact of non-synonymous single nucleotide polymorphisms of the DQA1 gene of three Nigerian goat breeds. S. Afr. j. anim. sci. [online]. 2017, vol.47, n.2, pp.146-156. ISSN 2221-4062. http://dx.doi.org/10.4314/sajas.v47i2.6.. The DQA1 gene is a member of the highly polymorphic MHC class II locus that is responsible for the differences among individuals in immune response to infectious agents. In this study, the authors performed a comprehensive computational analysis of the functional and structural impact of non-synonymous or amino acid-changing single nucleotide polymorphisms (SNPs) (nsSNPs) that are deleterious to the DQA1 protein in Nigerian goats. A 310-bp fragment of exon 2 of the DQA1 gene was amplified and sequenced in 27 unrelated animals that are representative of three major Nigerian goat breeds (nine each of West African Dwarf, Red Sokoto, and Sahel of both sexes) using genomic DNA. Forty-two nsSNPs were ...

TY - JOUR. T1 - Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. AU - Pearce, C. L.. AU - Near, A. M.. AU - Van Den Berg, D. J.. AU - Ramus, S. J.. AU - Gentry-Maharaj, A.. AU - Menon, U.. AU - Gayther, S. A.. AU - Anderson, A. R.. AU - Edlund, C. K.. AU - Wu, A. H.. AU - Chen, X.. AU - Beesley, J.. AU - Webb, P. M.. AU - Holt, S. K.. AU - Chen, C.. AU - Doherty, J. A.. AU - Rossing, M. A.. AU - Whittemore, A. S.. AU - McGuire, V.. AU - DiCioccio, R. A.. AU - Goodman, M. T.. AU - Lurie, G.. AU - Carney, M. E.. AU - Wilkens, L. R.. AU - Ness, R. B.. AU - Moysich, K. B.. AU - Edwards, R.. AU - Jennison, E.. AU - Kjaer, S. K.. AU - Hogdall, E.. AU - Hogdall, C. K.. AU - Goode, E. L.. AU - Sellers, T. A.. AU - Vierkant, R. A.. AU - Cunningham, J. C.. AU - Schildkraut, J. M.. AU - Berchuck, A.. AU - Moorman, P. G.. AU - Iversen, E. S.. AU - Cramer, D. W.. AU - Terry, K. L.. AU - Vitonis, A. F.. AU - Titus-Ernstoff, L.. AU - Song, ...

The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.We identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta ,5.00E-08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and ...

Read Associations between three common single nucleotide polymorphisms (rs266729, rs2241766, and rs1501299) of ADIPOQ and cardiovascular disease: a meta-analysis, Lipids in Health and Disease on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.

GWAS has enormously contributed to the identification of susceptibility genes for T2D and many other complex disorders. The discovery of new susceptibility loci in GWAS of different ethnic groups emphasizes the need for conducting more GWAS in populations of diverse ethnic groups. Our study also shows the potential of identifying new signals through GWAS in population of different ethnicity. In this study, we performed a GWAS in Indians and identified a new signal for T2D on chromosome 2q21.. The strongest signal on newly identified locus 2q21 mapped to TMEM163. The association of TMEM163 variants (rs6723108 and rs998451) with reduced fasting plasma insulin levels and HOMA-IR indicates that it might modulate susceptibility to T2D by affecting insulin secretion. Previously, rs6723108 has also been suggested to be associated with waist circumference. These data indicate the biological relevance of the identified locus with T2D. TMEM163 encodes a synaptic vesicle membrane protein with six putative ...

Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was...

Background: More than 60 genetic susceptibility loci associated with type 2 diabetes mellitus (T2DM) have been established in populations of Asian and European ancestry. Given ethnic differences and environmental factors, validation of the effects of genetic risk variants with reported associations identified by Genome-Wide Association Studies (GWASs) is essential. The study aims at evaluating the associations of T2DM with 29 single nucleotide polymorphisms (SNPs) from 19 candidate genes derived from GWASs in a northern Han Chinese population. Method: In this case-control study, 461 T2DM-diagnosed patients and 434 controls were recruited at the Jidong oil field hospital (Hebei, China) from January 2009 to October 2013. A cumulative genetic risk score (cGRS) was calculated by summation of the number of risk alleles, and a weight GRS (wGRS) was calculated as the sum of risk alleles at each locus multiplied by their effect sizes for T2DM, using the independent variants selected. Result: The allelic

Bei, J.-X., Jia, W.-H., Feng, B.-J., Chen, L.-Z., Feng, Q.-S., Kang, T., Liu, J., Zeng, Y.-X., Li, Y., Low, H.-Q., Zhou, G., Zhang, H., He, F., Tai, E.S., Liu, E.T. (2010). A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nature Genetics 42 (7) : 599-603. ScholarBank@NUS Repository. https://doi.org/10.1038/ng. ...

