共查询到20条相似文献,搜索用时 15 毫秒
1.
Wright FA Strug LJ Doshi VK Commander CW Blackman SM Sun L Berthiaume Y Cutler D Cojocaru A Collaco JM Corey M Dorfman R Goddard K Green D Kent JW Lange EM Lee S Li W Luo J Mayhew GM Naughton KM Pace RG Paré P Rommens JM Sandford A Stonebraker JR Sun W Taylor C Vanscoy LL Zou F Blangero J Zielenski J O'Neal WK Drumm ML Durie PR Knowles MR Cutting GR 《Nature genetics》2011,43(6):539-546
A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder. 相似文献
2.
Identification of ten loci associated with height highlights new biological pathways in human growth 总被引:1,自引:0,他引:1
Lettre G Jackson AU Gieger C Schumacher FR Berndt SI Sanna S Eyheramendy S Voight BF Butler JL Guiducci C Illig T Hackett R Heid IM Jacobs KB Lyssenko V Uda M;Diabetes Genetics Initiative;FUSION;KORA;Prostate Lung Colorectal Ovarian Cancer Screening Trial;Nurses' Health Study;SardiNIA Boehnke M Chanock SJ Groop LC Hu FB Isomaa B Kraft P Peltonen L Salomaa V Schlessinger D Hunter DJ Hayes RB Abecasis GR Wichmann HE Mohlke KL Hirschhorn JN 《Nature genetics》2008,40(5):584-591
Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait. 相似文献
3.
RA Scott V Lagou RP Welch E Wheeler ME Montasser J Luan R Mägi RJ Strawbridge E Rehnberg S Gustafsson S Kanoni LJ Rasmussen-Torvik L Yengo C Lecoeur D Shungin S Sanna C Sidore PC Johnson JW Jukema T Johnson A Mahajan N Verweij G Thorleifsson JJ Hottenga S Shah AV Smith B Sennblad C Gieger P Salo M Perola NJ Timpson DM Evans BS Pourcain Y Wu JS Andrews J Hui LF Bielak W Zhao M Horikoshi P Navarro A Isaacs JR O'Connell K Stirrups V Vitart C Hayward T Esko E Mihailov RM Fraser T Fall BF Voight 《Nature genetics》2012,44(9):991-1005
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control. 相似文献
4.
Barton A Thomson W Ke X Eyre S Hinks A Bowes J Plant D Gibbons LJ;Wellcome Trust Case Control Consortium;YEAR Consortium;BIRAC Consortium Wilson AG Bax DE Morgan AW Emery P Steer S Hocking L Reid DM Wordsworth P Harrison P Worthington J 《Nature genetics》2008,40(10):1156-1159
The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry. 相似文献
5.
MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability 总被引:24,自引:0,他引:24
Lipkin SM Wang V Jacoby R Banerjee-Basu S Baxevanis AD Lynch HT Elliott RM Collins FS 《Nature genetics》2000,24(1):27-35
DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families. 相似文献
6.
Thye T Owusu-Dabo E Vannberg FO van Crevel R Curtis J Sahiratmadja E Balabanova Y Ehmen C Muntau B Ruge G Sievertsen J Gyapong J Nikolayevskyy V Hill PC Sirugo G Drobniewski F van de Vosse E Newport M Alisjahbana B Nejentsev S Ottenhoff TH Hill AV Horstmann RD Meyer CG 《Nature genetics》2012,44(3):257-259
After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10(-9)). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10(-11). 相似文献
7.
Heid IM Jackson AU Randall JC Winkler TW Qi L Steinthorsdottir V Thorleifsson G Zillikens MC Speliotes EK Mägi R Workalemahu T White CC Bouatia-Naji N Harris TB Berndt SI Ingelsson E Willer CJ Weedon MN Luan J Vedantam S Esko T Kilpeläinen TO Kutalik Z Li S Monda KL Dixon AL Holmes CC Kaplan LM Liang L Min JL Moffatt MF Molony C Nicholson G Schadt EE Zondervan KT Feitosa MF Ferreira T Lango Allen H Weyant RJ Wheeler E Wood AR;MAGIC Estrada K Goddard ME Lettre G Mangino M Nyholt DR Purcell S 《Nature genetics》2010,42(11):949-960
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?3 to P = 1.2 × 10?13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. 相似文献
8.
