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Carrasquillo, Minerva, Belbin Olivia, Hunter Talisha, et al. "P1-217: Replication of LOAD GWAS Associations." Alzheimer's & Dementia 7 (July 2011): S180—S181. http://dx.doi.org/10.1016/j.jalz.2011.05.496.
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Li, Jin, Qiushi Zhang, Feng Chen, et al. "Genetic Interactions Explain Variance in Cingulate Amyloid Burden: An AV-45 PET Genome-Wide Association and Interaction Study in the ADNI Cohort." BioMed Research International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/647389.
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of “missing heritability.” We performed a genome-wide association study (GWAS) and a genome-wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from Alzheimer’s Disease Neuroimaging Initiative. We investigated the genetic main effects and interaction effects on cingulate amyloid-beta (Aβ) load in an effort to better understand the genetic etiology of Aβdeposition that is a widely studied AD biomarker. PLINK was used in the single marker GWAS, and INTERSNP was used to perform the two-marker GWIS, focusing only on SNPs withp≤0.01for the GWAS analysis. Age, sex, and diagnosis were used as covariates in both analyses. Correctedpvalues using the Bonferroni method were reported. The GWAS analysis revealed significant hits within or proximal toAPOE,APOC1, andTOMM40genes, which were previously implicated in AD. The GWIS analysis yielded 8 novel SNP-SNP interaction findings that warrant replication and further investigation.
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Jia, Yumeng, Xin Qi, Mei Ma, et al. "Integrating genome-wide association study with regulatory SNP annotations identified novel candidate genes for osteoporosis." Bone & Joint Research 12, no. 2 (2023): 147–54. http://dx.doi.org/10.1302/2046-3758.122.bjr-2022-0206.r1.
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AimsOsteoporosis (OP) is a metabolic bone disease, characterized by a decrease in bone mineral density (BMD). However, the research of regulatory variants has been limited for BMD. In this study, we aimed to explore novel regulatory genetic variants associated with BMD.MethodsWe conducted an integrative analysis of BMD genome-wide association study (GWAS) and regulatory single nucleotide polymorphism (rSNP) annotation information. Firstly, the discovery GWAS dataset and replication GWAS dataset were integrated with rSNP annotation database to obtain BMD associated SNP regulatory elements and SNP regulatory element-target gene (E-G) pairs, respectively. Then, the common genes were further subjected to HumanNet v2 to explore the biological effects.ResultsThrough discovery and replication integrative analysis for BMD GWAS and rSNP annotation database, we identified 36 common BMD-associated genes for BMD irrespective of regulatory elements, such as FAM3C (pdiscovery GWAS = 1.21 × 10-25, preplication GWAS = 1.80 × 10-12), CCDC170 (pdiscovery GWAS = 1.23 × 10-11, preplication GWAS = 3.22 × 10-9), and SOX6 (pdiscovery GWAS = 4.41 × 10-15, preplication GWAS = 6.57 × 10-14). Then, for the 36 common target genes, multiple gene ontology (GO) terms were detected for BMD such as positive regulation of cartilage development (p = 9.27 × 10-3) and positive regulation of chondrocyte differentiation (p = 9.27 × 10-3).ConclusionWe explored the potential roles of rSNP in the genetic mechanisms of BMD and identified multiple candidate genes. Our study results support the implication of regulatory genetic variants in the development of OP.Cite this article: Bone Joint Res 2023;12(2):147–154.
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Joo, Jungnam, Ju-Hyun Park, Bora Lee, et al. "Robust Association Tests for the Replication of Genome-Wide Association Studies." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/461593.
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In genome-wide association study (GWAS), robust genetic association tests such as maximum of three CATTs (MAX3), each corresponding to recessive, additive, and dominant genetic models, the minimumpvalue of Pearson’s Chi-square test with 2 degrees of freedom, and CATT based on additive genetic model (MIN2), genetic model selection (GMS), and genetic model exclusion (GME) methods have been shown to provide better power performance under wide range of underlying genetic models. In this paper, we demonstrate how these robust tests can be applied to the replication study of GWAS and how the overall statistical significance can be evaluated using the combined test formed bypvalues of the discovery and replication studies.
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Barnekow, Elin, Wen Liu, Emil Andersson, et al. "A Swedish genome-wide haplotype association analysis identifies novel candidate loci associated with endometrial cancer risk." PLOS ONE 20, no. 3 (2025): e0316086. https://doi.org/10.1371/journal.pone.0316086.
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Genome-wide association studies [GWAS] have identified a limited number of endometrial cancer risk loci by analyzing single nucleotide polymorphisms [SNPs]. We hypothesized that analyzing haplotypes rather than SNPs could provide novel and more detailed information on genetic cancer susceptibility loci. To examine the association of a SNP or haplotype with endometrial cancer risk we performed a two-stage haplotype GWAS. The discovery GWAS included a sub-cohort of 1,116 Swedish endometrial cancer cases and 5,021 controls from previously published GWAS data. A sliding window analysis was employed with window sizes of 1-25 SNPs using a logistic regression model. The Swedish haplotype analysis identified 15 novel candidate risk loci (2q31.1, 4p16.1, 4p15.31, 6q13, 7p21.1, 9p13.3, 10q26.3, 11q21, 12q13.11, 13q12.11, 15q13.3, 16q24.3, 19q13.32, 20p12.3 and 22q13.2) with OR ranging from 1.6 to 3.3 and p-values from 4.25 × 10−8 to 9.86 × 10−15. A second replication haplotype analysis of the Swedish novel loci was performed using two cohorts from Belgium and Germany. In spite of small sample sizes in the replication cohorts, there was still support for most loci with positive ORs. In addition, the findings in the two European cohorts motivates further studies to search for founder haplotypes. These novel findings suggested that endometrial cancer loci, identified through haplotype analysis, conferred a higher risk compared to previous single-variant GWAS.
