| 1. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 2. |
- Chung, Sharon A, et al.
(författare)
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European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:8, s. 2448-2456
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease. METHODS: SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations. RESULTS: In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96). CONCLUSION: This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
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| 3. |
- Dudding, Tom, et al.
(författare)
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Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.
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| 4. |
- Ferreira, Manuel A R, et al.
(författare)
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Eleven loci with new reproducible genetic associations with allergic disease risk.
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 691-699
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
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| 5. |
- Hom, Geoffrey, et al.
(författare)
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Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
- 2008
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 358:9, s. 900-909
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4are established susceptibility genes; there is strong evidence for the existence of additional risk loci.METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10−10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10−11).
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| 6. |
- Kosoy, Roman, et al.
(författare)
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Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:1, s. 69-78
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Tidskriftsartikel (refereegranskat)abstract
- To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.
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| 7. |
- Meng, Wen-Jian, et al.
(författare)
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Microsatellite instability did not predict individual survival in sporadic stage II and III rectal cancer patients
- 2007
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Ingår i: Oncology. - : S. Karger AG. - 0890-9091 .- 0030-2414 .- 1423-0232. ; 72:1-2, s. 82-88
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Tumors with high-frequency microsatellite instability (MSI-H) have unique biological behavior and the predictive role of microsatellite instability (MSI) status on survival of colorectal cancer is still debated. The prognostic significance of MSI status in sporadic stage II and III rectal cancer patients needs to be more precisely defined. So we investigated the relationship between MSI status and clinicopathological features and prognosis in these patients. Methods: DNAs from fresh-frozen paired samples of tumors and corresponding normal tissue from 128 stage II and III rectal cancer patients were analyzed for MSI by PCR amplification using markers recommended by a National Cancer Institute workshop on MSI. To assess prognostic significance, Cox proportional hazards modeling was used. Results: Twelve (9.3%) tumors in our study were MSI-H, 28 (21.9%) were low-frequency MSI (MSI-L) and 88 (68.8%) were microsatellite stable (MSS). Most of the MSI-H tumors compared with MSI-L and MSS tumors were found in female patients (p = 0.031), had mucinous histology (p = 0.023), high grade of differentiation (p = 0.002) and high level of preoperative serum carcinoembryonic antigen (p = 0.005). Rectal cancer patients with MSI-H did not show a better clinical outcome than those with MSI-L/MSS, neither in all cases (p = 0.986) nor in stage II and stage III disease analyzed separately (p = 0.705 and p = 0.664, respectively). Conclusions: Data provided here demonstrated there was high incidence of MSI-H and MSI was not a prognostic factor in sporadic stage II and III rectal cancers from the Chinese Han population included in this study. Tumor stage is more suitable than MSI status for prediction of individual survival in sporadic stage II and III rectal cancer patients. Copyright © 2007 S. Karger AG.
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| 8. |
- Meng, Wen-Jian, et al.
(författare)
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Novel mutations and sequence variants in exons 3-9 of human T Cell Factor-4 gene in sporadic rectal cancer patients stratified by microsatellite instability
- 2007
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Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 13:27, s. 3747-3751
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To establish the role of human T Cell Factor-4 (hTCF-4) gene exons 3-9 mutation status in association with sporadic rectal cancer with microsatellite instability (MSI). Methods: Microsatellite markers were genotyped in 93 sporadic rectal cancer patients. Eleven cases were found to be high-frequency MSI (MSI-H). Sequence analysis of the coding region of the exons 3-9 of hTCF-4 gene was carried out for the 11 MSI-H cases and 10 controls (5 microsatellite stability (MSS) cases and 5 cases with normal mucosa). The sequencing and MSI identification were used. Results: Several novel mutations and variants were revealed. In exon 4, one is a 4-position continuous alteration which caused amino acid change from Q131T and S132I (391insA, 392 G > A, 393 A > G and 395delC) and another nucleotide deletion (395delC) is present in MSI-H cases (5/10 and 4/10, respectively) but completely absent in the controls. Conclusion: Novel mutations in exon 4 of hTCF-4 gene were revealed in this study, which might be of importance in the pathogenesis of sporadic rectal cancer patients with MSI-H. © 2007 WJG. All rights reserved.
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| 9. |
- Nassir, Rami, et al.
(författare)
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An ancestry informative marker set for determining continental origin : validation and extension using human genome diversity panels
- 2009
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 10, s. 39-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia. Results: In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups. Conclusion: These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.
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| 10. |
- Okbay, Aysu, et al.
(författare)
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Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 437-449
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Tidskriftsartikel (refereegranskat)abstract
- We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.
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