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 ...
To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we
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 …
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts ...
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 ...
Image_6_Genome-Wide Association Studies Reveal Genomic Regions Associated With the Response of Wheat (Triticum aestivum L.) to Mycorrhizae Under Drought Stress Conditions.pdf
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 are set to become the method of choice for uncovering the genetic basis of human diseases. A central challenge in this area is the development of powerful multipoint methods that can detect causal variants that have not been directly genotyped. We propose a coherent analysis framework that treats the problem as one involving missing or uncertain genotypes. Central to our approach is a model-based imputation method for inferring genotypes at observed or unobserved SNPs, leading to improved power over existing methods for multipoint association mapping. Using real genome-wide association study data, we show that our approach (i) is accurate and well calibrated, (ii) provides detailed views of associated regions that facilitate follow-up studies and (iii) can be used to validate and correct data at genotyped markers. A notable future use of our method will be to boost power by combining data from genome-wide scans that use different SNP sets.
The American Association for Cancer Research (AACR) began publishing scientific articles in 1916, and now proudly publishes eight peer-reviewed journals which cover a diverse array of cancer-related topics. The editors from these esteemed journals identify one must read article from each issue, and their picks for the month of August are highlighted below. These featured articles are freely available for a limited time.. Journal: Cancer Epidemiology, Biomarkers & Prevention. A Review of Prostate Cancer Genome-Wide Association Studies (GWAS). This review outlines findings from over 40 prostate cancer genome-wide association studies (GWAS), which have identified approximately 170 common variants. The authors discuss GWAS in non-European populations, GWAS from patients who have received long-term radiotherapy, and the use of common variants to guide a personalized treatment pathway. Furthermore, the authors suggest how this information may be utilized to facilitate the screening and management of ...
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., ...
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) | 0.05) and 2.7 million low-frequency (0.005 | MAF | 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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 ...
Given the success of the first volume Statistical Methods, Computing, and Resources for Genome-Wide Association Studies, we are pleased to launch a second volume for further submissions.Genome-wide association studies (GWAS) have been a powerful tool for genetic discovery in the last decade, leading to identification of numerous genetic variants underlying various characteristics of biological, agronomic, or ecological importance in plants, animals, and humans such as human diseases and crop yields. Challenges in GWAS include statistical modelling, computation, and multiplicity of testing. Typically, there exists population stratification or cryptic relatedness as well as other possibly influential factors in GWAS data. Statistical analysis needs to properly handle these factors to control false positives and/or improve power. The linear mixed-effect model, which has been widely used in GWAS, is a great success. A competitive alternative is the Bayesian approach. Computation in GWAS is challenging due
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
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 ...
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 ×
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry includ …
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also ...
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
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 ...
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, ...
Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P | 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the
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)).
Eye pigmentation abnormalities in cattle are often related to albinism, Chediak-Higashi or Tietz like syndrome. However, mutations only affecting pigmentation of coat color and eye have also been described. Herein 18 Holstein Friesian cattle affected by bicolored and hypopigmented irises have been investigated. Affected animals did not reveal any ophthalmological or neurological abnormalities besides the specific iris color differences. Coat color of affected cattle did not differ from controls. Histological examination revealed a reduction of melanin pigment in the iridal anterior border layer and stroma in cases as cause of iris hypopigmentation. To analyze the genetics of the iris pigmentation differences, a genome-wide association study was performed using Illumina BovineSNP50 BeadChip genotypes of the 18 cases and 172 randomly chosen control animals. A significant association on bovine chromosome 8 (BTA8) was identified at position 60,990,733 with a -log10(p) = 9.17. Analysis of genotypic and
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...
in Nature Genetics (2019), 51(3), 414. Risk for late-onset Alzheimers disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of ... [more ▼]. Risk for late-onset Alzheimers disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimers or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor ...
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 ...
