TY - JOUR. T1 - A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. AU - Zhao, Han. AU - Xu, Jianfeng. AU - Zhang, Haobo. AU - Sun, Jielin. AU - Sun, Yingpu. AU - Wang, Zhong. AU - Liu, Jiayin. AU - Ding, Qiang. AU - Lu, Shaoming. AU - Shi, Rong. AU - You, Li. AU - Qin, Yingying. AU - Zhao, Xiaoming. AU - Lin, Xiaoling. AU - Li, Xiao. AU - Feng, Junjie. AU - Wang, Li. AU - Trent, Jeffrey M.. AU - Xu, Chengyan. AU - Gao, Ying. AU - Zhang, Bo. AU - Gao, Xuan. AU - Hu, Jingmei. AU - Chen, Hong. AU - Li, Guangyu. AU - Zhao, Junzhao. AU - Zou, Shuhua. AU - Jiang, Hong. AU - Hao, Cuifang. AU - Zhao, Yueran. AU - Ma, Jinglong. AU - Zheng, S. Lilly. AU - Chen, Zi Jiang. PY - 2012/5/4. Y1 - 2012/5/4. N2 - A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery stage, 802 azoospermia cases and 1,863 controls were ...
Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected by clinical teams after clinical examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also in only participants with pathological diagnosis. In the replication stage, we ...
Skol, A. D., Scott, L. J., Abecasis, G. R. and Boehnke, M. (2007), Optimal designs for two-stage genome-wide association studies. Genet. Epidemiol., 31: 776-788. doi: 10.1002/gepi.20240 ...
Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.
A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.s profile, publications, research topics, and co-authors
The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 2 …
We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P 1.4 10(7)) and replicated convincingly (P 3.9 10(5)) in 798 cases and 2931 controls [per allele odds ratio (OR) 1.27 in replication cohort, P 7.7 10(11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P 1.7 10(7)) and replicated convincingly (P 1.2 10(5)) in 789 cases and 2927 controls (per allele OR 1.31 in replication cohort, P 3.03 10(11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.. ...
TY - JOUR. T1 - Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. AU - Rioux, John D.. AU - Xavier, Ramnik J.. AU - Taylor, Kent D.. AU - Silverberg, Mark S.. AU - Goyette, Philippe. AU - Huett, Alan. AU - Green, Todd. AU - Kuballa, Petric. AU - Barmada, M. Michael. AU - Datta, Lisa. AU - Shugart, Yin Yao. AU - Griffiths, Anne M.. AU - Targan, Stephan R.. AU - Ippoliti, Andrew F.. AU - Bernard, Edmond Jean. AU - Mei, Ling. AU - Nicolae, Dan L.. AU - Regueiro, Miguel. AU - Schumm, L. Philip. AU - Steinhart, A. Hillary. AU - Rotter, Jerome I.. AU - Duerr, Richard H.. AU - Cho, Judy H.. AU - Daly, Mark J.. AU - Brant, Steven R.. PY - 2007/5. Y1 - 2007/5. N2 - We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we ...
TY - JOUR. T1 - 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population. AU - Takata, Ryo. AU - Takahashi, Atsushi. AU - Fujita, Masashi. AU - Momozawa, Yukihide. AU - Saunders, Edward J.. AU - Yamada, Hiroki. AU - Maejima, Kazuhiro. AU - Nakano, Kaoru. AU - Nishida, Yuichiro. AU - Hishida, Asahi. AU - Matsuo, Keitaro. AU - Wakai, Kenji. AU - Yamaji, Taiki. AU - Sawada, Norie. AU - Iwasaki, Motoki. AU - Tsugane, Shoichiro. AU - Sasaki, Makoto. AU - Shimizu, Atsushi. AU - Tanno, Kozo. AU - Minegishi, Naoko. AU - Suzuki, Kichiya. AU - Matsuda, Koichi. AU - Kubo, Michiaki. AU - Inazawa, Johji. AU - Egawa, Shin. AU - Haiman, Christopher A.. AU - Ogawa, Osamu. AU - Obara, Wataru. AU - Kamatani, Yoichiro. AU - Akamatsu, Shusuke. AU - Nakagawa, Hidewaki. PY - 2019/12/1. Y1 - 2019/12/1. N2 - Genome-wide association studies (GWAS) have identified ~170 genetic loci associated with prostate cancer (PCa) risk, but most of them were identified in ...
hi ml-stat-talks a reminder that barbara engelhardt is speaking tomorrow. she does top notch research at the intersection of graphical models and computational biology. best dave ---------- Forwarded message ---------- From: David Mimno ,mimno at cs.princeton.edu, Date: Sun, Sep 18, 2011 at 8:55 PM Subject: [Ml-stat-talks] Wed 9/21: Barbara Englehardt on genome-wide associations To: ml-stat-talks at lists.cs.princeton.edu For our first ML talk of the year, we have Barbara Englehardt from Duke. The talk will be this Wednesday (9/21) at 12:30 in CS 402. Title: Genome-wide associations studies with complex phenotypes: How statistics can help Abstract: Genome-wide association studies (GWAS), or studies to identify genetic variants that are associated with a particular phenotype or disease, can be performed trivially using available software given sufficient numbers of individuals and simple quantitative or case-control phenotypes. However, when the phenotype of interest is complex (e.g., ...
