| 1. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 3. |
- Jiang, Ziyu, et al.
(författare)
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HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64:9, s. 2026-2036
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. Methods: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. Results: The susceptible DR3 (β = −0.09, p = 0.0009) and DR4-DQ8 (β = −0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = −0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. Conclusions/interpretation: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies. Graphical abstract: [Figure not available: see fulltext.].
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| 4. |
- Li, Xueying, et al.
(författare)
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Assessing the effects of time interpolation of ndvi composites on phenology trend estimation
- 2021
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Ingår i: Remote Sensing. - : MDPI AG. - 2072-4292. ; 13:24
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Tidskriftsartikel (refereegranskat)abstract
- The accurate evaluation of shifts in vegetation phenology is essential for understanding of vegetation responses to climate change. Remote-sensing vegetation index (VI) products with multi-day scales have been widely used for phenology trend estimation. VI composites should be interpolated into a daily scale for extracting phenological metrics, which may not fully capture daily vegetation growth, and how this process affects phenology trend estimation remains unclear. In this study, we chose 120 sites over four vegetation types in the mid-high latitudes of the northern hemisphere, and then a Moderate Resolution Imaging Spectroradiometer (MODIS) MCD43A4 daily surface reflectance data was used to generate a daily normalized difference vegetation index (NDVI) dataset in addition to an 8-day and a 16-day NDVI composite datasets from 2001 to 2019. Five different time interpolation methods (piecewise logistic function, asymmetric Gaussian function, polynomial curve function, linear interpolation, and spline interpolation) and three phenology extraction methods were applied to extract data from the start of the growing season and the end of the growing season. We compared the trends estimated from daily NDVI data with those from NDVI composites among (1) different interpolation methods; (2) different vegetation types; and (3) different combinations of time interpolation methods and phenology extraction methods. We also analyzed the differences between the trends estimated from the 8-day and 16-day composite datasets. Our results indicated that none of the interpolation methods had significant effects on trend estimation over all sites, but the discrepancies caused by time interpolation could not be ignored. Among vegetation types with apparent seasonal changes such as deciduous broadleaf forest, time interpolation had significant effects on phenology trend estimation but almost had no significant effects among vegetation types with weak seasonal changes such as evergreen needleleaf forests. In addition, trends that were estimated based on the same interpolation method but different extraction methods were not consistent in showing significant (insignificant) differences, implying that the selection of extraction methods also affected trend estimation. Compared with other vegetation types, there were generally fewer discrepancies between trends estimated from the 8-day and 16-day dataset in evergreen needleleaf forest and open shrubland, which indicated that the dataset with a lower temporal resolution (16-day) can be applied. These findings could be conducive for analyzing the uncertainties of monitoring vegetation phenology changes.
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| 5. |
- Li, Xueying, et al.
(författare)
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Triple collocation-based merging of multi-source gridded evapotranspiration data in the Nordic Region
- 2023
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Ingår i: Agricultural and Forest Meteorology. - 1873-2240. ; 335
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Tidskriftsartikel (refereegranskat)abstract
- Accurate evapotranspiration (ET) data are required for many hydro-meteorological applications. Compared with the traditional evaluation that requires in-situ measurements, the triple collocation (TC) technique estimates geophysical product errors without the need for ground truth, which is especially suitable over large areas lacking a dense in-situ network. However, violations of the zero-error cross-correlation (ECC) assumption are found to be the dominant sources of impairing the TC robustness. This study presents the first application of a TC-based merging framework that optimally considers ECC to merge multi-source gridded ET products in the Nordic Region during 2003–2018. The ECC estimates of each ET dataset pair calculated by the quadruple collocation approach are used to select the qualified triplets from four products, including FLUXCOM, Global Land Surface Satellite (GLASS), Global Land Evaporation and Amsterdam Model (GLEAM), and Penman-Monteith-Leuning Version 2 (PML-V2). Then the ET merged datasets are generated by weighting TC-based rescaled error variances of the parent datasets through least square merging. Finally, the accuracy of both the parent and the merged datasets are assessed with the Integrated Carbon Observation System (ICOS) flux data in the Nordic Region based on multiple statistical metrics. Results demonstrate that the ECC values provide intuitive evidence for filtering unqualified TC triplets. Both the absolute and relative error variances (signal-to-noise ratio) are considered for ET dataset evaluation. Overall PML-V2 has the best performance among the evaluated four products. Two merged ET datasets with the reference climatology of FLUXCOM outperform all parent products with the lowest errors by using ICOS data as reference among all sites – indicating the feasibility of TC technique for improving ET accuracy in the Nordic Region. This study also analyses the impacts of reference climatology selection on the TC merged results.