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P , 10 -4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10 -8 to P = 1.9 × 10 -11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10 -4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased ...

We have conducted a pathway-based analysis of genome-wide single-nucleotide polymorphism (SNP) data in order to identify genetic susceptibility factors for cervical cancer in situ. Genotypes derived from Affymetrix 500k or 5.0 arrays for 1076 cases and 1426 controls were analyzed for association, and pathways with enriched signals were identified using the SNP ratio test. The most strongly associated KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were Asthma (empirical P=0.03), Folate biosynthesis (empirical P=0.04) and Graft-versus-host disease (empirical P=0.05). Among the 11 top-ranking pathways were 6 related to the immune response with the common denominator being genes in the major histocompatibility complex (MHC) region on chromosome 6. Further investigation of the MHC revealed a clear effect of HLA-DPB1 polymorphism on disease susceptibility. At a functional level, DPB1 alleles associated with risk and protection differ in key amino-acid residues affecting peptide-binding motifs ...

TY - JOUR. T1 - Disease susceptibility genes shared by primary biliary cirrhosis and Crohns disease in the Japanese population. AU - Aiba, Yoshihiro. AU - Yamazaki, Keiko. AU - Nishida, Nao. AU - Kawashima, Minae. AU - Hitomi, Yuki. AU - Nakamura, Hitomi. AU - Komori, Atsumasa. AU - Fuyuno, Yuta. AU - Takahashi, Atsushi. AU - Kawaguchi, Takaaki. AU - Takazoe, Masakazu. AU - Suzuki, Yasuo. AU - Motoya, Satoshi. AU - Matsui, Toshiyuki. AU - Esaki, Motohiro. AU - Matsumoto, Takayuki. AU - Kubo, Michiaki. AU - Tokunaga, Katsushi. AU - Nakamura, Minoru. N1 - Publisher Copyright: © 2015 The Japan Society of Human Genetics. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.. PY - 2015/9/29. Y1 - 2015/9/29. N2 - We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohns diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. ...

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: ...

TY - JOUR. T1 - A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. AU - Kerns, Sarah L.. AU - Stock, Richard. AU - Stone, Nelson. AU - Buckstein, Michael. AU - Shao, Yongzhao. AU - Campbell, Christopher. AU - Rath, Lynda. AU - De Ruysscher, Dirk. AU - Lammering, Guido. AU - Hixson, Rosetta. AU - Cesaretti, Jamie. AU - Terk, Mitchell. AU - Ostrer, Harry. AU - Rosenstein, Barry S.. PY - 2013/1/1. Y1 - 2013/1/1. N2 - Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix ...

Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer. The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing. Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to

BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS:

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS: A combined GRS for atrial fibrillation, coronary artery disease

OBJECTIVE: Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS: We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology,

Background and Purpose - Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Methods - Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. Results - A combined GRS for atrial fibrillation, coronary ...

TY - JOUR. T1 - Evidence for asthma susceptibility genes on chromosome 11 in an African-American population. AU - Huang, Shau Ku. AU - Mathias, Rasika A.. AU - Ehrlich, Eva. AU - Plunkett, Beverly. AU - Liu, Xin. AU - Cutting, Garry R.. AU - Wang, Xin Jing. AU - Li, Xiao Dong. AU - Togias, Alkis. AU - Barnes, Kathleen C.. AU - Malveaux, Floyd. AU - Rich, Stephen. AU - Mellen, Beverly. AU - Lange, Ethan. AU - Beaty, Terri H.. PY - 2003/7/1. Y1 - 2003/7/1. N2 - Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at ...

Maternal glucose metabolism during pregnancy differs from the nongravid state to meet the needs of the growing fetus and compensate for pregnancy-induced insulin resistance (7). Multiple GWAS and other studies in nongravid cohorts have demonstrated the contribution of variation in multiple genes to glucose and insulin levels (15,16,19). However, given the pregnancy-induced changes in glucose metabolism, the question arises whether the genetic architecture of glucose metabolism during pregnancy and the nongravid state are similar. We report now the first GWAS of maternal metabolic traits during pregnancy and have demonstrated both similarities and differences between the gravid and nongravid states. We also report evidence for association of many loci in multiple ancestry groups.. Five loci that exhibited genome-wide significant association with maternal metabolic traits have been identified previously in nongravid cohorts, primarily of EU. These include four loci that have demonstrated ...

