共查询到20条相似文献,搜索用时 31 毫秒
1.
Ka-Po Tse Wen-Hui Su Kai-Ping Chang Chia-Jung Yu Lee-Chu See Chuen Hsueh Min-Lee Yang Hong-Yi Li Ming-Hsi Wang Lih-Chyang Chen Timothy J. Jorgensen Yu-Sun Chang Yin Yao Shugart 《American journal of human genetics》2009,85(2):194-203
Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; pcombined = 3.9 × 10−20 and 1.6 × 10−19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; pcombined = 8.97 × 10−17) and HLA-F (rs3129055 and rs9258122; pcombined = 7.36 × 10−11 and 3.33 × 10−10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10−4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABAB receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development. 相似文献
2.
Denny JC Crawford DC Ritchie MD Bielinski SJ Basford MA Bradford Y Chai HS Bastarache L Zuvich R Peissig P Carrell D Ramirez AH Pathak J Wilke RA Rasmussen L Wang X Pacheco JA Kho AN Hayes MG Weston N Matsumoto M Kopp PA Newton KM Jarvik GP Li R Manolio TA Kullo IJ Chute CG Chisholm RL Larson EB McCarty CA Masys DR Roden DM de Andrade M 《American journal of human genetics》2011,(4):529-542
We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms'' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10−9). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10−6). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10−5), nodular (OR = 0.76, p = 3.1 × 10−5) and multinodular (OR = 0.69, p = 3.9 × 10−5) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10−3), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10−13), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost. 相似文献
3.
Shi Y Qu J Zhang D Zhao P Zhang Q Tam PO Sun L Zuo X Zhou X Xiao X Hu J Li Y Cai L Liu X Lu F Liao S Chen B He F Gong B Lin H Ma S Cheng J Zhang J Chen Y Zhao F Yang X Chen Y Yang C Lam DS Li X Shi F Wu Z Lin Y Yang J Li S Ren Y Xue A Fan Y Li D Pang CP Zhang X Yang Z 《American journal of human genetics》2011,(6):438-813
High myopia, which is extremely prevalent in the Chinese population, is one of the leading causes of blindness in the world. Genetic factors play a critical role in the development of the condition. To identify the genetic variants associated with high myopia in the Han Chinese, we conducted a genome-wide association study (GWAS) of 493,947 SNPs in 1088 individuals (419 cases and 669 controls) from a Han Chinese cohort and followed up on signals that were associated with p < 1.0 × 10−4 in three independent cohorts (combined, 2803 cases and 5642 controls). We identified a significant association between high myopia and a variant at 13q12.12 (rs9318086, combined p = 1.91 × 10−16, heterozygous odds ratio = 1.32, and homozygous odds ratio = 1.64). Furthermore, five additional SNPs (rs9510902, rs3794338, rs1886970, rs7325450, and rs7331047) in the same linkage disequilibrium (LD) block with rs9318086 also proved to be significantly associated with high myopia in the Han Chinese population; p values ranged from 5.46 × 10−11 to 6.16 × 10−16. This associated locus contains three genes—MIPEP, C1QTNF9B-AS1, and C1QTNF9B. MIPEP and C1QTNF9B were found to be expressed in the retina and retinal pigment epithelium (RPE) and are more likely than C1QTNF9B-AS1 to be associated with high myopia given the evidence of retinal signaling that controls eye growth. Our results suggest that the variants at 13q12.12 are associated with high myopia. 相似文献
4.
Pei-Lung Chen Dimitrios Avramopoulos Virginia K. Lasseter John A. McGrath M. Daniele Fallin Kung-Yee Liang Gerald Nestadt Ningping Feng Gary Steel Andrew S. Cutting Paula Wolyniec Ann E. Pulver David Valle 《American journal of human genetics》2009,84(1):21-34
Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 × 10−5), we performed a peakwide association fine mapping study by using 1414 SNPs across ~12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the “delusion” factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 × 10−7. We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 × 10−2), with a combined p value of 2.30 × 10−7. After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 × 10−3. NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ. 相似文献
5.