O'Donovan MC Craddock N Norton N Williams H Peirce T Moskvina V Nikolov I Hamshere M Carroll L Georgieva L Dwyer S Holmans P Marchini JL Spencer CC Howie B Leung HT Hartmann AM Möller HJ Morris DW Shi Y Feng G Hoffmann P Propping P Vasilescu C Maier W Rietschel M Zammit S Schumacher J Quinn EM Schulze TG Williams NM Giegling I Iwata N Ikeda M Darvasi A Shifman S He L Duan J Sanders AR Levinson DF Gejman PV Cichon S Nöthen MM Gill M Corvin A Rujescu D Kirov G Owen MJ Buccola NG Mowry BJ 《Nature genetics》2008,40(9):1053-1055
We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)). 相似文献
9.
Estrada K Styrkarsdottir U Evangelou E Hsu YH Duncan EL Ntzani EE Oei L Albagha OM Amin N Kemp JP Koller DL Li G Liu CT Minster RL Moayyeri A Vandenput L Willner D Xiao SM Yerges-Armstrong LM Zheng HF Alonso N Eriksson J Kammerer CM Kaptoge SK Leo PJ Thorleifsson G Wilson SG Wilson JF Aalto V Alen M Aragaki AK Aspelund T Center JR Dailiana Z Duggan DJ Garcia M Garcia-Giralt N Giroux S Hallmans G Hocking LJ Husted LB Jameson KA Khusainova R Kim GS Kooperberg C Koromila T Kruk M Laaksonen M 《Nature genetics》2012,44(5):491-501
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. 相似文献
10.
J Dong Z Hu C Wu H Guo B Zhou J Lv D Lu K Chen Y Shi M Chu C Wang R Zhang J Dai Y Jiang S Cao Z Qin D Yu H Ma G Jin J Gong C Sun X Zhao Z Yin L Yang Z Li Q Deng J Wang W Wu H Zheng G Zhou H Chen P Guan Z Peng Y Chen Y Shu L Xu X Liu L Liu P Xu B Han C Bai Y Zhao H Zhang Y Yan CI Amos F Chen W Tan L Jin T Wu D Lin H Shen 《Nature genetics》2012,44(8):895-899
To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10(-8)) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10(-10)), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10(-9)) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10(-8)). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10(-8)) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10(-6)). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10(-10), P = 5.07 × 10(-3), P = 6.77 × 10(-3) and P = 4.49 × 10(-2) for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer. 相似文献
11.
Sotoodehnia N Isaacs A de Bakker PI Dörr M Newton-Cheh C Nolte IM van der Harst P Müller M Eijgelsheim M Alonso A Hicks AA Padmanabhan S Hayward C Smith AV Polasek O Giovannone S Fu J Magnani JW Marciante KD Pfeufer A Gharib SA Teumer A Li M Bis JC Rivadeneira F Aspelund T Köttgen A Johnson T Rice K Sie MP Wang YA Klopp N Fuchsberger C Wild SH Mateo Leach I Estrada K Völker U Wright AF Asselbergs FW Qu J Chakravarti A Sinner MF Kors JA Petersmann A Harris TB Soliman EZ Munroe PB Psaty BM 《Nature genetics》2010,42(12):1068-1076
12.
Hu Z Wu C Shi Y Guo H Zhao X Yin Z Yang L Dai J Hu L Tan W Li Z Deng Q Wang J Wu W Jin G Jiang Y Yu D Zhou G Chen H Guan P Chen Y Shu Y Xu L Liu X Liu L Xu P Han B Bai C Zhao Y Zhang H Yan Y Ma H Chen J Chu M Lu F Zhang Z Chen F Wang X Jin L Lu J Zhou B Lu D Wu T Lin D Shen H 《Nature genetics》2011,43(8):792-796
Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese. 相似文献
13.
Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. 总被引:25,自引:0,他引:25
M Corral-Debrinski T Horton M T Lott J M Shoffner M F Beal D C Wallace 《Nature genetics》1992,2(4):324-329
We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67-77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing. 相似文献
14.
Kugathasan S Baldassano RN Bradfield JP Sleiman PM Imielinski M Guthery SL Cucchiara S Kim CE Frackelton EC Annaiah K Glessner JT Santa E Willson T Eckert AW Bonkowski E Shaner JL Smith RM Otieno FG Peterson N Abrams DJ Chiavacci RM Grundmeier R Mamula P Tomer G Piccoli DA Monos DS Annese V Denson LA Grant SF Hakonarson H 《Nature genetics》2008,40(10):1211-1215
Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively. 相似文献
15.