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset |60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P|5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated

Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. In Swedish families with hereditary prostate cancer, linkage to the HPC1 (ital) locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer

Breast cancer is the most common type of cancer and the second leading cause of cancer-death among women in Poland. The known high-risk mutations account for 25% of familial aggregation cases and 5% of total breast cancer predisposition. Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. To verify selected associations with breast cancer susceptibility among Polish women, the replication study was performed, included 1424 women with breast cancer and 1788 healthy persons. Sixteen single-nucleotide polymorphisms (SNPs) were analyzed using TaqMan SNP Genotyping Assays. Allele frequency differences were tested using chi2-test implemented in PLINK v1.07 and Cochran-Armitage trend test was performed using R software. Significant differences (Bonferroni corrected p-valuecor ≤ 0.0197) in the frequency of alleles distribution between all cancer and control subjects were observed for four

We investigated the association between genetic risk of stroke, lifestyle, and incident risk of stroke in 306 473 people within the population based UK Biobank study. Risk of incident stroke was 35% higher among those at high genetic risk compared with those at low genetic risk, and these associations were independent of lifestyle profile. Furthermore, an unfavourable lifestyle was associated with a 66% increased risk of incident stroke compared with a favourable lifestyle, and this increased risk was present within any genetic risk category. A high genetic risk combined with an unfavourable lifestyle profile was associated with a more than twofold increased risk of stroke compared with a low genetic risk and a favourable lifestyle.. The present study provides further support that common genetic variants are implicated in the development of stroke. Our findings showing that a polygenic risk score is associated with incident stroke is in line with both clinical and population based ...

PubMed journal article TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak populatio were found in PRIME PubMed. Download Prime PubMed App to iPhone or iPad.

Genome-wide association studies (GWAS) have proved the association of IKZF1 polymorphisms with childhood acute lymphoblastic leukemia (ALL). In the present study, we aimed to inspect the impact of IKZF1 gene polymorphisms and childhood ALL in a sample of Iranian population who live in south east of Iran. This case-control study was done on 110 children diagnosed with ALL and 120 healthy children. The IKZF1 (rs4132601 T > G, rs11978267 A > G, rs11980379 T > C, and rs10272724 T > C) polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs4132601 T > G polymorphism increased the risk of ALL in the codominant (OR = 2.96, 95 % CI = 1.58-5.54, p = 0.0008, TG vs TT; and OR = 2.75, 95 % CI = 1.31-5.76, p = 0.0094, GG vs TT) and dominant (OR = 2.89, 95 % CI = 1.61-5.19, p = 0.0004, TG + GG vs TT) inheritance models. On the other hand, the rs4132601 G allele increased the risk of ALL (OR = 1.86, 95 % CI = 1.28-2.96; p = ...

The C1858T polymorphism in the Ptpn22 gene is associated with increased susceptibility to several autoimmune disorders including Type 1 Diabetes (T1D). This produces a gain-of-function R620W variant with diminished binding affinity to Csk, which, like PTPN22 is an inhibitor of antigen receptor signaling. In the T1D-prone BioBreeding (BB) rat, this gene is located in the Iddm3 locus on chromosome 2, making it a likely candidate gene. Sequencing revealed a non-synonymous SNP causing an A629T substitution C-terminal to the PTPN22 P1 domain that binds to Csk. Co-immunoprecipitations examining the PTPN22-Csk interaction have shown a 2-fold reduction in binding affinity of the BB compared to the ACI variant. Importantly, a genome-wide segregation analysis of an F2(BBxACI.1u.lyp) cohort revealed the dominant effect of the BB allele to confer a 3-fold increased T1D risk compared to the allele carried by the T1D-resistant ACI strain. Homozygosity for the BB allele is also associated with phenotypes ...

Author Summary Obesity is a major health concern worldwide. In the past two years, genome-wide association studies of DNA markers known as SNPs (single nucleotide polymorphisms) have identified two novel genetic factors that may help scientists better understand why some people may be more susceptible to obesity. Similarly, this paper describes results from a large scale genome-wide association analysis for obesity susceptibility genes that includes 31,373 individuals from 8 separate studies. We uncovered a new gene influencing waist circumference, the neurexin 3 gene (NRXN3), which has been previously implicated in studies of addiction and reward behavior. These findings lend further evidence that our genes may influence our desire and consumption of food and, in turn, our susceptibility to obesity.