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
The genome-wide association study (GWAS) publications listed here include a primary GWAS analysis, defined as array-based genotyping and analysis of 100,000+ pre-QC SNPs selected to tag variation across the genome and without regard to gene content. GWAS data from published studies which are incorporated into new GWAS analyses are eligible, provided they meet the other criteria. Studies imputing sequencing data to genotyping arrays are eligible as long as the arrays include sufficient genome-wide coverage so that the post-imputation analysis meets the definition of a GWAS analysis, as described above. Customized gene-based arrays without a clearly described GWAS backbone, including those selected to replicate published GWAS findings (e.g., Metabochip, Immunochip, etc.) are not eligible. Publications are organized from most to least recent date of publication, indexing from online publication if available. Studies are identified through weekly PubMed literature searches, daily NIH-distributed ...
The genome-wide association study (GWAS) publications listed here include a primary GWAS analysis, defined as array-based genotyping and analysis of 100,000+ pre-QC SNPs selected to tag variation across the genome and without regard to gene content. GWAS data from published studies which are incorporated into new GWAS analyses are eligible, provided they meet the other criteria. Studies imputing sequencing data to genotyping arrays are eligible as long as the arrays include sufficient genome-wide coverage so that the post-imputation analysis meets the definition of a GWAS analysis, as described above. Customized gene-based arrays without a clearly described GWAS backbone, including those selected to replicate published GWAS findings (e.g., Metabochip, Immunochip, etc.) are not eligible. Publications are organized from most to least recent date of publication, indexing from online publication if available. Studies are identified through weekly PubMed literature searches, daily NIH-distributed ...
The American Beech tree (Fagus grandifolia Ehrh.), native to eastern North America, is ecologically important and provides high quality wood products. This species is susceptible to beech bark disease (BBD) and is facing high rates of mortality in North America. The disease occurs from an interaction between the woolly beech scale insect (Cryptococcus fagisuga), one of two species of the fungus Neonectria (N. faginata or N. ditissima), and American Beech trees. In this case-control genome-wide association study (GWAS), we tested 16 K high quality SNPs using the Affymetrix Axiom 1.5 K - 50 K assay to genotype an association population of 514 individuals. We also conducted linkage analysis in a full-sib family of 115 individuals. Fishers exact test and logistic regression tests were performed to test associations between SNPs and phenotypes. Association tests revealed four highly significant SNPs on chromosome (Chr) 5 for a single gene (Mt), which encodes a mRNA for metallothionein-like protein (metal
Purpose: Previous genome-wide association study (GWAS) of keratoconus in a US-based Caucasian population reported 15 potentially associated single nucleotide polymorphisms (SNPs) from 13 distinct loci. A replication study of the GWAS findings in an Australian Caucasian population showed significant association (p,0.05) in SNPs in KCND3, RAB3GAP1, UBXD2, IMMP2L, and 13q33.3 loci. In this study, we sought to replicate the GWAS findings in East Asian populations.. Methods: Six hundred and thirty-nine Japanese samples (179 keratoconus cases and 460 controls) and 419 Korean samples (190 keratoconus cases and 229 controls) were recruited. We genotyped 15 SNPs reported in the previous GWAS using TaqMan assay. Association analysis was performed in SNP & Variation Suite 8.2.1. A meta-analysis combining the Japanese and Korean populations was performed using the Mantel-Haenszel method.. Results: The significant association was observed for rs6792542 in 3q26.2 in the meta-analysis (meta-p=0.00095: p=0.0025 ...
1958BC: Statistical analyses were funded by the Academy of Finland (Project 24300796 and SALVE/PREVMEDSYN). DNA collection was funded by MRC grant G0000934 and cell-line creation by Wellcome Trust grant 068545/Z/02. This research used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of investigators who contributed to generation of the data is available from the Wellcome Trust Case-Control Consortium website. Funding for the project was provided by the Wellcome Trust under the award 076113. Great Ormond Street ...
