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861.
Stein JL Medland SE Vasquez AA Hibar DP Senstad RE Winkler AM Toro R Appel K Bartecek R Bergmann Ø Bernard M Brown AA Cannon DM Chakravarty MM Christoforou A Domin M Grimm O Hollinshead M Holmes AJ Homuth G Hottenga JJ Langan C Lopez LM Hansell NK Hwang KS Kim S Laje G Lee PH Liu X Loth E Lourdusamy A Mattingsdal M Mohnke S Maniega SM Nho K Nugent AC O'Brien C Papmeyer M Pütz B Ramasamy A Rasmussen J Rijpkema M Risacher SL Roddey JC Rose EJ Ryten M Shen L Sprooten E Strengman E Teumer A 《Nature genetics》2012,44(5):552-561
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)). 相似文献
862.
CL Cheung KS Lau AY Ho KK Lee SC Tiu EY Lau J Leung MW Tsang KW Chan CY Yeung YC Woo EY Cheung VH Hung HK Pang CS Hung PC Sham AW Kung 《Nature genetics》2012,44(9):1026-1029
Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; P(meta-analysis) = 1.8 × 10(-14)). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression (P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP. 相似文献
863.
Cathy W.S. Chen Richard Gerlach Edward M. H. Lin W. C. W. Lee 《Journal of forecasting》2012,31(8):661-687
Value‐at‐risk (VaR) forecasting via a computational Bayesian framework is considered. A range of parametric models is compared, including standard, threshold nonlinear and Markov switching generalized autoregressive conditional heteroskedasticity (GARCH) specifications, plus standard and nonlinear stochastic volatility models, most considering four error probability distributions: Gaussian, Student‐t, skewed‐t and generalized error distribution. Adaptive Markov chain Monte Carlo methods are employed in estimation and forecasting. A portfolio of four Asia–Pacific stock markets is considered. Two forecasting periods are evaluated in light of the recent global financial crisis. Results reveal that: (i) GARCH models outperformed stochastic volatility models in almost all cases; (ii) asymmetric volatility models were clearly favoured pre crisis, while at the 1% level during and post crisis, for a 1‐day horizon, models with skewed‐t errors ranked best, while integrated GARCH models were favoured at the 5% level; (iii) all models forecast VaR less accurately and anti‐conservatively post crisis. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
864.
Laurie CC Laurie CA Rice K Doheny KF Zelnick LR McHugh CP Ling H Hetrick KN Pugh EW Amos C Wei Q Wang LE Lee JE Barnes KC Hansel NN Mathias R Daley D Beaty TH Scott AF Ruczinski I Scharpf RB Bierut LJ Hartz SM Landi MT Freedman ND Goldin LR Ginsburg D Li J Desch KC Strom SS Blot WJ Signorello LB Ingles SA Chanock SJ Berndt SI Le Marchand L Henderson BE Monroe KR Heit JA de Andrade M Armasu SM Regnier C Lowe WL Hayes MG Marazita ML Feingold E Murray JC Melbye M Feenstra B Kang JH Wiggs JL 《Nature genetics》2012,44(6):642-650
We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18). 相似文献
865.
Ellinor PT Lunetta KL Albert CM Glazer NL Ritchie MD Smith AV Arking DE Müller-Nurasyid M Krijthe BP Lubitz SA Bis JC Chung MK Dörr M Ozaki K Roberts JD Smith JG Pfeufer A Sinner MF Lohman K Ding J Smith NL Smith JD Rienstra M Rice KM Van Wagoner DR Magnani JW Wakili R Clauss S Rotter JI Steinbeck G Launer LJ Davies RW Borkovich M Harris TB Lin H Völker U Völzke H Milan DJ Hofman A Boerwinkle E Chen LY Soliman EZ Voight BF Li G Chakravarti A Kubo M Tedrow UB Rose LM Ridker PM Conen D Tsunoda T 《Nature genetics》2012,44(6):670-675
866.
Sung WK Zheng H Li S Chen R Liu X Li Y Lee NP Lee WH Ariyaratne PN Tennakoon C Mulawadi FH Wong KF Liu AM Poon RT Fan ST Chan KL Gong Z Hu Y Lin Z Wang G Zhang Q Barber TD Chou WC Aggarwal A Hao K Zhou W Zhang C Hardwick J Buser C Xu J Kan Z Dai H Mao M Reinhard C Wang J Luk JM 《Nature genetics》2012,44(7):765-769
To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival. 相似文献
867.
868.
Raychaudhuri S Sandor C Stahl EA Freudenberg J Lee HS Jia X Alfredsson L Padyukov L Klareskog L Worthington J Siminovitch KA Bae SC Plenge RM Gregersen PK de Bakker PI 《Nature genetics》2012,44(3):291-296
The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC. 相似文献
869.
Jongsung Lee Eunsun Jung Jienny Lee Sungran Huh Young-Soo Kim Yong-Woo Kim Yeong Shik Kim Deokhoon Park 《Cellular and molecular life sciences : CMLS》2010,67(3):467-481
Adipocyte dysfunction is associated with the development of obesity. This study shows that 6-thioinosine inhibits adipocyte
differentiation. The mRNA levels of PPAR γ and C/EBPα, but not C/EBPβ and δ, were reduced by 6-thioinosine. Moreover, the
mRNA levels of PPAR γ target genes (LPL, CD36, aP2, and LXRα) were down-regulated by 6-thioinosine. We also demonstrated that
6-thioinosine inhibits the transactivation activity and the mRNA level of PPAR γ. Additionally, attempts to elucidate a possible
mechanism underlying the 6-thioinosine-mediated effects revealed that 6-thioinosine induced iNOS gene expression without impacting
eNOS expression, and that this was mediated through activation of AP-1, especially, JNK. In addition, 6-thioinosine was found
to operate upstream of MEKK-1 in JNK activation signaling. Taken together, these findings suggest that the inhibition of adipocyte
differentiation by 6-thioinosine occurs primarily through the reduced expression of PPAR γ, which is mediated by upregulation
of iNOS via the activation of JNK. 相似文献
870.
Church C Moir L McMurray F Girard C Banks GT Teboul L Wells S Brüning JC Nolan PM Ashcroft FM Cox RD 《Nature genetics》2010,42(12):1086-1092
Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice. 相似文献