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Sandoval-Plata, Gabriela, Kevin Morgan, and Abhishek Abhishek. "Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank." Annals of the Rheumatic Diseases 80, no. 9 (2021): 1220–26. http://dx.doi.org/10.1136/annrheumdis-2020-219796.
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ObjectivesTo perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status.MethodsGout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively.ResultsThirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds.ConclusionThe association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.
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Hubacek, Jaroslav A., Vera Adamkova, Vera Lanska, and Dana Dlouha. "Polygenous hypercholesterolemia. Replication of GWAS results on Czech slavonic population." Atherosclerosis 263 (August 2017): e226-e227. http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.739.
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Fan, Xiaoping, Jing Wang, Wen Fan, et al. "Replication of Migraine GWAS Susceptibility Loci in Chinese Han Population." Headache: The Journal of Head and Face Pain 54, no. 4 (2014): 709–15. http://dx.doi.org/10.1111/head.12329.
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Okamoto, D., Y. Kakuta, N. Takeo, et al. "P822 Genetic analysis of ulcerative colitis in Japanese individuals using population-specific SNP array." Journal of Crohn's and Colitis 14, Supplement_1 (2020): S638—S639. http://dx.doi.org/10.1093/ecco-jcc/jjz203.950.
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Abstract Background Previous genome wide association studies (GWASs) have identified over 200 susceptibility loci for inflammatory bowel diseases (IBD), but studies in non-European population are limited. To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted GWAS using a population specific SNP array (Japonica Array). Methods Discovery GWAS included 624 UC patients and 2004 healthy controls (HC) and replication study included 1075 UC patients and 419 HCs. We performed GWAS using a Japonica Array and the subsequent imputation with a Japanese population reference panel (referred to as 2KJPN). After GWAS, significant and candidate loci were identified and the representative top SNPs of each region were analysed in replication study and combined analysis. The probability of colectomy between genotypes of rs117506082, the top hit SNP at HLA loci, was analysed using the Kaplan–Meier method. Results In the GWAS, only the HLA loci showed genome wide significant association [rs117506082, p = 6.69E−28, OR=1.29, 95%CI=1.23–1.35]. 7 regions with nominal significance included 2 known loci: IL23R [rs76418789, p = 6.29E−7, OR=0.89, 95%CI=0.85–0.93], IRF8 [rs16940202, p = 1.03E−6, OR=1.07, 95%CI=1.04–1.10] and 5 novel loci: miR-622 [rs9560575, p = 8.23E−7, OR=1.06, 95%CI=1.04–1.09], 14q31 [rs117618617, p = 1.53E−6, OR=1.13, 95%CI=1.09–1.19], KAT6B [rs12260609, p = 1.81E−6, OR=1.06, 95%CI=1.04–1.09], PAX3-CCDC140-SGPP2 [rs7589797, p = 2.87E−6, OR=0.94, 95%CI=0.93–0.97], KCNA2 [rs118020656, p = 4.01E−6, OR=1.12, 95%CI=1.07–1.18]. Combined analysis revealed that the HLA loci [rs117506082, p = 1.10E−23, OR=3.43, 95%CI=2.99–3.83] and IL23R p.G149R [rs76418789, p = 9.03E−11, OR=0.51, 95%CI=0.42–0.63] had a genome wide significant association. The GG genotype of rs117506082 had a significantly lower probability for total colectomy compared with the GA+AA genotype (p = 1.72E−2). Conclusion IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci, a risk genotype for UC susceptibility, may predict a better clinical course.
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Yu, Xinting, and Shisong Rong. "Genome-Wide Associations and Confirmatory Meta-Analyses in Diabetic Retinopathy." Genes 14, no. 3 (2023): 653. http://dx.doi.org/10.3390/genes14030653.
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The present study aimed to summarize and validate the genomic association signals for diabetic retinopathy (DR), proliferative DR, and diabetic macular edema/diabetic maculopathy. A systematic search of the genome-wide association study (GWAS) catalog and PubMed/MELINE databases was conducted to curate a comprehensive list of significant GWAS discoveries. The top signals were then subjected to meta-analysis using established protocols. The results indicate the need for improved consensus among DR GWASs, highlighting the importance of validation efforts. A subsequent meta-analysis confirmed the association of two SNPs, rs4462262 (ZWINT-MRPS35P3) (odds ratio = 1.38, p = 0.001) and rs7903146 (TCF7L2) (odd ratio = 1.30, p < 0.001), with DR in independent populations, strengthening the evidence of their true association. We also compiled a list of candidate SNPs for further validation. This study highlights the importance of consistent validation and replication efforts in the field of DR genetics. The two identified gene loci warrant further functional investigation to understand their role in DR pathogenesis.
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Kleinstern, Geffen, Huihuang Yan, Michelle A. T. Hildebrandt, et al. "Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways." Human Molecular Genetics 29, no. 1 (2019): 70–79. http://dx.doi.org/10.1093/hmg/ddz228.
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Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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Tkachenko, Alexander A., Anton I. Changalidis, Evgeniia M. Maksiutenko, Yulia A. Nasykhova, Yury A. Barbitoff, and Andrey S. Glotov. "Replication of Known and Identification of Novel Associations in Biobank-Scale Datasets: A Survey Using UK Biobank and FinnGen." Genes 15, no. 7 (2024): 931. http://dx.doi.org/10.3390/genes15070931.