Lanktree MB Guo Y Murtaza M Glessner JT Bailey SD Onland-Moret NC Lettre G Ongen H Rajagopalan R Johnson T Shen H Nelson CP Klopp N Baumert J Padmanabhan S Pankratz N Pankow JS Shah S Taylor K Barnard J Peters BJ Maloney CM Lobmeyer MT Stanton A Zafarmand MH Romaine SP Mehta A van Iperen EP Gong Y Price TS Smith EN Kim CE Li YR Asselbergs FW Atwood LD Bailey KM Bhatt D Bauer F Behr ER Bhangale T Boer JM Boehm BO Bradfield JP Brown M Braund PS Burton PR Carty C Chandrupatla HR Chen W Connell J 《American journal of human genetics》2011,(1):688-18
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. 相似文献
6.
Amy Murphy Kelan G. Tantisira Manuel E. Soto-Quirós Barbara J. Klanderman Stephen Lake Juan C. Celedón 《American journal of human genetics》2009,85(1):87-96
Asthma incidence and prevalence are higher in obese individuals. A potential mechanistic basis for this relationship is pleiotropy. We hypothesized that significant linkage and candidate-gene association would be found for body mass index (BMI) in a population ascertained on asthma affection status. Linkage analysis for BMI was performed on 657 subjects in eight Costa Rican families enrolled in a study of asthma. Family-based association studies were conducted for BMI with SNPs within a positional candidate gene, PRKCA. SNPs within PRKCA were also tested for association with asthma. Association studies were conducted in 415 Costa Rican parent-child trios and 493 trios participating in the Childhood Asthma Management Program (CAMP). Although only modest evidence of linkage for BMI was obtained for the whole cohort, significant linkage was noted for BMI in females on chromosome 17q (peak LOD = 3.39). Four SNPs in a candidate gene in this region (PRKCA) had unadjusted association p values < 0.05 for BMI in both cohorts, with the joint p value for two SNPs remaining significant after adjustment for multiple comparisons (rs228883 and rs1005651, joint p values = 9.5 × 10−5 and 5.6 × 10−5). Similarly, eight SNPs had unadjusted association p values < 0.05 for asthma in both populations, with one SNP remaining significant after adjustment for multiple comparisons (rs11079657, joint p value = 2.6 × 10−5). PRKCA is a pleiotropic locus that is associated with both BMI and asthma and that has been identified via linkage analysis of BMI in a population ascertained on asthma. 相似文献
7.
Johnson T Gaunt TR Newhouse SJ Padmanabhan S Tomaszewski M Kumari M Morris RW Tzoulaki I O'Brien ET Poulter NR Sever P Shields DC Thom S Wannamethee SG Whincup PH Brown MJ Connell JM Dobson RJ Howard PJ Mein CA Onipinla A Shaw-Hawkins S Zhang Y Davey Smith G Day IN Lawlor DA Goodall AH;Cardiogenics Consortium Fowkes FG Abecasis GR Elliott P Gateva V;Global BPgen Consortium Braund PS Burton PR Nelson CP Tobin MD van der Harst P Glorioso N Neuvrith H Salvi E Staessen JA Stucchi A Devos N 《American journal of human genetics》2011,(6):688-700
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Festen EA Goyette P Green T Boucher G Beauchamp C Trynka G Dubois PC Lagacé C Stokkers PC Hommes DW Barisani D Palmieri O Annese V van Heel DA Weersma RK Daly MJ Wijmenga C Rioux JD 《PLoS genetics》2011,7(1):e1001283
Crohn''s disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. 相似文献
10.
Maria Teresa Landi Nilanjan Chatterjee Lynn R. Goldin Melissa Rotunno Kevin Jacobs Meredith Yeager Qizhai Li Dario Consonni Sholom Wacholder Ryan Diver Jarmo Virtamo Zhaoming Wang Kimberly F. Doheny Cathy Laurie Rayjean Hung James D. McKay John McLaughlin Ming-Sound Tsao Yufei Wang Lars Vatten Egil Arnesen Christine Bouchard Tonu Vooder Kristian Välk Chu Chen Patrick Sulem Thorunn Rafnar Wiebke Sauter Heike Bickeböller Jenny Chang-Claude Kari Stefansson Christopher I. Amos Sharon A. Savage Margaret A. Tucker Neil E. Caporaso 《American journal of human genetics》2009,85(5):679-74
Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10−7), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma. 相似文献
11.
