共查询到15条相似文献,搜索用时 15 毫秒
1.
Common variants in WFS1 confer risk of type 2 diabetes 总被引:10,自引:0,他引:10
Sandhu MS Weedon MN Fawcett KA Wasson J Debenham SL Daly A Lango H Frayling TM Neumann RJ Sherva R Blech I Pharoah PD Palmer CN Kimber C Tavendale R Morris AD McCarthy MI Walker M Hitman G Glaser B Permutt MA Hattersley AT Wareham NJ Barroso I 《Nature genetics》2007,39(8):951-953
We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes. 相似文献
2.
Helgason A Pálsson S Thorleifsson G Grant SF Emilsson V Gunnarsdottir S Adeyemo A Chen Y Chen G Reynisdottir I Benediktsson R Hinney A Hansen T Andersen G Borch-Johnsen K Jorgensen T Schäfer H Faruque M Doumatey A Zhou J Wilensky RL Reilly MP Rader DJ Bagger Y Christiansen C Sigurdsson G Hebebrand J Pedersen O Thorsteinsdottir U Gulcher JR Kong A Rotimi C Stefánsson K 《Nature genetics》2007,39(2):218-225
3.
Gudmundsson J Sulem P Rafnar T Bergthorsson JT Manolescu A Gudbjartsson D Agnarsson BA Sigurdsson A Benediktsdottir KR Blondal T Jakobsdottir M Stacey SN Kostic J Kristinsson KT Birgisdottir B Ghosh S Magnusdottir DN Thorlacius S Thorleifsson G Zheng SL Sun J Chang BL Elmore JB Breyer JP McReynolds KM Bradley KM Yaspan BL Wiklund F Stattin P Lindström S Adami HO McDonnell SK Schaid DJ Cunningham JM Wang L Cerhan JR St Sauver JL Isaacs SD Wiley KE Partin AW Walsh PC Polo S Ruiz-Echarri M 《Nature genetics》2008,40(3):281-283
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease. 相似文献
4.
Stacey SN Manolescu A Sulem P Rafnar T Gudmundsson J Gudjonsson SA Masson G Jakobsdottir M Thorlacius S Helgason A Aben KK Strobbe LJ Albers-Akkers MT Swinkels DW Henderson BE Kolonel LN Le Marchand L Millastre E Andres R Godino J Garcia-Prats MD Polo E Tres A Mouy M Saemundsdottir J Backman VM Gudmundsson L Kristjansson K Bergthorsson JT Kostic J Frigge ML Geller F Gudbjartsson D Sigurdsson H Jonsdottir T Hrafnkelsson J Johannsson J Sveinsson T Myrdal G Grimsson HN Jonsson T von Holst S 《Nature genetics》2007,39(7):865-869
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone. 相似文献
5.
Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk 总被引:16,自引:0,他引:16
Xu J Zheng SL Komiya A Mychaleckyj JC Isaacs SD Hu JJ Sterling D Lange EM Hawkins GA Turner A Ewing CM Faith DA Johnson JR Suzuki H Bujnovszky P Wiley KE DeMarzo AM Bova GS Chang B Hall MC McCullough DL Partin AW Kassabian VS Carpten JD Bailey-Wilson JE Trent JM Ohar J Bleecker ER Walsh PC Isaacs WB Meyers DA 《Nature genetics》2002,32(2):321-325
Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent. 相似文献
6.
Jaeger E Webb E Howarth K Carvajal-Carmona L Rowan A Broderick P Walther A Spain S Pittman A Kemp Z Sullivan K Heinimann K Lubbe S Domingo E Barclay E Martin L Gorman M Chandler I Vijayakrishnan J Wood W Papaemmanuil E Penegar S Qureshi M;CORGI Consortium Farrington S Tenesa A Cazier JB Kerr D Gray R Peto J Dunlop M Campbell H Thomas H Houlston R Tomlinson I 《Nature genetics》2008,40(1):26-28
We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)). 相似文献
7.