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Over the last two decades, numerous genome-wide association studies (GWAS) have been performed to unveil the genetic architecture of human complex traits. Despite multiple efforts aimed at the trans-biobank integration of GWAS results, no systematic analysis of the variant-level properties affecting the replication of known associations (or identifying novel ones) in genome-wide meta-analysis has yet been performed using biobank-scale data. To address this issue, we performed a systematic comparison of GWAS summary statistics for 679 complex traits in the UK Biobank (UKB) and FinnGen (FG) cohorts. We identified 37,148 index variants with genome-wide associations with at least one trait in either cohort or in the meta-analysis, only 3528 (9.5%) of which were shared between UKB and FG. Nearly twice as many variants (6577) were replicated in another dataset at the significance level adjusted for the number of variants selected for replication. However, as many as 9230 loci failed to be replicated. Moreover, as many as 5813 loci were observed as significant associations only in meta-analysis results, highlighting the importance of trans-biobank meta-analysis efforts. We showed that variants that failed to replicate in UKB or FG tend to correspond to rare, less pleiotropic variants with lower effect sizes and lower LD score values. Genome-wide associations specific to meta-analysis were also enriched in low-effect variants; however, such variants tended to be more common and have more consistent frequencies between populations. Taken together, our results show a relatively high rate of non-replication of genome-wide associations in the studied cohorts and highlight both widely appreciated and less acknowledged properties of the associations affecting their identification and replication.
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Demirkan, A., J. Lahti, N. Direk, et al. "Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies." Psychological Medicine 46, no. 8 (2016): 1613–23. http://dx.doi.org/10.1017/s0033291715002081.
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BackgroundMajor depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.MethodWe performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).ResultsOne single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.ConclusionsDespite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
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Sato, Youichi, Atsushi Tajima, Takehiro Sato, et al. "Genome-wide association study identifies ERBB4 on 2q34 as a novel locus associated with sperm motility in Japanese men." Journal of Medical Genetics 55, no. 6 (2018): 415–21. http://dx.doi.org/10.1136/jmedgenet-2017-104991.
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BackgroundThe decrease in sperm motility has a potent influence on fertilisation. Sperm motility, represented as the percentage of motile sperm in ejaculated sperms, is influenced by lifestyle habits or environmental factors and by inherited factors. However, genetic factors contributing to individual differences in sperm motility remain unclear. To identify genetic factors that influence human sperm motility, we performed a genome-wide association study (GWAS) of sperm motility.MethodsA two-stage GWAS was conducted using 811 Japanese men in a discovery stage, followed by a replication study using an additional 779 Japanese men.ResultsIn the two-staged GWAS, a single nucleotide polymorphism rs3791686 in the intron of gene for erb-b2 receptor tyrosine kinase 4 (ERBB4) on chromosome 2q34 was identified as a novel locus for sperm motility, as evident from the discovery and replication results using meta-analysis (β=−4.01, combined P=5.40×10−9).ConclusionsTogether with the previous evidence that Sertoli cell-specific Erbb4-knockout mice display an impaired ability to produce motile sperm, this finding provides the first genetic evidence for further investigation of the genome-wide significant association at the ERBB4 locus in larger studies across diverse human populations.
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Hadjigeorgiou, Georgios M., Persia-Maria Kountra, Georgios Koutsis, et al. "Replication study of GWAS risk loci in Greek multiple sclerosis patients." Neurological Sciences 40, no. 2 (2018): 253–60. http://dx.doi.org/10.1007/s10072-018-3617-6.
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Schafmayer, Clemens, James William Harrison, Stephan Buch, et al. "Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms." Gut 68, no. 5 (2019): 854–65. http://dx.doi.org/10.1136/gutjnl-2018-317619.
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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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Thibord, Florian, Derek Klarin, Jennifer A. Brody, et al. "Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors." Circulation 146, no. 16 (2022): 1225–42. http://dx.doi.org/10.1161/circulationaha.122.059675.
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Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
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Thio, Chris H. L., Anna Reznichenko, Peter J. van der Most, et al. "Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci." American Journal of Nephrology 49, no. 3 (2019): 193–202. http://dx.doi.org/10.1159/000496930.
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Background: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. Methods: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. Results: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. Conclusions: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.
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Koller, Daniel L., Shoji Ichikawa, Dongbing Lai, et al. "Genome-Wide Association Study of Bone Mineral Density in Premenopausal European-American Women and Replication in African-American Women." Journal of Clinical Endocrinology & Metabolism 95, no. 4 (2010): 1802–9. http://dx.doi.org/10.1210/jc.2009-1903.
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Abstract Context: Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men. Objective: The objective of the study was to identify genes contributing to BMD in premenopausal women. Design: GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African-American (AA) women. Subjects: Subjects included 1524 premenopausal EA women aged 20–45 yr from 762 sibships and 669 AA premenopausal women aged 20–44 yr from 383 sibships. Interventions: There were no interventions. Main Outcome Measures: BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation. Results: SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 × 10−5; rs1285635, P = 3.0 × 10−5) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS. Conclusions: Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women.
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Bartram, Thies, Peter Schütte, Anja Möricke, et al. "Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia." Journal of Clinical Medicine 10, no. 21 (2021): 4815. http://dx.doi.org/10.3390/jcm10214815.
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Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.