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 ...
Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for ,15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = ...
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = ...
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
Matthew Brown, John Reveille and colleagues report a genome-wide association study for ankylosing spondylitis. They identify four genetic loci outside of the MHC newly associated to AS susceptibility. To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P | 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 ×
TY - JOUR. T1 - Genome-wide association study of leukotriene modifier response in asthma. AU - Dahlin, A.. AU - Litonjua, A.. AU - Irvin, C. G.. AU - Peters, S. P.. AU - Lima, J. J.. AU - Kubo, M.. AU - Tamari, M.. AU - Tantisira, K. G.. PY - 2016/4/1. Y1 - 2016/4/1. N2 - Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV 1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a ...
Genome-wide association studies are important tools to reconstruct the genotype phenotype map to understand the underlying genetic architecture of complex traits. This enables us to better understand the genetic architecture of these phenotypes. With the advances in genotyping and high throughput sequencing technologies, millions of markers can be identified for individual populations in very short durations of time. Due to the multiple loci control nature of complex phenotypes, there is great interest to test markers simultaneously instead of one by one. In chapter 2, we compare three model selection methods for genome wide association studies using simulations: the Stochastic Search Variable Selection (SSVS), the Least Absolute Shrinkage and Selection Operator (LASSO) and the Elastic Net. We apply the three methods to identify genetic variants that are associated with daunorubicin-induced cytotoxicity. We also compare the LASSO and the SSVS to a dataset of two quantitative phenotypes related ...
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 ...
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)).
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
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...
More than 20 genetic loci have been associated with risk for Alzheimers disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were ...
The recent genome-wide association (GWA) meta-analysis of lifetime cannabis use by the International Cannabis Consortium marks a milestone in the study of the genetics of cannabis use. Similar milestones for the genetics of substance use were the GWA meta-analyses of four smoking related traits, of coffee consumption and of alcohol consumption. Combined, 315 981 partly overlapping individuals were genotyped, phenotyped and their data analyzed in genetic association studies, reflecting a huge communal effort by the substance use/addiction genetics community. These genome-wide association study (GWAS) efforts considered different stages of substance use: lifetime use (ever versus never use) was analyzed for cannabis and smoking, quantity of use (in users) was analyzed for coffee, alcohol, and smoking and age of initiation and cessation were analyzed for smoking. There are other GWA efforts and publications in the realm of addiction, but here we limit ourselves to the largest meta-analyses per ...
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,
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 ...
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. [email protected] Repository. https://doi.org/10.1038/ng. ...
Mosaicism is defined as the presence of two or more genetically distinct cellular populations in an individual who developed from a single zygote. With the advent of genome-wide association studies, it is possible to evaluate the relative intensities of the genotype signals to detect large structural mosaicism in human populations. We performed an analysis of germline DNA derived from blood or buccal specimens from 24,849 individuals in 46 cancer-related studies using a modified mosaic alteration detection algorithm on renormalized B-allele frequencies and log2 relative probe intensity ratios from commercially available Illumina SNP arrays. Overall, we confirmed our previously reported findings (Jacobs et al Nat Gen 2012) including a similar distribution of types of events with respect to chromosomal position, an increase with age (overall and in cancer free-controls) and an increase in men versus women. Our segmentation algorithm detected 341 clonal mosaic events ,2 Mb in size in 168 ...
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS ...
Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CT-pro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1.23E-122 and P=1.26E-67, respectively). Epistasis analyses showed a significant ...
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.
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P , 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid ...
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.