Association of carriers of single nucleotide polymorphisms rs1143634 and rs16944 of the Il-1B gene and rs6265 of the BDNF gene with temporal lobe epilepsy

TY - JOUR. T1 - A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. AU - Olama, Ali Amin Al. AU - Kote-Jarai, Zsofia. AU - Berndt, Sonja I.. AU - Conti, David V.. AU - Schumacher, Fredrick. AU - Han, Ying. AU - Benlloch, Sara. AU - Hazelett, Dennis J.. AU - Wang, Zhaoming. AU - Saunders, Ed. AU - Leongamornlert, Daniel. AU - Lindstrom, Sara. AU - Jugurnauth-Little, Sara. AU - Dadaev, Tokhir. AU - Tymrakiewicz, Malgorzata. AU - Stram, Daniel O.. AU - Rand, Kristin. AU - Wan, Peggy. AU - Stram, Alex. AU - Sheng, Xin. AU - Pooler, Loreall C.. AU - Park, Karen. AU - Xia, Lucy. AU - Tyrer, Jonathan. AU - Kolonel, Laurence N.. AU - Marchand, Loic Le. AU - Hoover, Robert N.. AU - Machiela, Mitchell J.. AU - Yeager, Merideth. AU - Burdette, Laurie. AU - Chung, Charles C.. AU - Hutchinson, Amy. AU - Yu, Kai. AU - Goh, Chee. AU - Ahmed, Mahbubl. AU - Govindasami, Koveela. AU - Guy, Michelle. AU - Tammela, Teuvo L.J.. AU - Auvinen, Anssi. AU - Wahlfors, ...

1. HainesJL, HauserMA, SchmidtS, ScottWK, OlsonLM, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419-421.. 2. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678.. 3. RipkeS, ODushlaineC, ChambertK, MoranJL, KählerAK, et al. (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45: 1150-1159.. 4. CARDIoGRAMplusC4D Consortium, DeloukasP, KanoniS, WillenborgC, FarrallM, et al. (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45: 25-33.. 5. MorrisAP, VoightBF, TeslovichTM, FerreiraT, SegrèAV, et al. (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44: 981-990.. 6. WrayGA (2007) The evolutionary significance of cis-regulatory mutations. ...

BACKGROUND: Breast cancer (BC) is primarily considered a genetic disorder with a complex interplay of factors including age, gender, ethnicity, family history, personal history and lifestyle with associated hormonal and non-hormonal risk factors. The SNP rs2910164 in miR146a (a G to C polymorphism) was previously associated with increased risk of BC in cases with at least a single copy of the C allele in breast cancer, though results in other cancers and populations have shown significant variation. METHODS: In this study, we examined this SNP in an Australian sporadic breast cancer population of 160 cases and matched controls, with a replicate population of 403 breast cancer cases using High Resolution Melting. RESULTS: Our analysis indicated that the rs2910164 polymorphism is associated with breast cancer risk in both primary and replicate populations (p=0.03 and 0.0013, respectively). In contrast to the results of familial breast cancer studies, however, we found that the presence of the G allele of

TY - JOUR. T1 - Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans. AU - Hansen, Helen M.. AU - Xiao, Yuanyuan. AU - Rice, Terri. AU - Bracci, Paige M.. AU - Wrensch, Margaret R.. AU - Sison, Jennette D.. AU - Chang, Jeffery S.. AU - Smirnov, Ivan V.. AU - Patoka, Joseph. AU - Seldin, Michael F. AU - Quesenberry, Charles P.. AU - Kelsey, Karl T.. AU - Wiencke, John K.. PY - 2010/6/29. Y1 - 2010/6/29. N2 - Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P , 10-20). In order to narrow the region of association and identify potential causal variations, we performed a fine-mapping study using 77 SNPs in a ...

Background and Purpose: Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.. Methods: Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.. Results: Despite having power to detect odds ratio of ...

Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification of the genes or non-coding RNAs that mediate these associations. Here, we use Capture Hi-C (CHi-C) to annotate 63 loci; we identify 110 putative target genes at 33 loci. To assess the support for these target genes in other data sources we test for associations between levels of expression and SNP genotype (eQTLs), disease-specific survival (DSS), and compare them with somatically mutated cancer genes. 22 putative target genes are eQTLs, 32 are associated with DSS and 14 are somatically mutated in breast, or other, cancers. Identifying the target genes at GWAS risk loci will lead to a greater understanding of the mechanisms that influence breast cancer risk and prognosis ...

Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger ...

Therefore, recommendations for breast cancer screening or treatments will remain unchanged for most women. The study, led by investigators from the National Cancer Institute (NCI), part of the National Institutes of Health, and the Harvard School of Public Health (HSPH) appears in the March 18, 2010 issue of the New England Journal of Medicine. Unlike the situation for women with a strong family history of breast cancer, in which a search for rare disease-causing variants may be useful, for women without a strong family history breast cancer risk prediction based on common risk variants is currently of marginal utility, said lead author David Hunter, Dean for Academic Affairs and Vincent L. Gregory Professor in Cancer Prevention at HSPH. Findings from genome-wide association studies have identified multiple genetic variants associated with breast cancer. To test whether this information would increase the value of breast cancer risk models, the researchers assembled information on traditional ...