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Wong, Gunther, Xavier Bledsoe, Eric Gamazon, and Rohan V. Chitale. "280 A Transcriptome-Wide Association Study of Intracranial Aneurysm Identifies Novel Risk Genes and Overlapping Genetic Architecture With Other Vascular Disorders." Neurosurgery 71, Supplement_1 (2025): 68. https://doi.org/10.1227/neu.0000000000003360_280.
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INTRODUCTION: Intracranial aneurysms (IAs) are common cerebrovascular lesions with well-documented heritability. Numerous genome-wide association studies (GWAS) have attempted to define IA genetic architecture. However, linking individual risk SNPs from these studies to genes and causal pathways is challenging. To address this, transcriptome-wide association studies (TWAS) directly analyze gene-trait associations. METHODS: We conducted a two-stage TWAS using summary-level GWAS. The discovery cohort was European (GWAS from Bakker et al) and the replication cohort was Japanese (GWAS from Sakaue et al). S-PrediXcan and MASHR-based eQTLs from GTEx v8 were used. We corrected for multiple testing using a study-wide Benjamini-Hochberg FDR <0.05 for each TWAS and for replication. We used less stringent criteria for gene set analysis (GSA) by including genes replicated at a nominal p-value (0.05). GSA was conducted using gene ontology (GO) and a literature review. Additionally, we explored the pleiotropic effects of IA risk genes in other vascular and neurological pathologies, using existing GWAS summary statistics. RESULTS: We identified 20 significant risk genes for IA replicated between cohorts, 12 of which are novel. We used an expanded set of 31 risk genes for GSA. Vascular processes were highly enriched in GO, including vascular smooth muscle function and endothelin signaling. Using GO and literature review, we divided risk genes into five broad categories: vascular function, endothelin signaling, adherens junctions, magnesium levels, and smoking risk. IA risk genes were highly pleiotropic across other vascular and neurological pathologies including, notably, in schizophrenia, migraine, and age-related macular degeneration (AMD). CONCLUSIONS: We conducted the largest TWAS of IA to date, finding 12 novel risk genes and validating 8 previously identified risk genes. We provide plausible causal mechanisms for many of these genes. Finally, we present the first implication of shared genetic architecture between IA and schizophrenia, AMD, and migraine.
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Li-Gao, Ruifang, Salma M. Wakil, Brian F. Meyer, Nduna Dzimiri, and Dennis O. Mook-Kanamori. "Replication of Type 2 diabetes-associated variants in a Saudi Arabian population." Physiological Genomics 50, no. 4 (2018): 296–97. http://dx.doi.org/10.1152/physiolgenomics.00100.2017.
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Over 120 Type 2 diabetes (T2D) loci have been identified from genome-wide association studies (GWAS), mainly from Caucasian populations. Very limited knowledge is available on the Saudi Arabian population. In this study, 122 previously reported T2D-related variants from 84 loci were examined in a Saudi Arabian cohort of 1,578 individuals (659 T2D cases and 919 controls). Eleven single nucleotide polymorphisms (SNPs) corresponding to nine independent loci had a P value <0.05. If a more stringent Bonferroni threshold of P = 4.1 × 10−4 ( = 0.05/122) were applied, none of the SNPs would have reached the significance level. Nine of the SNPs with a P value <0.05 showed similar odds ratios as previously described, but rs11605924 ( CRY2) and rs9470794 ( ZFAND3) were in the opposite direction. This study demonstrates the importance of large-scale GWAS in the Saudi Arabian population to identify ethnicity-specific disease-associated variants.
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McLaren, Christine E., Chad P. Garner, Clare C. Constantine, et al. "Genome-Wide Association Study Identifies Genetic Loci Associated with Iron Deficiency." Blood 114, no. 22 (2009): 4048. http://dx.doi.org/10.1182/blood.v114.22.4048.4048.
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Abstract Abstract 4048 Poster Board III-983 Introduction Iron deficiency is the most common nutritional disorder in the world with an estimated two billion affected persons. Although commonly considered environmental in origin, the existence of multiple genetic disorders of iron metabolism in man, rodents and other vertebrates suggest a genetic contribution to iron deficiency. Methods: The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. To identify genomic locations associated with iron deficiency, we performed a genome-wide association study (GWAS) using DNA collected from white HEIRS Study participants who had SF ≤ 12 μg/L (cases) and an equal number of white controls (SF > 100 μg/L in men, SF > 50 μg/L in women) frequency-matched to cases by sex and geographic location. Men aged ≥ 25 y and women ≥ 50 y were included in both groups. Tissue body iron, an index of iron deficiency, was estimated from serum transferrin receptor (sTfR) and SF. Genotyping was performed with the Illumina HumanCNV370K Beadchip platform. Quality control filters excluded single nucleotide polymorphisms (SNPs) or samples with > 5% missing genotypes, SNPs showing heterozygosity or Hardy-Weinberg deviations (P<10−7), and SNPs with minor allele frequency < 0.02. Population admixture/structure was assessed using principal component analysis. Regression analysis was used to examine the association between outcomes (case-control status, tissue body iron, serum ferritin, transferrin receptor, serum iron, total iron-binding capacity [TIBC], and unsaturated iron-binding capacity [UIBC]) and each SNP genotype variable; covariates included age, sex, and geographic location. Replication for 56 SNPs was conducted in a population attending primary care clinics at a Veterans Affairs (VA) medical center using the iPlex platform. Eligibility within the VA replication population was restricted to age and self-reported white ethnicity as for the HEIRS subset from a total of 2559 people (138 women). VA participants with SF ≤ 20 μg/L were classified as iron-deficient cases and frequency matched 1:2 with controls (men with SF > 100 μg/L and women with SF > 50 μg/L). Results The GWAS genomic control parameter was not significantly different from 1.0. There were 392 cases (96 men) and 390 controls (96 men) in the HEIRS