| 1. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 2. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 3. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 4. |
- Ainsworth, Elizabeth A., et al.
(författare)
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Next generation of elevated [CO2] experiments with crops: a critical investment for feeding the future world
- 2008
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Ingår i: Plant, Cell and Environment. - : Wiley. - 0140-7791 .- 1365-3040. ; 31:9, s. 1317-1324
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Tidskriftsartikel (refereegranskat)abstract
- A rising global population and demand for protein-rich diets are increasing pressure to maximize agricultural productivity. Rising atmospheric [CO2] is altering global temperature and precipitation patterns, which challenges agricultural productivity. While rising [CO2] provides a unique opportunity to increase the productivity of C-3 crops, average yield stimulation observed to date is well below potential gains. Thus, there is room for improving productivity. However, only a fraction of available germplasm of crops has been tested for CO2 responsiveness. Yield is a complex phenotypic trait determined by the interactions of a genotype with the environment. Selection of promising genotypes and characterization of response mechanisms will only be effective if crop improvement and systems biology approaches are closely linked to production environments, that is, on the farm within major growing regions. Free air CO2 enrichment (FACE) experiments can provide the platform upon which to conduct genetic screening and elucidate the inheritance and mechanisms that underlie genotypic differences in productivity under elevated [CO2]. We propose a new generation of large-scale, low-cost per unit area FACE experiments to identify the most CO2-responsive genotypes and provide starting lines for future breeding programmes. This is necessary if we are to realize the potential for yield gains in the future.
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| 5. |
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| 6. |
- Cantor-Graae, Elizabeth, et al.
(författare)
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Migration as a risk factor for schizophrenia: a Danish population-based cohort study.
- 2003
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Ingår i: British Journal of Psychiatry. - 0007-1250. ; 182, s. 117-122
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Tidskriftsartikel (refereegranskat)abstract
- Background A growing body of evidence suggests that migration is a risk factor for the development of schizophrenia, although the putative mechanism remains obscure. Aims To examine immigrant background and history of foreign residence as risk factors for schizophrenia. Method Using data from the Danish Civil Registration System, we established a population-based cohort of 2.14 million persons resident in Denmark by their fifteenth birthday. Schizophrenia in cohort members and parental psychiatric disorder were identified by cross-linkage with the Danish Psychiatric Case Register. Results The relative risk of developing schizophrenia was 2.45 (95% Cl 2.25-2.67) and 1.92 (95% Cl 1.74-2.12) among first- and second-generation immigrants respectively, and 1.60 (95% Cl 1.25-2.05) among Danes with a history of foreign residence. Conclusions Migration confers an increased risk for schizophrenia that is not solely attributable to selection factors and may also be independent of foreign birth.
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| 7. |
- El-Saadi, O, et al.
(författare)
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Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia
- 2004
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Ingår i: Schizophrenia Research. - 0920-9964. ; 67:2-3, s. 227-236
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Tidskriftsartikel (refereegranskat)abstract
- Background: While the association between increased maternal age and congenital disorders has long been recognized, the offspring of older fathers are also at increased risk of congenital disorders related to DNA errors during spermatogenesis. Recent studies have drawn attention to an association between increased paternal age and increased risk of schizophrenia. The aim of the current study was to examine both paternal and maternal age as risk factors for the broader category of psychosis. Method: We used data from three sources examining psychosis: a population-based cohort study (Denmark), and two case-control studies (Sweden and Australia). Results: When controlling for the effect of maternal age, increased paternal age was significantly associated with increased risk of psychosis in the Danish and Swedish studies. The Australian study found no association between adjusted paternal age and risk of psychosis. When controlling for the effect of paternal age, younger maternal a-e was associated with an increased risk of psychoses in the Danish study alone. Conclusions: The offspring of older fathers are at increased risk of developing psychosis. The role of paternally derived mutations and/or psychosocial factors associated with older paternal age warrants further research. (C) 2003 Elsevier B.V. All rights reserved.
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| 8. |
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| 9. |
- Khanna, Chand, et al.
(författare)
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The dog as a cancer model
- 2006
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 24:9, s. 1065-1066
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Tidskriftsartikel (refereegranskat)
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| 10. |
- McNeil, T F, et al.
(författare)
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Unwanted pregnancy as a risk factor for offspring schizophrenia-spectrum and affective disorders in adulthood: a prospective high-risk study.
- 2009
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Ingår i: Psychological Medicine. - 1469-8978. ; 39:6, s. 957-965
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study investigated whether 'unwanted pregnancy' (i.e. a negative or ambivalent attitude towards the pregnancy/reproduction) is associated with schizophrenia-spectrum and affective disorders in the offspring in adulthood, and if so, whether other pregnancy, perinatal, childhood or genetic-risk factors account for this association.MethodIn a prospective study beginning during pregnancy, unwanted pregnancy (in combination with other early life risk factors) was studied in relation to adult mental disorders in 75 genetic high-risk (HR) and 91 normal-risk (NR) offspring, defined through maternal psychosis history. Early life risk factors were studied through personal interviews, observations and medical records, and offspring mental disorders were independently diagnosed through follow-up examination at about 22 years of age. RESULTS: Unwanted pregnancy by itself was significantly related to adult offspring schizophrenia-spectrum disorders in both the total sample and the HR subgroup, but the effect was found to be limited to the HR group and occurred in interaction with genetic risk. Other co-temporaneous pregnancy stressors and later perinatal complications, malformations and early childhood environmental stressors could not explain this relationship. Unwanted pregnancy also interacted with genetic-risk status in relating to affective disorders in the offspring. CONCLUSIONS: Unwanted pregnancy, when occurring together with genetic risk for psychosis, was found to be related to both adult schizophrenia-spectrum and affective mental disorders in the offspring. Although the effect of unwanted pregnancy could be mediated by other yet-unidentified factors, unwanted pregnancy might be a functional, discrete environmental psychosocial factor with its own deleterious impact on offspring mental development, when co-occurring with genetic risk.
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| 11. |
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| 12. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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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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| 13. |
- Zolkowska, Krystyna, et al.
(författare)
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Increased rates of psychosis among immigrants to Sweden: is migration a risk factor for psychosis?
- 2001
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Ingår i: Psychological Medicine. - 1469-8978. ; 31:4, s. 669-678
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Tidskriftsartikel (refereegranskat)abstract
- Background. Previous studies have shown high rates of psychosis among Afro-Caribbean immigrants to the UK and immigrants to the Netherlands. Rates of schizophrenia-like psychoses (SLP), i.e. schizophrenia or other non-affective psychosis, among the native-born and immigrant populations were assessed in Malm, the city in Sweden with the highest proportion of immigrants.Methods. All adult patients admitted for in-patient psychiatric treatment in Malm during the course of a 1-year period (N = 1162) were studied with regard to ethnicity and SLP diagnosis. A smaller sample consisting only of first-onset SLP cases (regardless of in- or out-patient status) was also studied (N = 56). Risks for admission and first-onset were calculated on the basis of current background population figures for Malm.Results. Compared with those who were native-born, immigrants had increased risk for admission for SLP, with a similar tendency for increased risk for first-onset of SLP. Relative risk for SLP admission was most markedly increased in immigrants from East-Africa. Background factors specifically associated with migration (e.g. extreme duress) did not appear to contribute strongly to SLP in immigrants.Conclusion. While the current results add to the growing body of evidence showing increased risk for psychosis in immigrants, vulnerability to psychosis may have been determined by factors other than the migration process.
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| 14. |
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