Steinthorsdottir V Thorleifsson G Reynisdottir I Benediktsson R Jonsdottir T Walters GB Styrkarsdottir U Gretarsdottir S Emilsson V Ghosh S Baker A Snorradottir S Bjarnason H Ng MC Hansen T Bagger Y Wilensky RL Reilly MP Adeyemo A Chen Y Zhou J Gudnason V Chen G Huang H Lashley K Doumatey A So WY Ma RC Andersen G Borch-Johnsen K Jorgensen T van Vliet-Ostaptchouk JV Hofker MH Wijmenga C Christiansen C Rader DJ Rotimi C Gurney M Chan JC Pedersen O Sigurdsson G Gulcher JR Thorsteinsdottir U Kong A 《Nature genetics》2007,39(6):770-775
8.
Shea J Agarwala V Philippakis AA Maguire J Banks E Depristo M Thomson B Guiducci C Onofrio RC Kathiresan S Gabriel S Burtt NP Daly MJ Groop L Altshuler D;Myocardial Infarction Genetics Consortium 《Nature genetics》2011,43(8):801-805
Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals. 相似文献
9.
Akamatsu S Takata R Haiman CA Takahashi A Inoue T Kubo M Furihata M Kamatani N Inazawa J Chen GK Le Marchand L Kolonel LN Katoh T Yamano Y Yamakado M Takahashi H Yamada H Egawa S Fujioka T Henderson BE Habuchi T Ogawa O Nakamura Y Nakagawa H 《Nature genetics》2012,44(4):426-9, S1
We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations. 相似文献
10.
A predisposing gene for breast and ovarian cancer has recently been mapped to chromosome 17q12-21. If this gene is a tumour suppressor gene, allele losses would be expected in the tumours of affected family members and the losses should affect the wild-type chromosome, reflecting the need for inactivation of the wild-type allele at the predisposing locus. In four multiple case breast-ovarian cancer families, we have found that in each of nine tumours which showed allele losses, the losses were from the wild-type chromosome. This suggests that the putative 'breast-ovarian' cancer gene is indeed a tumour suppressor gene. 相似文献
11.
Meyre D Bouatia-Naji N Tounian A Samson C Lecoeur C Vatin V Ghoussaini M Wachter C Hercberg S Charpentier G Patsch W Pattou F Charles MA Tounian P Clément K Jouret B Weill J Maddux BA Goldfine ID Walley A Boutin P Dina C Froguel P 《Nature genetics》2005,37(8):863-867
We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions. 相似文献
12.
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 总被引:14,自引:0,他引:14
van Heel DA Franke L Hunt KA Gwilliam R Zhernakova A Inouye M Wapenaar MC Barnardo MC Bethel G Holmes GK Feighery C Jewell D Kelleher D Kumar P Travis S Walters JR Sanders DS Howdle P Swift J Playford RJ McLaren WM Mearin ML Mulder CJ McManus R McGinnis R Cardon LR Deloukas P Wijmenga C 《Nature genetics》2007,39(7):827-829
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. 相似文献
13.
Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes 总被引:7,自引:0,他引:7
Lowe CE Cooper JD Brusko T Walker NM Smyth DJ Bailey R Bourget K Plagnol V Field S Atkinson M Clayton DG Wicker LS Todd JA 《Nature genetics》2007,39(9):1074-1082
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5' regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70-2.45; P = 1.92 x 10(-28); control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to T1D. 相似文献
14.
Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination 总被引:20,自引:0,他引:20
Otto EA Schermer B Obara T O'Toole JF Hiller KS Mueller AM Ruf RG Hoefele J Beekmann F Landau D Foreman JW Goodship JA Strachan T Kispert A Wolf MT Gagnadoux MF Nivet H Antignac C Walz G Drummond IA Benzing T Hildebrandt F 《Nature genetics》2003,34(4):413-420
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination. 相似文献