subset GWAS with average age (SD) of 59 (10) y and 61 (11) y, respectively. Geometric mean SF (minimum, maximum), and mean (SD) for sTfR and tissue body iron in the HEIRS subset were 7.5 (1.2, 12) μg/L, 6.4 (3.77) mg/kg and -2.0 (2.50) for cases and 141 (51, 881) μg/L, 3.0 (0.98) mg/kg and 10.8 (2.5) for controls. After quality control tests, GWAS analysis included genotype data for 331,060 SNPs in 734 individuals (364 cases, 370 controls). For the VA replication population there were 67 male and 11 female cases, and 136 male and 27 female controls for whom DNA was successfully prepared; the average age (SD) was 68 (12) y for cases and 65 (11) y for controls. Regression analysis identified seven SNPs within four independent regions that replicated associations found in the GWAS (GWAS P<1×10-4 and VA P<0.05).The SNP rs6735681 on chromosome 2p24 was associated with serum iron (GWAS P<3.9×10-5, VA P=0.038). Three SNPs on chromosome 2p14 (rs6750096, rs2698541 and rs2698530) significantly influenced both TIBC and UIBC (GWAS P<2.9×10-5, VA P< 0.04 for all). Two SNPs in the TF gene region on chromosome 3q22 also showed significant effects on TIBC and UIBC (GWAS P<4.7×10-6, VA P<0.03 for all). The SNP rs10512064 on chromosome 9q21 was associated with serum ferritin concentration and tissue body iron (GWAS P<2.5×10-5, VA P<0.05 for both). Conclusion: From these GWAS and replication studies, we have identified three new genetic loci and one known iron gene, TF, associated with iron phenotype variability. These results point to specific loci as targets for gene identification and TF polymorphisms as determinants of iron metabolism, which in turn may play a role in regulation of body iron status. Disclosures: No relevant conflicts of interest to declare.
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Márquez, Ana, Laura Vidal-Bralo, Luis Rodríguez-Rodríguez, et al. "A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus." Annals of the Rheumatic Diseases 76, no. 1 (2016): 286–94. http://dx.doi.org/10.1136/annrheumdis-2016-209436.
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ObjectivesDuring the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE.MethodsWe performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls.ResultsThe rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E−13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein–protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE.ConclusionsIn conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.
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Pastor, P. "Genetic heterogeneity in Parkinson disease: The meaning of GWAS and replication studies." Neurology 79, no. 7 (2012): 619–20. http://dx.doi.org/10.1212/wnl.0b013e318264e3d2.
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Albertsen, H., R. Chettier, P. Farrington, and K. Ward. "Replication of endometriosis GWAS signal across multiple studies support involvement of WNT4." Fertility and Sterility 98, no. 3 (2012): S220. http://dx.doi.org/10.1016/j.fertnstert.2012.07.1153.
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Montgomery, Grant W. "Commentary: lessons from molecular genetic studies on reporting false-positive results." Reproduction, Fertility and Development 32, no. 16 (2020): 1298. http://dx.doi.org/10.1071/rd20281.
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Poor replication of published research results is the subject of debate. A common problem is the failure to adequately account for multiple testing issues. In this regard, the evolution of mapping studies to identify genetic risk factors for common diseases has been instructive. Large genome-wide association studies (GWAS) reliably detect the genetic factors with small effects that contribute to risk for many common diseases. GWAS superseded candidate gene studies from the previous decade and looking back, almost no genetic risk factors reported from earlier candidate gene studies replicate in the GWAS results. Candidate gene studies often used small samples and failed to appreciate and adequately account for the multiple testing issues. The failure to replicate results from most candidate gene studies highlights the importance of study power and appropriate statistical analysis to prevent publication of false-positive results.
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Ebejer, Jane L., David L. Duffy, Julius van der Werf, et al. "Genome-Wide Association Study of Inattention and Hyperactivity–Impulsivity Measured as Quantitative Traits." Twin Research and Human Genetics 16, no. 2 (2013): 560–74. http://dx.doi.org/10.1017/thg.2013.12.
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Genome-wide association studies (GWAS) of attention-deficit/hyperactivity disorder (ADHD) offer the benefit of a hypothesis-free approach to measuring the quantitative effect of genetic variants on affection status. Generally the findings of GWAS relying on ADHD status have been non-significant, but the one study using quantitative measures of symptoms found SLC9A9 and SLC6A1 were associated with inattention and hyperactivity–impulsivity. Accordingly, we performed a GWAS using quantitative measures of each ADHD subtype measured with the Strengths and Weaknesses of ADHD and Normal Behaviour (SWAN) scale in two community-based samples. This scale captures the full range of attention and kinetic behavior; from high levels of attention and appropriate activity to the inattention and hyperactivity–impulsivity associated with ADHD within two community-based samples. Our discovery sample comprised 1,851 participants (mean age = 22.8 years [4.8]; 50.6% female), while our replication sample comprised 155 participants (mean age = 26.3 years [3.1]; 68.4% females). Age, sex, age × sex, and age2 were included as covariates and the results from each sample were combined using meta-analysis, then analyzed with a gene-based test to estimate the combined effect of markers within genes. We compare our results with markers that have previously been found to have a strong association with ADHD symptoms. Neither the GWAS nor subsequent meta-analyses yielded genome-wide significant results; the strongest effect was observed at rs2110267 (4.62 × 10−7) for symptoms of hyperactivity–impulsivity. The strongest effect in the gene-based test was for GPR139 on symptoms of inattention (6.40 × 10−5). Replication of this study with larger samples will add to our understanding of the genetic etiology of ADHD.