Association signals in GWAS are usually prioritized solely by p values. Here, we attempt to improve the power of GWAS by using a weighted false discovery rate control procedure to detect associations of low-frequency variants with effect sizes similar to or even larger than those of common variants. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to test for association with fasting glucose levels in the Atherosclerosis Risk in Communities Study (ARIC) population. In addition to finding several previously identified sequence variations, we identified a low-frequency variant (rs1209523; minor allele frequency = 0.043) near FOXA2 that was associated with fasting glucose levels in European Americans (EAs) (n = 7428, p value = 1.3 × 10−5). The association between rs1209523 and glucose levels was also significant in African Americans (AAs) (n = 2029, p value = 6.7 × 10−3) of the ARIC and was confirmed by replication in both EAs and AAs of the Dallas Heart Study (n = 963 and 1571, respectively; p values = 5.3 × 10−3 and 5.8 × 10−4, respectively) and in EAs of the Cooper Center Longitudinal Study (n = 2862; p value = 1.6 × 10−2). A meta-analysis of these five populations yielded an estimated effect size of −1.31 mg/dl per minor allele (p value = 2.2 × 10−11). This study reveals that there is a cache of less-frequent variants in GWAS arrays that can be identified via analytical approaches accounting for allele frequencies. 相似文献
12.
Zhernakova A Stahl EA Trynka G Raychaudhuri S Festen EA Franke L Westra HJ Fehrmann RS Kurreeman FA Thomson B Gupta N Romanos J McManus R Ryan AW Turner G Brouwer E Posthumus MD Remmers EF Tucci F Toes R Grandone E Mazzilli MC Rybak A Cukrowska B Coenen MJ Radstake TR van Riel PL Li Y de Bakker PI Gregersen PK Worthington J Siminovitch KA Klareskog L Huizinga TW Wijmenga C Plenge RM 《PLoS genetics》2011,7(2):e1002004
13.
Recent advances in genotyping technology make it possible to utilize large-scale association analysis for disease-gene mapping. Powerful and robust family-based association methods are crucial for successful gene mapping. We propose a family-based association method, the generalized disequilibrium test (GDT), in which the genotype differences of all discordant relative pairs are utilized in assessing association within a family. The improvement of the GDT over existing methods is threefold: (1) information beyond first-degree relatives is incorporated efficiently, yielding substantial gains in power in comparison to existing tests; (2) the GDT statistic is implemented via a robust technique that does not rely on large sample theory, resulting in further power gains, especially at high levels of significance; and (3) covariates and weights based on family size are incorporated. Advantages of the GDT over existing methods are demonstrated by extensive computer simulations and by application to recently published large-scale genome-wide linkage data from the Type 1 Diabetes Genetics Consortium (T1DGC). In our simulations, the GDT consistently outperforms other tests for a common disease and frequently outperforms other tests for a rare disease; the power improvement is > 13% in 6 out of 8 extended pedigree scenarios. All of the six strongest associations identified by the GDT have been reported by other studies, whereas only three or four of these associations can be identified by existing methods. For the T1D association at gene UBASH3A, the GDT resulted in a genome-wide significance (p = 4.3 × 10−6), much stronger than the published significance (p = 10−4). 相似文献
14.
Allanore Y Saad M Dieudé P Avouac J Distler JH Amouyel P Matucci-Cerinic M Riemekasten G Airo P Melchers I Hachulla E Cusi D Wichmann HE Wipff J Lambert JC Hunzelmann N Tiev K Caramaschi P Diot E Kowal-Bielecka O Valentini G Mouthon L Czirják L Damjanov N Salvi E Conti C Müller M Müller-Ladner U Riccieri V Ruiz B Cracowski JL Letenneur L Dupuy AM Meyer O Kahan A Munnich A Boileau C Martinez M 《PLoS genetics》2011,7(7):e1002091
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis. 相似文献
15.
N'Diaye A Chen GK Palmer CD Ge B Tayo B Mathias RA Ding J Nalls MA Adeyemo A Adoue V Ambrosone CB Atwood L Bandera EV Becker LC Berndt SI Bernstein L Blot WJ Boerwinkle E Britton A Casey G Chanock SJ Demerath E Deming SL Diver WR Fox C Harris TB Hernandez DG Hu JJ Ingles SA John EM Johnson C Keating B Kittles RA Kolonel LN Kritchevsky SB Le Marchand L Lohman K Liu J Millikan RC Murphy A Musani S Neslund-Dudas C North KE Nyante S Ogunniyi A Ostrander EA Papanicolaou G Patel S Pettaway CA 《PLoS genetics》2011,7(10):e1002298
Adult height is a classic polygenic trait of high heritability (h
2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits. 相似文献
16.