TY - JOUR. T1 - Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy. AU - Ghesquieres, Hervé. AU - Slager, Susan L.. AU - Jardin, Fabrice. AU - Veron, Amelie S.. AU - Asmann, Yan W.. AU - Maurer, Matthew J.. AU - Fest, Thierry. AU - Habermann, Thomas M.. AU - Bene, Marie C.. AU - Novak, Anne J.. AU - Mareschal, Sylvain. AU - Haioun, Corinne. AU - Lamy, Thierry. AU - Ansell, Stephen M.. AU - Tilly, Herve. AU - Witzig, Thomas E.. AU - Weiner, George J.. AU - Feldman, Andrew L.. AU - Dogan, Ahmet. AU - Cunningham, Julie M.. AU - Olswold, Curtis L.. AU - Molina, Thierry Jo. AU - Link, Brian K.. AU - Milpied, Noel. AU - Cox, David G.. AU - Salles, Gilles A.. AU - Cerhan, James R.. PY - 2015/11/20. Y1 - 2015/11/20. N2 - Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted ...
Introduction: Sudden Cardiac Death (SCD) is a complex trait with an established genetic component and recent genome-wide association studies have identified novel loci associated with SCD. However, identified DNA variants explain relatively little of the overall risk of SCD, suggesting that additional loci remain to be discovered. We hypothesized that use of the MetaboChip custom array would facilitate the discovery of novel genes involved in mechanisms of SCD.. Methods: The MetaboChip custom array includes common and rare DNA variants previously associated with cardiovascular, anthropometric and metabolic traits. We conducted a case-control association study of 119,160 SNPs in 948 SCD cases from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 coronary artery disease controls (CAD) from the Wellcome Trust Case-Control Consortium (WTCCC). Association analyses were performed using logistic regression assuming an additive genetic model adjusting for age, sex and the first 3 ...
TY - JOUR. T1 - Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. AU - Thompson, Alexander J.. AU - Clark, Paul J.. AU - Singh, Abanish. AU - Ge, Dongliang. AU - Fellay, Jacques. AU - Zhu, Mingfu. AU - Zhu, Qianqian. AU - Urban, Thomas J.. AU - Patel, Keyur. AU - Tillmann, Hans L.. AU - Naggie, Susanna. AU - Afdhal, Nezam H.. AU - Jacobson, Ira M.. AU - Esteban, Rafael. AU - Poordad, Fred. AU - Lawitz, Eric J.. AU - McCone, Jonathan. AU - Shiffman, Mitchell L.. AU - Galler, Greg W.. AU - King, John W.. AU - Kwo, Paul Y.. AU - Shianna, Kevin V.. AU - Noviello, Stephanie. AU - Pedicone, Lisa D.. AU - Brass, Clifford A.. AU - Albrecht, Janice K.. AU - Sulkowski, Mark S.. AU - Goldstein, David B.. AU - McHutchison, John G.. AU - Muir, Andrew J.. PY - 2012/2/1. Y1 - 2012/2/1. N2 - Background & Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 ...
Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance ...
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 x 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the ...
Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value|2.2×10(-9)),
Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids $$(smallest P-value = 9.88×10^{−204})$$ and 10 loci for sphingolipids $$(smallest P-value = 3.10 \times 10^{-57})$$. After a correction for multiple ...
BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of studyspecific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ...
Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the ...
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of |12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P | 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency |0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
|jats:title|Abstract|/jats:title||jats:sec||jats:title|Background|/jats:title||jats:p|Varicose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around \$14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.|/jats:p||/jats:sec||jats:sec||jats:title|Methods|/jats:title||jats:p|We performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111
The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes - especially southern Swedes - were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced genetic differences both within the area and relative to the rest of the country. These distinctive genetic features of
Lung cancer is a common malignant tumor including Small Cell Lung Cancer (SCLC) with 10 - 15 % and Non-Small Cell Lung Cancer (NSCLC) with 70 - 80%. Currently, there are several approaches to be used to treat lung cancer including surgery, chemotherapy, radiation therapy and molecular therapy/immunotherapy, Metastatic SCLC, metastatic mixed type of lung cancer and unclassified lung cancer are still difficult to be cured because this kind of lung cancer is easy to be widely disseminated. For example, if a patient has several metastatic SCLC, the patient will reveal poor outcome. In order to resolve the poor prognosis with recurrent and metastatic SCLC, here we reported a pathway-based approaches for analysis of Genome-Wide Association Studies (GWAS) to screen drugs, hence we used the drugs to treat a patient suffering from SCLC with multiple metastases. In the beginning, we harvested a pair of SCLC cells and normal cells from FFPE samples under laser capture microscopy to achieve the tumor cell DNA for
...LEXINGTON Ky. (April 29 2014) -- A genome-wide association study (G...Researchers from 16 different institutions compared 363 persons with a...Dr. Nelson and his team found that small changes in the ABCC9 gene -- ... This is the first genome-wide association study of its kind and it h...,GWAS,study,ties,ABCC9,anomalies,,sulfonylurea,exposure,to,HS-Aging,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters
A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis Academic Article ...