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Kazantseva, A. V., Yu D. Davydova, R. F. Enikeeva, et al. "Replication Study of GWAS-Associated Variants in the <i>TUFM</i>, <i>SH2B1</i>, <i>ZNF638</i>, <i>NEGR1</i>, <i>ATP2A1</i>, <i>EXOC4</i>, and <i>CSE1L</i> Genes and Cognitive Abilities." Генетика 59, no. 9 (2023): 1059–69. http://dx.doi.org/10.31857/s0016675823090060.
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To date, a large number of genome-wide association analyses (GWAS) of cognitive abilities (i.e. intelligence, educational level, executive functions, etc.) have been conducted in European populations. A replication analysis of GWAS-associated variants of the general factor of intelligence in the development of spatial (3D) abilities in the individuals from Russia is relevant. In order to estimate the main effect of the most significant GWAS loci on spatial abilities in the Russian cohort (N = 1011, 18–25 years old) a set of seven “top” SNPs (p 10–13) was formed: TUFM rs7187776, SH2B1 rs7198606, ZNF638 rs2287326, NEGR1 rs12128707, ATP2A1 rs8055138, EXOC4 rs1362739, and CSE1L rs6063353. Statistically significant differences (р 0.05) in genotype frequencies distribution of ATP2A1 rs8055138, NEGR1 rs12128707, and ZNF638 rs2287326 between Russians, Tatars, and Udmurts have been observed. As a result of analysis of genotype-by-environment interactions we revealed ethnicity-specific character of associations: in Russians maternal age at delivery (βST = 0.84, p = 0.005) and in Tatars bilingual/unilingual rearing (βST = 0.44, р = 0.020) modulated association of ZNF638 rs2287326 with spatial abilities. Moreover, urban/rural residency in childhood modulated association of TUFM rs7187776 with 3D abilities (βST = 0.41, р = 0.009). The data obtained indicate the involvement of the ZNF638, TUFM, SH2B1, and EXOC4 genes, which are responsible for adipogenesis, in the manifestation of cognitive abilities, and, therefore, confirms the relationship between cognitive and metabolic disorders. Nevertheless, ethnicity-specific character of demonstrated associations and differences in genotype frequencies of analyzed GWAS-SNPs point to the specific pattern of associated genetic loci characteristic for the Russian cohort and to the complexity of replication of data reported for the combined samples of Europeans.
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Myung, W., J. Kim, S.-W. Lim, et al. "A genome-wide association study of antidepressant response in Koreans." Translational Psychiatry 5, no. 9 (2015): e633-e633. http://dx.doi.org/10.1038/tp.2015.127.
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Abstract We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P=3.57 × 10-8). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20–0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.
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Mbarek, Hamdi, Yuri Milaneschi, Jouke-Jan Hottenga, et al. "Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder." Twin Research and Human Genetics 20, no. 4 (2017): 267–70. http://dx.doi.org/10.1017/thg.2017.30.
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In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10−8) and gene-based (p = 1.48 × 10−7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.
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Heilbronner, U. "Genetic Predictors of Lithium Response." V.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY, no. 4-1 (December 9, 2019): 26–27. http://dx.doi.org/10.31363/2313-7053-2019-4-1-26-27.
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Lithium remains a first-line pharmacological treatment of bipolar disorder (BD). However, treatment response is heterogeneous, with several lines of evidence implicating genetic factors. Unfortunately, neither hypothesis-driven approaches nor initial genome-wide association studies (GWAS) were successful in identifying genetic drivers of response heterogeneity, probably due to low statistical power and different phenotype measurements. Recently, a GWAS of the Consortium of Lithium Genetics (ConLiGen) has identified four single nucleotide polymorphisms (SNPs) mediating response to lithium, located in genes for two long non-coding RNAs. This success was only possible by international collaboration and the use of an established lithium response scale. The findings await further replication.
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Hishida, Asahi, Tomotaka Ugai, Ryosuke Fujii, et al. "GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy." Carcinogenesis 40, no. 5 (2019): 661–68. http://dx.doi.org/10.1093/carcin/bgz016.
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Abstract Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10−7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10−8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10−27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.
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Chen, Shih-Pin, Jong-Ling Fuh, Ming-Yi Chung, et al. "Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan." Cephalalgia 38, no. 3 (2017): 466–75. http://dx.doi.org/10.1177/0333102417695105.
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Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10−4 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10−12, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10−7, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14–1.54, Ppermutation = 9.99 × 10−5; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04–1.45, Ppermutation = 2.9 × 10−2; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.
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Fitzgerald, Joan, Laura Fahey, Laurena Holleran, Pilib Ó Broin, Gary Donohoe, and Derek W. Morris. "Thirteen Independent Genetic Loci Associated with Preserved Processing Speed in a Study of Cognitive Resilience in 330,097 Individuals in the UK Biobank." Genes 13, no. 1 (2022): 122. http://dx.doi.org/10.3390/genes13010122.
