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Sökning: WFRF:(Qu CX)

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  • Bien, Stephanie A., et al. (författare)
  • Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
  • 2019
  • Ingår i: ; 138:4, s. 307-326
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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  • Schmit, Stephanie L, et al. (författare)
  • Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
  • 2018
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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  • Tidskriftsartikel (refereegranskat)
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  • Tidskriftsartikel (refereegranskat)
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  • Tidskriftsartikel (refereegranskat)
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  • Heiland, Emerald G., et al. (författare)
  • Association of mobility limitations with incident disability among older adults : a population-based study
  • 2016
  • Ingår i: Age and Ageing. - 0002-0729 .- 1468-2834. ; 45:6, s. 812-819
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: mobility-related limitations predict future disability; however, the extent to which individual and combined mobility tests may predict disability remains unclear.Objectives: to estimate the odds of developing disability in activities of daily living (ADL) according to limitations in walking speed, balance or both; and explore the role of chronic diseases and cognitive function.Design: a prospective cohort study.Setting: urban area of Stockholm, Sweden.Subjects: one thousand nine hundred and seventy-one disability-free persons (age >= 60 years, 63% women) from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), who underwent baseline examination in 2001-04 and follow-up assessments for 6 years.Measurements: mobility limitation was defined as a one-leg balance stand <5 s or walking speed <0.8 m/s. ADL disability was defined as the inability to complete one or more ADL: bathing, dressing, using the toilet, transferring and eating.Results: during a total of 11,404 person-years (mean per person 5.8 years, SD 0.30) of follow-up, 119 (incidence 1.5/100 person-years) participants developed ADL disability. The demographic adjusted odds ratios (OR) (95% confidence intervals, CI) of incident ADL disability related to balance stand and walking speed limitations were 3.8 (2.3-6.3) and 8.4 (5.2-13.3), respectively. The associations remained statistically significant after controlling for number of chronic diseases and cognitive status. People with limitations in both balance and walking speed had an OR of 12.9 (95% CI 7.0-23.7) for incident disability compared with no limitation.Conclusion: balance and walking speed tests are simple clinical procedures that can indicate hierarchical risk of ADL dependence in older adults.
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