S W Ballinger J M Shoffner E V Hedaya I Trounce M A Polak D A Koontz D C Wallace 《Nature genetics》1992,1(1):11-15
Diabetes mellitus (DM) is one of the most common chronic disorders of children and adults. Several reports have suggested an increased incidence of maternal transmission in some forms of DM. Therefore, we tested a pedigree with maternally transmitted DM and deafness for mitochondrial DNA mutations and discovered a 10.4 kilobase (kb) mtDNA deletion. This deletion is unique because it is maternally inherited, removes the light strand origin (OL) of mtDNA replication, inhibits mitochondrial protein synthesis, and is not associated with the hallmarks of mtDNA deletion syndromes. This discovery demonstrates that DM can be caused by mtDNA mutations and suggests that some of the heterogeneity of this disease results from the novel features of mtDNA genetics. 相似文献
16.
Bis JC DeCarli C Smith AV van der Lijn F Crivello F Fornage M Debette S Shulman JM Schmidt H Srikanth V Schuur M Yu L Choi SH Sigurdsson S Verhaaren BF DeStefano AL Lambert JC Jack CR Struchalin M Stankovich J Ibrahim-Verbaas CA Fleischman D Zijdenbos A den Heijer T Mazoyer B Coker LH Enzinger C Danoy P Amin N Arfanakis K van Buchem MA de Bruijn RF Beiser A Dufouil C Huang J Cavalieri M Thomson R Niessen WJ Chibnik LB Gislason GK Hofman A Pikula A Amouyel P Freeman KB Phan TG Oostra BA Stein JL 《Nature genetics》2012,44(5):545-551
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. 相似文献
17.
Ikram MA Fornage M Smith AV Seshadri S Schmidt R Debette S Vrooman HA Sigurdsson S Ropele S Taal HR Mook-Kanamori DO Coker LH Longstreth WT Niessen WJ DeStefano AL Beiser A Zijdenbos AP Struchalin M Jack CR Rivadeneira F Uitterlinden AG Knopman DS Hartikainen AL Pennell CE Thiering E Steegers EA Hakonarson H Heinrich J Palmer LJ Jarvelin MR McCarthy MI Grant SF St Pourcain B Timpson NJ Smith GD Sovio U;Early Growth Genetics Consortium Nalls MA Au R Hofman A Gudnason H van der Lugt A Harris TB 《Nature genetics》2012,44(5):539-544
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. 相似文献
18.
Hüffmeier U Uebe S Ekici AB Bowes J Giardina E Korendowych E Juneblad K Apel M McManus R Ho P Bruce IN Ryan AW Behrens F Lascorz J Böhm B Traupe H Lohmann J Gieger C Wichmann HE Herold C Steffens M Klareskog L Wienker TF Fitzgerald O Alenius GM McHugh NJ Novelli G Burkhardt H Barton A Reis A 《Nature genetics》2010,42(11):996-999
Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV. 相似文献
19.
Shaw-Smith C Pittman AM Willatt L Martin H Rickman L Gribble S Curley R Cumming S Dunn C Kalaitzopoulos D Porter K Prigmore E Krepischi-Santos AC Varela MC Koiffmann CP Lees AJ Rosenberg C Firth HV de Silva R Carter NP 《Nature genetics》2006,38(9):1032-1037
Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination. 相似文献
20.
Taal HR St Pourcain B Thiering E Das S Mook-Kanamori DO Warrington NM Kaakinen M Kreiner-Møller E Bradfield JP Freathy RM Geller F Guxens M Cousminer DL Kerkhof M Timpson NJ Ikram MA Beilin LJ Bønnelykke K Buxton JL Charoen P Chawes BL Eriksson J Evans DM Hofman A Kemp JP Kim CE Klopp N Lahti J Lye SJ McMahon G Mentch FD Müller-Nurasyid M O'Reilly PF Prokopenko I Rivadeneira F Steegers EA Sunyer J Tiesler C Yaghootkar H;Cohorts for Heart Aging Research in Genetic Epidemiology Consortium 《Nature genetics》2012,44(5):532-538
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. 相似文献