| 1. |
|
|
| 2. |
- Momozawa, Y, et al.
(författare)
-
IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
-
Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
|
|
| 3. |
|
|
| 4. |
- Alberts, R, et al.
(författare)
-
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
- 2018
-
Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:8, s. 1517-1524
-
Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Besser, Jana, et al.
(författare)
-
Speech-in-Speech Listening on the LiSN-S Test by Older Adults With Good Audiograms Depends on Cognition and Hearing Acuity at High Frequencies
- 2015
-
Ingår i: Ear and Hearing. - : LIPPINCOTT WILLIAMS and WILKINS. - 0196-0202 .- 1538-4667. ; 36:1, s. 24-41
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: The main objective was to investigate age-related differences on the listening in spatialized noise-sentences (LiSN-S) test in adults with normal audiometric thresholds in most of the speech range. A second objective was to examine the contributions of auditory, cognitive, and linguistic abilities to LiSN-S outcomes. Design: The LiSN-S test was administered to participants in an older group (M-Age = 72.0, SD = 4.3 years) and a younger group (M-Age = 21.7, SD = 2.6 years) with N = 26 per group. All the participants had clinically normal audiometric thresholds at frequencies up to and including 3000 Hz. The LiSN-S test yields a speech reception threshold (SRT) in each of the four speech-in-speech listening conditions that differ in the availability of voice difference cues and/or spatial separation cues. Based on these four SRTs, the scores were calculated for the talker advantage, the spatial advantage, and the total advantage as a result of both the types of cues. Additionally, the participants completed four auditory temporal-processing tests, a cognitive screening test, a vocabulary test, and tests of linguistic closure for high-and low-context sentences. The contributions of these predictor variables and measures of pure-tone hearing acuity to LiSN-S outcomes were analyzed for both the groups using regression analyses. Results: Younger listeners outperformed the older listeners on all four LiSN-S SRTs and all the three LiSN-S advantage measures. Age-related differences were larger for conditions involving the use of spatial cues. For the younger group, all LiSN-S SRTs were predicted by the measure of linguistic closure in low-context sentences; in addition, the SRT for the condition with voice difference cues but without spatial separation cues was predicted by vocabulary, and the SRT for the condition with both voice difference cues and spatial separation cues was predicted by temporal resolution at low frequencies. Vocabulary also contributed to the talker advantage in the younger group, whereas the spatial advantage was predicted by high-frequency pure-tone hearing acuity in the range 6,000 to 10,000 Hz (pure-tone average [ PTA] HIGH). For the older group, the LiSN-S SRT in the condition with neither voice difference cues nor spatial separation cues was predicted by age; their other three LiSN-S SRTs and all advantage measures were predicted by PTA HIGH. In addition, for the older group, cognition predicted LiSN-S SRT outcomes in three of the four conditions. Measures of auditory temporal processing, linguistic abilities, or hearing acuity up to and including 4000 Hz did not predict LiSN-S outcomes in this group. Conclusions: LiSN-S outcomes were poorer for adults aged 65 years or older, even those with good audiograms, compared with younger adults and also compared with people up to the age of 60 years from a previous study. In the present study, regardless of the types of cues, auditory and cognitive interactions were reflected by the combined influences on LiSN-S outcomes of high-frequency hearing acuity and measures of linguistic and cognitive processing. The data also suggest a hierarchy in the deployment of processing resources, which would account for the observed shift from linguistic abilities in the younger group to general cognitive abilities in the older group.
|
|
| 8. |
- Franke, Andre, et al.
(författare)
-
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
-
Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
|
|
| 9. |
- van der Heijde, Nicky, et al.
(författare)
-
Use and outcome of minimally invasive pancreatic surgery in the European E-MIPS registry
- 2023
-
Ingår i: HPB. - : ELSEVIER SCI LTD. - 1365-182X .- 1477-2574. ; 25:4, s. 400-408
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The European registry for minimally invasive pancreatic surgery (E-MIPS) collects data on laparoscopic and robotic MIPS in low-and high-volume centers across Europe.Methods: Analysis of the first year (2019) of the E-MIPS registry, including minimally invasive distal pancreatectomy (MIDP) and minimally invasive pancreatoduodenectomy (MIPD). Primary outcome was 90-day mortality.Results: Overall, 959 patients from 54 centers in 15 countries were included, 558 patients underwent MIDP and 401 patients MIPD. Median volume of MIDP was 10 (7-20) and 9 (2-20) for MIPD. Median use of MIDP was 56.0% (IQR 39.0-77.3%) and median use of MIPD 27.7% (IQR 9.7-45.3%). MIDP was mostly performed laparoscopic (401/558, 71.9%) and MIPD mostly robotic (234/401, 58.3%). MIPD was performed in 50/54 (89.3%) centers, of which 15/50 (30.0%) performed >= 20 MIPD annually. This was 30/ 54 (55.6%) centers and 13/30 (43%) centers for MIPD respectively. Conversion rate was 10.9% for MIDP and 8.4% for MIPD. Overall 90 day mortality was 1.1% (n = 6) for MIDP and 3.7% (n = 15) for MIPD.Conclusion: Within the E-MIPS registry, MIDP is performed in about half of all patients, mostly using laparoscopy. MIPD is performed in about a quarter of patients, slightly more often using the robotic approach. A minority of centers met the Miami guideline volume criteria for MIPD.
|
|
| 10. |
|
|