TY - JOUR. T1 - Genome-wide association study identifies CDH13 as a susceptibility gene for rhododendrol-induced leukoderma. AU - Okamura, Ken. AU - Abe, Yuko. AU - Naka, Izumi. AU - Ohashi, Jun. AU - Yagami, Akiko. AU - Matsunaga, Kayoko. AU - Kobayashi, Yui. AU - Fukai, Kazuyoshi. AU - Tanemura, Atsushi. AU - Katayama, Ichiro. AU - Masui, Yukiko. AU - Ito, Akiko. AU - Yamashita, Toshiharu. AU - Nagai, Hiroshi. AU - Nishigori, Chikako. AU - Oiso, Naoki. AU - Aoyama, Yumi. AU - Araki, Yuta. AU - Saito, Toru. AU - Hayashi, Masahiro. AU - Hozumi, Yutaka. AU - Suzuki, Tamio. N1 - Funding Information: We are grateful to the patients with RIL and volunteers for providing saliva samples. We also thank Dr. M. Kondo, Biological Science Research, Kao Corporation, for his excellent technical advice. This work was supported by JSPS KAKENHI Grant Number JP16K10123, and in part, by Research Fund for Rhododenol‐induced leukoderma. Publisher Copyright: © 2020 John Wiley & Sons A/S. Published by John Wiley & ...
Accumulated to-date gene microarray data on Acute Respiratory Distress Syndrome (ARDS) in the Gene Expression Omnibus (GEO) represent a rich source for identifying new unsuspected targets and mechanisms of ARDS. The recently developed expression-based genome-wide association study (eGWAS) for analysis of GEO data was successfully used for analysis of gene expression of comparatively noncomplex adipose tissue, 75 % of which is represented by adipocytes. Although lung tissue is more heterogenic and does not possess a prevalent cell type for driving gene expression patterns, we hypothesized that eGWAS of ARDS samples will generate biologically meaningful results. The eGWAS was conducted according to (Proc Natl Acad Sci U S A 109:7049-7054, 2012) and genes were ranked according to p values of chi-square test. The search of GEO retrieved 487 ARDS related entries. These entries were filtered for multiple qualitative and quantitative conditions and 219 samples were selected: mouse nsham/ARDS = 67/92, rat n =
An exome sequencing based approach for genome-wide association studies in the dog: Genome-wide association studies (GWAS) are widely used to identify loci assoc
Introduction. Atrial fibrillation (AF) is a common arrhythmia in humans and a major cause of morbidity and mortality. We have previously reported a genome-wide study identifying sequence variants on chromosome 4q25 that confer risk of AF. We have now expanded our cohort for genome-wide association stud, in the attempt to discover additional variants that associate with the common forms of AF.. Methods. A sample set of 2,385 Icelandic patients with AF and/or atrial flutter (AFl) and 33,752 Icelandic population controls were genotyped with the Illumina HumanHap300 and HumanHapCNV370 bead chips, yielding 304,226 SNPs that were tested individually for association. Of the top ten SNPs, seven represented the previously discovered signal on chromosome 4q25. The remaining three SNPs were genotyped in three replication cohorts of European descent, from Iceland (989 cases and 2,027 controls), Norway (725 cases and 725 controls) and the United States (735 cases and 729 controls).. Results. One SNP, ...