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Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. The UK Biobank does not have measurements of the same cognitive phenotype at distal time points. Therefore, we used education years (EY) as a proxy phenotype for past cognitive performance and current cognitive performance was based on processing speed. This represented an average time span of 40 years between past and current cognitive performance in 330,097 individuals. A confounding factor was that EY is highly polygenic and masked the genetics of resilience. To overcome this, we employed Genomics Structural Equation Modelling (GenomicSEM) to perform a genome-wide association study (GWAS)-by-subtraction using two GWAS, one GWAS of EY and resilience and a second GWAS of EY but not resilience, to generate a GWAS of Resilience. Using independent discovery and replication samples, we found 13 independent genetic loci for Resilience. Functional analyses showed enrichment in several brain regions and specific cell types. Gene-set analyses implicated the biological process “neuron differentiation”, the cellular component “synaptic part” and the “WNT signalosome”. Mendelian randomisation analysis showed a causative effect of white matter volume on cognitive resilience. These results may contribute to the neurobiological understanding of resilience.
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Zhao, Jianhua, and Struan F. A. Grant. "Genetics of Childhood Obesity." Journal of Obesity 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/845148.
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Obesity is a major health problem and an immense economic burden on the health care systems both in the United States and the rest of the world. The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. Genome-wide association studies (GWAS) have revealed strongly associated genomic variants associated with most common disorders; indeed there is general consensus on these findings from generally positive replication outcomes by independent groups. To date, there have been only a few GWAS-related reports for childhood obesity specifically, with studies primarily uncovering loci in the adult setting instead. It is clear that a number of loci previously reported from GWAS analyses of adult BMI and/or obesity also play a role in childhood obesity.
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Farber, Charles R. "Systems-Level Analysis of Genome-Wide Association Data." G3 Genes|Genomes|Genetics 3, no. 1 (2013): 119–29. http://dx.doi.org/10.1534/g3.112.004788.
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Abstract Genome-wide association studies (GWAS) have emerged as the method of choice for identifying common variants affecting complex disease. In a GWAS, particular attention is placed, for obvious reasons, on single-nucleotide polymorphisms (SNPs) that exceed stringent genome-wide significance thresholds. However, it is expected that many SNPs with only nominal evidence of association (e.g., P &lt; 0.05) truly influence disease. Efforts to extract additional biological information from entire GWAS datasets have primarily focused on pathway-enrichment analyses. However, these methods suffer from a number of limitations and typically fail to lead to testable hypotheses. To evaluate alternative approaches, we performed a systems-level analysis of GWAS data using weighted gene coexpression network analysis. A weighted gene coexpression network was generated for 1918 genes harboring SNPs that displayed nominal evidence of association (P ≤ 0.05) from a GWAS of bone mineral density (BMD) using microarray data on circulating monocytes isolated from individuals with extremely low or high BMD. Thirteen distinct gene modules were identified, each comprising coexpressed and highly interconnected GWAS genes. Through the characterization of module content and topology, we illustrate how network analysis can be used to discover disease-associated subnetworks and characterize novel interactions for genes with a known role in the regulation of BMD. In addition, we provide evidence that network metrics can be used as a prioritizing tool when selecting genes and SNPs for replication studies. Our results highlight the advantages of using systems-level strategies to add value to and inform GWAS.
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Kawamura, Yusuke, Hirofumi Nakaoka, Akiyoshi Nakayama, et al. "Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout." Annals of the Rheumatic Diseases 78, no. 10 (2019): 1430–37. http://dx.doi.org/10.1136/annrheumdis-2019-215521.
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ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10–8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.
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Ohka, Seii, Souichi Yamada, Daisuke Nishizawa, et al. "Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus–mediated fusogenic activity." Molecular Pain 17 (January 2021): 174480692110521. http://dx.doi.org/10.1177/17448069211052171.
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Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3- O-sulfotransferase 4 ( HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.
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Hale, Andrew T., Oluwatoyin Akinnusotu, Jing He, et al. "Genome-Wide Association Study Identifies Genetic Risk Factors for Spastic Cerebral Palsy." Neurosurgery 89, no. 3 (2021): 435–42. http://dx.doi.org/10.1093/neuros/nyab184.
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Abstract BACKGROUND Although many clinical risk factors of spastic cerebral palsy (CP) have been identified, the genetic basis of spastic CP is largely unknown. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU) with replication in the UK Biobank and FinnGen, we perform the first genome-wide association study (GWAS) for spastic CP. OBJECTIVE To define the genetic basis of spastic CP. METHODS Whole-genome data were obtained using the multi-ethnic genotyping array (MEGA) genotyping array capturing single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) &gt; 0.01, and imputation quality score (r2) &gt; 0.3, imputed based on the 1000 genomes phase 3 reference panel. Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (P &lt; 5.0 × 10–8). Replication analysis (defined as P &lt; .05) was performed in the UK Biobank and FinnGen. RESULTS We identify 1 SNP (rs78686911) reaching genome-wide significance with spastic CP. Expression quantitative trait loci (eQTL) analysis suggests that rs78686911 decreases expression of GRIK4, a gene that encodes a high-affinity kainate glutamatergic receptor of largely unknown function. Replication analysis in the UK Biobank and FinnGen reveals additional SNPs in the GRIK4 loci associated with CP. CONCLUSION To our knowledge, we perform the first GWAS of spastic CP. Our study indicates that genetic variation contributes to CP risk.
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Su, Shaoyong, Haidong Zhu, Xiaojing Xu, et al. "DNA Methylation of the LY86 Gene is Associated With Obesity, Insulin Resistance, and Inflammation." Twin Research and Human Genetics 17, no. 3 (2014): 183–91. http://dx.doi.org/10.1017/thg.2014.22.