Palmer ND McDonough CW Hicks PJ Roh BH Wing MR An SS Hester JM Cooke JN Bostrom MA Rudock ME Talbert ME Lewis JP;DIAGRAM Consortium;MAGIC Investigators Ferrara A Lu L Ziegler JT Sale MM Divers J Shriner D Adeyemo A Rotimi CN Ng MC Langefeld CD Freedman BI Bowden DW Voight BF Scott LJ Steinthorsdottir V Morris AP Dina C Welch RP Zeggini E Huth C Aulchenko YS Thorleifsson G McCulloch LJ Ferreira T Grallert H Amin N Wu G Willer CJ Raychaudhuri S McCarroll SA Langenberg C Hofmann OM Dupuis J Qi L 《PloS one》2012,7(1):e29202
African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10−8). SNP rs7560163 (P = 7.0×10−9, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10−5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations. 相似文献
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Carrasquillo MM Nicholson AM Finch N Gibbs JR Baker M Rutherford NJ Hunter TA DeJesus-Hernandez M Bisceglio GD Mackenzie IR Singleton A Cookson MR Crook JE Dillman A Hernandez D Petersen RC Graff-Radford NR Younkin SG Rademakers R 《American journal of human genetics》2010,87(6):890-897
Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Using an enzyme-linked immunosorbent assay, we previously showed that GRN is detectable in human plasma and can be used to predict GRN mutation status. This study also showed a wide range in plasma GRN levels in non-GRN mutation carriers, including controls. We have now performed a genome-wide association study of 313,504 single-nucleotide polymorphisms (SNPs) in 533 control samples and identified on chromosome 1p13.3 two SNPs with genome-wide significant association with plasma GRN levels (top SNP rs646776; p = 1.7 × 10−30). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10−19) and 197 FTLD patients (p = 6.4 × 10−12). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (SORT1), and the minor C allele of rs646776 was previously associated with increased SORT1 mRNA levels. Supporting these findings, overexpression of SORT1 in cultured HeLa cells dramatically reduced GRN levels in the conditioned media, whereas knockdown of SORT1 increased extracellular GRN levels. In summary, we identified significant association of a locus on chromosome 1p13.3 with plasma GRN levels through an unbiased genome-wide screening approach and implicated SORT1 as an important regulator of GRN levels. This finding opens avenues for future research into GRN biology and the pathophysiology of neurodegenerative diseases. 相似文献
19.
Vijay Panicker Scott G. Wilson John P. Walsh J. Brent Richards Suzanne J. Brown Alexandra P. Bremner Emad Qweitin Nicole Soranzo Stephen J. Fletcher 《American journal of human genetics》2010,87(3):430-542
Thyroid hormones are key regulators of cellular growth, development, and metabolism, and thyroid disorders are a common cause of ill health in the community. Circulating concentrations of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) have a strong heritable component and are thought to be under polygenic control, but the genes responsible are mostly unknown. In order to identify genetic loci associated with these metabolic phenotypes, we performed a genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study and found a significant association between rs10917469 on chromosome 1p36.13 and serum TSH (p = 3.2 × 10−8). The association of rs10917469 with serum TSH was replicated (p = 2.0 × 10−4) in an independent community-based sample of 1154 participants in the Busselton Health Study. This SNP is located near CAPZB, which might be a regulator of TSH secretion and thus of pituitary-thyroid axis function. Twenty-nine percent of white individuals carry the variant, and the difference in mean TSH concentrations between wild-type individuals and those homozygous for the minor G allele was 0.5 mU/l, which is likely to be clinically relevant. We also provide evidence of suggestive association (p < 5.0 × 10−6) of other SNPs with serum TSH, free T4, and free T3 concentrations, and these SNPs might be good targets for further studies. These results advance understanding of the genetic basis of pituitary-thyroid axis function and metabolic regulation. 相似文献
20.
Obeidat M Wain LV Shrine N Kalsheker N Soler Artigas M Repapi E Burton PR Johnson T Ramasamy A Zhao JH Zhai G Huffman JE Vitart V Albrecht E Igl W Hartikainen AL Pouta A Cadby G Hui J Palmer LJ Hadley D McArdle WL Rudnicka AR Barroso I Loos RJ Wareham NJ Mangino M Soranzo N Spector TD Gläser S Homuth G Völzke H Deloukas P Granell R Henderson J Grkovic I Jankovic S Zgaga L Polašek O Rudan I Wright AF Campbell H Wild SH Wilson JF Heinrich J Imboden M Probst-Hensch NM Gyllensten U Johansson Å 《PloS one》2011,6(5):e19382