Largest genome-wide association study of an infectious disease. In the first genome-wide association study (GWAS) of leprosy and the largest GWAS on an infectious disease, scientists at the Genome Institute of Singapore (GIS) and 26 institutes in China identified seven genes that increase an individuals susceptibility to leprosy.. The discovery of these genes, reported in the 16 Dec. 2009 New England Journal of Medicine, highlights the important role of the innate immune response in the development of leprosy, said the scientists, who analyzed over 10,000 samples from leprosy patients and healthy controls in China.. Though leprosy is not common, the discoveries have significant ramifications for chronic infectious disorders and for host-pathogen interactions in other more prevalent mycobacterial diseases such as tuberculosis, said Edison Liu, M.D., Executive Director of GIS, one of the research institutes sponsored by Singapores Agency for Science, Technology and Research (A*STAR).. This ...
Genome-wide association (GWA) has been used as a tool for dissecting the genetic architecture of quantitatively inherited traits. We demonstrate here that GWA can also be highly useful for detecting many major genes governing categorically defined phenotype variants that exist for qualitatively inherited traits in a germplasm collection. Genome-wide association mapping was applied to categorical phenotypic data available for 10 descriptive traits in a collection of ∼13,000 soybean [ (L.) Merr.] accessions that had been genotyped with a 50,000 single nucleotide polymorphism (SNP) chip. A GWA on a panel of accessions of this magnitude can offer substantial statistical power and mapping resolution, and we found that GWA mapping resulted in the identification of strong SNP signals for 24 classical genes as well as several heretofore unknown genes controlling the phenotypic variants in those traits. Because some of these genes had been cloned, we were able to show that the narrow GWA mapping SNP ...
Conference Paper: Pathway analysis of genome-wide association data on hepatocellular carcinoma in southern Chinese patients with chronic hepatitis B virus ...
Multiple sclerosis (MS) is a genetically complex disease that shares a substantial proportion of risk loci with other autoimmune diseases.1 Along these lines, ANKRD55, originally implicated in rheumatoid arthritis, was recently reported as a potential novel MS risk gene (rs6859219, p=1.9×10−7).2 Here, we comprehensively validated this effect in independent datasets comprising 8846 newly genotyped subjects from Germany and France as well as 5003 subjects from two genome-wide association studies (GWAS). Upon meta-analysis of all available data (19 686 subjects), ANKRD55 rs6859219 now shows compelling evidence for association with MS at genome-wide significance (OR=1.19, p=3.1×10−11). Our study adds ANKRD55 to the list of established MS risk loci and extends previous evidence suggesting an overlapping genetic foundation across autoimmune diseases.. Ankyrin repeats are abundant in a large number of different proteins in humans and mediate protein-protein interactions. DNA-sequence variants in ...
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases ...
en] OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 x 10(-11); odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations ...
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P , 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P , 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P , 0.05: ...
Background: The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment. Methods: We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with ...
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54…
Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/or sequences covaried with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance- associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hairlike organs distributed
TY - JOUR. T1 - The Basic Science of Dupuytren Disease. AU - Zhang, Andrew Y.. AU - Kargel, Jennifer S.. PY - 2018/1/1. Y1 - 2018/1/1. N2 - Dupuytren disease is a fibroproliferative condition affecting the hands of millions of patients worldwide. The hypothesis of pathogenesis involves genetic factors and internal factors. Recent genome-wide association studies have provided much needed evidence for the long-held belief of a strong genetic component to the pathogenesis of Dupuytren disease. Specifically, abnormal activation of the Wnt signaling pathway plays an important role. Regarding internal factors, microvascular angiopathy and ischemia have been shown to lead to activation of transforming growth factor-β1 and proliferation of myofibroblasts.. AB - Dupuytren disease is a fibroproliferative condition affecting the hands of millions of patients worldwide. The hypothesis of pathogenesis involves genetic factors and internal factors. Recent genome-wide association studies have provided much ...