A genome-wide association study (GWAS) identifies regions of the genome that likely affect the variable state of a phenotype of interest. These regions can then be studied with population genetic methods to make inferences about the evolutionary history of the trait. There are increasing opportunities to use GWAS results - even from clinically-motivated studies - for tests of classic anthropological hypotheses. One such example, presented here as a case study for this approach, involves tooth development variation related to dental crowding. Specifically, more than 10% of humans fail to develop one or more permanent third molars (M3 agenesis). M3 presence/absence variation within human populations has a significant genetic component (heritability estimate h2 = 0.47). The evolutionary significance of M3 agenesis has a long history of anthropological speculation. First, the modern frequency of M3 agenesis could reflect a relaxation of selection pressure to retain larger and more teeth following the
Using the prostate-specific antigen (PSA) test to screen for prostate cancer is controversial: it has modest predictive value and the potential to lead to over-diagnosis and over-treatment. One can improve the traditional single-cutpoint PSA screening test with more personalized thresholds to determine whether a man should be further evaluated for prostate cancer. Since there is a clear genetic component to PSA, integrating information about genetic factors that influence PSA independently of prostate cancer may improve test performance. To this end, we have undertaken a very large genome-wide association study of PSA concentrations among 35,520 men free of prostate cancer in the Kaiser Permanente Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort. These men had a total of 295,398 PSA measures from electronic health records. We evaluated the potential association between genome-wide variants and log(PSA) levels using a longitudinal generalized estimating equations model, ...
Author Summary We conducted a large genome-wide association study (GWAS) of Parkinsons disease (PD) with over 3,400 cases and 29,000 controls (the largest single PD GWAS cohort to date). We report two novel genetic associations and replicate a total of twenty previously described associations, showing that there are now many solid genetic factors underlying PD. We also estimate that genetic factors explain at least one-fourth of the variation in PD liability, of which currently discovered factors only explain a small fraction (6%-7%). Together, these results expand the set of genetic factors discovered to date and imply that many more associations remain to be found. Unlike traditional studies, participation in this study took place completely online, using a collection of cases recruited primarily via PD mailing lists and controls derived from the customer base of the personal genetics company 23andMe. Our study thus illustrates the ability of web-based methods for enrollment and data collection to
In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimers disease (LOAD). However, the genetic effect attributable to known loci is …
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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
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (Cooperative Health Research in the Region of Augsburg); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of
article{e0da950d-3e1b-428a-9f8b-09267d4f478e, abstract = {,p,More than 20 genetic loci have been associated with risk for Alzheimers disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ,sub,42,/sub,), tau, and phosphorylated tau (ptau,sub,181,/sub,) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify ...
Background: Atopic dermatitis (AD) is a highly heritable common chronic inflammatory skin disease. Twenty-one genetic risk loci have been previously identified. The largest genome-wide association study (GWAS) to date included around 5000 cases and 20 000 controls (of only European origin) and identified 3 risk loci, putting AD some way behind many other complex common diseases that have been studied in much larger numbers and for which many more risk loci have been identified. Method: We conducted the worlds largest GWAS of AD. Our discovery cohort consisted of 21 409 cases and 95 445 controls from 26 studies and used data imputed to the 1000 genomes reference panel (| 15 million variants). In addition to carrying out a fixed effects genome-wide meta-analysis of European individuals, we also included Japanese, Latino and African-American individuals in a multi-ethnic meta-analysis (using MANTRA software). Replication was sought in 30 582 cases and 226 518 controls from 17 studies. Results: The
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 =...
Data_Sheet_1_Genetic Dissection of Nitrogen Use Efficiency in Tropical Maize Through Genome-Wide Association and Genomic Prediction.xlsx
Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone ...
Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This ...
Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies.For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p|5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of
AbstractMultilocus haplotype analysis of candidate variants with genome wide association studies (GWAS) data may provide evidence of association with disease, even when the individual loci themselves do not. Unfortunately, when a large number of candidate variants are investigated, identifying risk haplotypes can be very difficult. To meet the challenge, a number of approaches have been put forward in recent years. However, most of them are not directly linked to the disease-penetrances of haplotypes and thus may not be efficient. To fill this gap, we propose a mixture model-based approach for detecting risk haplotypes. Under the mixture model, haplotypes are clustered directly according to their estimated disease penetrances. A theoretical justification of the above model is provided. Furthermore, we introduce a hypothesis test for haplotype inheritance patterns which underpin this model. The performance of the proposed approach is evaluated by simulations and real data analysis. The results show that
Abstract Background Recently introduced pathway-based approach is promising and advantageous to improve the efficiency of analyzing genome-wide association scan (GWAS) data to identify disease variants by jointly considering variants of the genes that belong to the same biological pathway. However, the current available pathway-based approaches for analyzing GWAS have limited power and efficiency. Results We proposed a new and efficient permutation strategy based on SNP randomization for determining significance in pathway analysis of GWAS. The developed permutation strategy was evaluated and compared to two previously available methods, i.e. sample permutation and gene permutation, through simulation studies and a study on a real dataset. Results showed that the proposed permutation strategy is more powerful and efficient with greatly reducing the computational complexity. Conclusion Our findings indicate the improved performance of SNP permutation and thus render pathway-based analysis of GWAS ...
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with ...
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