| 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. |
- Bień, Barbara, et al.
(författare)
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Disabled older people’s use of health and social care services and their unmet care needs in six European countries
- 2013
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 23:6, s. 1032-1038
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Tidskriftsartikel (refereegranskat)abstract
- Background: The national health and social care systems in Europe remain poorly integrated with regard to the care needs of older persons. The present study examined the range of health and social care services used by older people and their unmet care needs, across six European countries. Methods: Family carers of older people were recruited in six countries via a standard protocol. Those providing care for disabled older people (n = 2629) provided data on the older person’s service use over a 6-month period, and their current unmet care needs. An inventory of 21 services common to all six countries was developed. Analyses considered the relationship between older people’s service use and unmet care needs across countries. Results: Older people in Greece, Italy and Poland used mostly health-oriented services, used fewer services overall and also demonstrated a higher level of unmet care needs when compared with the other countries. Older people in the United Kingdom, Germany and Sweden used a more balanced profile of socio-medical services. A negative relationship was found between the number of different services used and the number of different areas of unmet care needs across countries. Conclusions: Unmet care needs in older people are particularly high in European countries where social service use is low, and where there is a lack of balance in the use of health and social care services. An expansion of social care services in these countries might be the most effective strategy for reducing unmet needs in disabled older people.
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| 3. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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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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| 4. |
- 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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| 5. |
- Di Rosa, Mirko, et al.
(författare)
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A typology of caregiving situations and service use in family carers of older people in six European countries : The EUROFAMCARE study
- 2011
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Ingår i: GeroPsych. - Bern : Hogrefe Publishing. - 1662-9647 .- 1662-971X. ; 24:1, s. 5-18
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the EUROFAMCARE study findings, examining a typology of care situations for family carers of older people, and the interplay of carers with social and health services. Despite the complexity of family caregiving situations across Europe, our analyses determined the existence of seven “caregiving situations,” varying on a range of critical indicators. Our study also describes the availability and use of different support services for carers and care receivers, and carers’ preferences for the characteristics of support services. Our findings have relevance for policy initiatives in Europe, where limited resources need to be more equitably distributed and services should be targeted to caregiving situations reflecting the greatest need, and organized to reflect the preferences of family carers.
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| 6. |
- 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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| 7. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 8. |
- Lüdecke, Daniel, et al.
(författare)
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For better or worse : Factors predicting outcomes of family care of older people over a one-year period. A six-country European study
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Demographic change has led to an increase of older people in need of long-term care in nearly all European countries. Informal carers primarily provide the care and support needed by dependent people. The supply and willingness of individuals to act as carers are critical to sustain informal care resources as part of the home health care provision. This paper describes a longitudinal study of informal care in six European countries and reports analyses that determine those factors predicting the outcomes of family care over a one-year period.METHODS: Analyses are based on data from the EUROFAMCARE project, a longitudinal survey study of family carers of older people with baseline data collection in 2004 and follow-up data collection a year later in six European countries (Germany, Greece, Italy, Poland, Sweden, and the United Kingdom), N = 3,348. Descriptive statistics of the sample characteristics are reported. Binary logistic random-intercept regressions were computed, predicting the outcome of change of the care dyad's status at follow-up.RESULTS: Where care is provided by a more distant family member or by a friend or neighbour, the care-recipient is significantly more likely to be cared for by someone else (OR 1.62) or to be in residential care (OR 3.37) after one year. The same holds true if the care-recipient has memory problems with a dementia diagnosis (OR 1.79/OR 1.84). Higher dependency (OR 1.22) and behavioural problems (OR 1.76) in the care-recipient also lead to a change of care dyad status. Country of residence explained a relatively small amount of variance (8%) in whether a care-recipient was cared for by someone else after one year, but explained a substantial amount of variance (52%) in whether a care-recipient was in residential care. Particularly in Sweden, care-recipients are much more likely to be cared for by another family or professional carer or to be in residential care, whereas in Greece the status of the care dyad is much less likely to change.DISCUSSION: The majority of family carers continued to provide care to their respective older relatives over a one-year period, despite often high levels of functional, cognitive and behavioural problems in the care-recipient. Those family carers could benefit most from appropriate support. The carer/care-recipient relationship plays an important role in whether or not a family care dyad remains intact over a one-year period. The support of health and social care services should be particularly targeted toward those care dyads where there is no partner or spouse acting as carer, or no extended family network that might absorb the caring role when required. Distant relatives, friends or acquaintances who are acting as carers might need substantial intervention if their caregiving role is to be maintained.
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| 9. |
- Principi, Andrea, et al.
(författare)
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Work restrictions experienced by midlife family care-givers of older people: evidence from six European countries
- 2014
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Ingår i: Ageing & Society. - : Cambridge University Press (CUP). - 0144-686X .- 1469-1779. ; 34:2, s. 209-231
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Tidskriftsartikel (refereegranskat)abstract
- This paper examines differences in work restrictions of midlife family carers of older people in terms of prevalence, gender and explanatory variables, in six European countries: Germany, Greece, Italy, Poland, Sweden and the United Kingdom. A sample of 2,897 carers aged 45-64 was extracted from the EUROFAMCARE (Services for Supporting Family Carers of Older People in Europe: Characteristics, Coverage and Usage) European project database, in order to analyse four possible work restrictions experienced in connection with the activity of care-giving: the reduction of working hours; giving up working; difficulties in career developments and forced occasional work. The results show that work restrictions are experienced differently between countries especially by women: they are reported to a higher degree in the United Kingdom, Germany and Greece, less so in Italy, and seldom in Poland and Sweden. Gender differences within countries are not so marked. Country differences are explained in the light of the different welfare regimes characterising the countries under investigation, in order to elucidate how policy makers may act to improve working carers conditions through appropriate policies.
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| 10. |
- 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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