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| 6. |
- Liang, Hua, et al.
(författare)
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Recognition of maturity-onset diabetes of the young in China
- 2021
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Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116 .- 2040-1124. ; 12:4, s. 501-509
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Tidskriftsartikel (refereegranskat)abstract
- Aims/Introduction: Given that mutations related to maturity-onset diabetes of the young (MODY) are rarely found in Chinese populations, we aim to characterize the mutation spectrum of MODY pedigrees. Materials and Methods: Maturity-onset diabetes of the young candidate gene- or exome-targeted capture sequencing was carried out in 76 probands from unrelated families fulfilling the clinical diagnostic criteria for MODY. MAF <0.01 in the GnomAD or ExAC database was used to filter significant variants. Sanger sequencing was then carried out to validate findings. Function prediction by SIFT, PolyPhen-2 and PROVEAN or CADD was carried out in missense mutations. Results: A total of 32 mutations in six genes were identified in 31 families, accounting for 40.79% of the potential MODY families. The MODY subtype detection rate was 18.42% for GCK, 15.79% for HNF1A, 2.63% for HNF4A, and 1.32% for KLF11, PAX4 and NEUROG3. Seven nonsense/frameshift mutations and four missense mutations with damaging prediction were newly identified novel mutations. The clinical features of MODY2, MODY3/1 and MODYX are similar to previous reports. Clinical phenotype of NEUROG3 p.Arg55Glufs*23 is characterized by hyperglycemia and mild intermittent abdominal pain. Conclusions: This study adds to the emerging pattern of MODY epidemiology that the proportion of MODY explained by known pathogenic genes is higher than that previously reported, and found NEUROG3 as a new causative gene for MODY.
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| 7. |
- Qi, Xingmei, et al.
(författare)
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Spider silk protein forms amyloid-like nanofibrils through a non-nucleation-dependent polymerization mechanism
- 2023
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Ingår i: Small. - : John Wiley & Sons. - 1613-6810 .- 1613-6829. ; 18:46
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid fibrils—nanoscale fibrillar aggregates with high levels of order—are pathogenic in some today incurable human diseases; however, there are also many physiologically functioning amyloids in nature. The process of amyloid formation is typically nucleation-elongation-dependent, as exemplified by the pathogenic amyloid-β peptide (Aβ) that is associated with Alzheimer's disease. Spider silk, one of the toughest biomaterials, shares characteristics with amyloid. In this study, it is shown that forming amyloid-like nanofibrils is an inherent property preserved by various spider silk proteins (spidroins). Both spidroins and Aβ capped by spidroin N- and C-terminal domains, can assemble into macroscopic spider silk-like fibers that consist of straight nanofibrils parallel to the fiber axis as observed in native spider silk. While Aβ forms amyloid nanofibrils through a nucleation-dependent pathway and exhibits strong cytotoxicity and seeding effects, spidroins spontaneously and rapidly form amyloid-like nanofibrils via a non-nucleation-dependent polymerization pathway that involves lateral packing of fibrils. Spidroin nanofibrils share amyloid-like properties but lack strong cytotoxicity and the ability to self-seed or cross-seed human amyloidogenic peptides. These results suggest that spidroins' unique primary structures have evolved to allow functional properties of amyloid, and at the same time direct their fibrillization pathways to avoid formation of cytotoxic intermediates.
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| 8. |
- Qi, Xingmei, et al.
(författare)
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Spider Silk Protein Forms Amyloid-Like Nanofibrils through a Non-Nucleation-Dependent Polymerization Mechanism (Small 46/2023)
- 2023
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Ingår i: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 19:46
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Tidskriftsartikel (refereegranskat)abstract
- Both spider silk protein and Alzheimer's disease associated amyloid-β peptide can assemble into silk-like fibers that consist of nanofibrils. Spider silk proteins' unique primary structures have evolved to allow functional amyloid-like properties and direct their fibrillization pathways to avoid formation of cytotoxic intermediates. More details can be found in article number 2304031 by Gefei Chen and co-workers.
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| 9. |
- Ren, Wenqian, et al.
(författare)
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Adult-onset type 1 diabetic patients with less severe clinical manifestation have less risk DR-DQ genotypes than childhood-onset patients
- 2021
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Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 37:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population. Materials and Methods: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing. Results: Adult-onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C-peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood-onset patients, adult-onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high-risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non-risk) genotypes. Conclusions: Adult-onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR-DQ haplotypes than childhood-onset patients, which suggested the association between less risk DR-DQ genotypes and the less severe clinical manifestation in adult-onset patients.
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| 10. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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