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Background: Previous genome-wide association studies (GWAS) have identified a large number of genetic variants for obesity and its related traits, representing a group of potential key genes in the etiology of obesity. Emerging evidence suggests that epigenetics may play an important role in obesity. It has not been explored whether the GWAS-identified loci contribute to obesity through epigenetics (e.g., DNA (deoxyribonucleic acid) methylation) in addition to genetics. Method: A multi-stage cross-sectional study was designed. We did a literature search and identified 117 genes discovered by GWAS for obesity and its related traits. Then we analyzed whether the methylation levels of these genes were also associated with obesity in two genome-wide methylation panels. We examined an initial panel of seven adolescent obese cases and seven age-matched lean controls, followed by a second panel of 48 adolescent obese cases and 48 age- and gender-matched lean controls. The validated CpG sites were further replicated in two independent replication panels of youth (46 vs. 46 and 230 cases vs. 413 controls, respectively) and a general population of youth, including 703 healthy subjects. Results: One CpG site in the lymphocyte antigen 86 (LY86) gene, which showed higher methylation in the obese in both the initial (p = .009) and second genome-wide DNA methylation panel (p = .008), was further validated in both replication panels (meta p = .00016). Moreover, in the general population of youth, the methylation levels of this region were significantly correlated with adiposity indices (p ≤ .02), insulin resistance (p = .001), and inflammatory markers (p < .001). Conclusion: By focusing on recent GWAS findings in genome-wide methylation profiles, we identified a solid association between LY86 gene DNA methylation and obesity.
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Antypa, N., A. Drago, and A. Serretti. "Genomewide interaction and enrichment analysis on antidepressant response." Psychological Medicine 44, no. 4 (2013): 753–65. http://dx.doi.org/10.1017/s0033291713001554.
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BackgroundGenomewide association studies (GWASs) on antidepressant efficacy have yielded modest results. A possible reason is that response is influenced by other factors, which possibly interact with genetic variation. We used a GWAS model to predict antidepressant response, by including predictors previously known to affect response, such as quality of life (QoL). We also evaluated the association between genes, previously implicated in gene–environment (G × E) interactions, and response using an enrichment analysis.MethodWe examined a sample of 1426 depressed patients from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: 774 responders, 652 non-responders and 418 865 single nucleotide polymorphisms (SNPs) were analysed. First, in a GWAS model, we investigated whether genetic variations interact with patients' levels of QoL to predict response, after controlling for demographic characteristics, severity and population stratification. Second, we conducted an enrichment analysis exploring whether candidate genes that have emerged from prior G × E interaction studies on depression are associated with treatment response.ResultsThe GWAS model, with QoL as a moderator, yielded one SNP (rs520210) associated with response in the NEDD4L gene (p = 3.64 × 10−8). In the Caucasian sample only, we observed a drop in significance for this SNP. The enrichment analysis showed that SNPs within serotonergic genes contained more significant markers that predicted response, compared with a random set of genes in the genome.ConclusionsOur findings point to possible target genes, which are proposed for further independent replication. Our enrichment analysis provides further support, in a genomewide context, of the role of serotonergic genes in influencing antidepressant response.
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van Rooij, Iris ALM, Kerstin U. Ludwig, Julia Welzenbach, et al. "Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene." Genes 10, no. 12 (2019): 1023. http://dx.doi.org/10.3390/genes10121023.
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Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10−7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
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Kakuta, Yoichi, Yosuke Kawai, Takeo Naito, et al. "A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn’s Disease in Japanese Individuals." Journal of Crohn's and Colitis 13, no. 5 (2018): 648–58. http://dx.doi.org/10.1093/ecco-jcc/jjy197.
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Abstract Background and Aims Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn’s disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10−26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10−19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p &lt;1 × 10−6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10−8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions RAP1A is a novel susceptibility locus for CD in the Japanese population.
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Rikos, Dimitrios, Vasileios Siokas, Tatyana I. Burykina, Nikolaos Drakoulis, Efthimios Dardiotis, and Elias Zintzaras. "Replication of chromosomal loci involved in Parkinson’s disease: A quantitative synthesis of GWAS." Toxicology Reports 8 (2021): 1762–68. http://dx.doi.org/10.1016/j.toxrep.2021.10.008.
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Wang, Yunpeng, Wesley K. Thompson, Andrew J. Schork, et al. "Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS." PLOS Genetics 12, no. 1 (2016): e1005803. http://dx.doi.org/10.1371/journal.pgen.1005803.
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Cheon, Eun Jeong, Do Hyeon Cha, Sung Kweon Cho, et al. "Novel association between CDKAL1 and cholesterol efflux capacity: Replication after GWAS-based discovery." Atherosclerosis 273 (June 2018): 21–27. http://dx.doi.org/10.1016/j.atherosclerosis.2018.04.011.
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Chan, W. C., T. F. Leung, H. Y. Sy, et al. "GWAS replication identifies PROC to be a novel candidate gene for childhood asthma." Paediatric Respiratory Reviews 13 (June 2012): S46. http://dx.doi.org/10.1016/s1526-0542(12)70049-0.
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Pharoah, Paul D. P., Ya-Yu Tsai, Susan J. Ramus, et al. "GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer." Nature Genetics 45, no. 4 (2013): 362–70. http://dx.doi.org/10.1038/ng.2564.
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Torrico, Bàrbara, Andreas G. Chiocchetti, Elena Bacchelli, et al. "Lack of replication of previous autism spectrum disorder GWAS hits in European populations." Autism Research 10, no. 2 (2016): 202–11. http://dx.doi.org/10.1002/aur.1662.
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