| 1. |
- Joshi, Peter K, et al.
(författare)
-
Directional dominance on stature and cognition in diverse human populations
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
-
Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
|
|
| 2. |
- Arndt, D. S., et al.
(författare)
-
STATE OF THE CLIMATE IN 2017
- 2018
-
Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
-
Forskningsöversikt (refereegranskat)
|
|
| 3. |
- Iveson, Timothy J., et al.
(författare)
-
3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT) : an international, randomised, phase 3, non-inferiority trial
- 2018
-
Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 19:4, s. 562-578
-
Tidskriftsartikel (refereegranskat)abstract
- Background: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1: 1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1.13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.Findings: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76.7% (95% CI 75.1-78.2) for the 3 month group and 77.1% (75.6-78.6) for the 6 month group, giving a hazard ratio of 1.006 (0.909-1.114, test for non-inferiority p=0.012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).Interpretation: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.
|
|
| 4. |
- Arndt, D. S., et al.
(författare)
-
State of the Climate in 2016
- 2017
-
Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280
-
Tidskriftsartikel (refereegranskat)abstract
- In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
|
|
| 5. |
- Ntalla, Ioanna, et al.
(författare)
-
Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
|
|
| 6. |
- Robles-Zurita, Jose, et al.
(författare)
-
SCOT : a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer
- 2018
-
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 119:11, s. 1332-1338
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer.METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken.RESULTS: The 3M arm is less costly (-4881; pound 95% CI: -6269; pound -3492) pound and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3M had lower QALYs than 6M (not statistically significant).CONCLUSIONS: Overall, 3M dominates 6M with no significant detrimental impact on QALYs. The results provide the economic case that a 3M treatment strategy should be considered a new standard of care.
|
|
| 7. |
- Silvano, Alessandro, et al.
(författare)
-
Observing Antarctic Bottom Water in the Southern Ocean
- 2023
-
Ingår i: Frontiers in Marine Science. - 2296-7745. ; 10
-
Forskningsöversikt (refereegranskat)abstract
- Dense, cold waters formed on Antarctic continental shelves descend along the Antarctic continental margin, where they mix with other Southern Ocean waters to form Antarctic Bottom Water (AABW). AABW then spreads into the deepest parts of all major ocean basins, isolating heat and carbon from the atmosphere for centuries. Despite AABW's key role in regulating Earth's climate on long time scales and in recording Southern Ocean conditions, AABW remains poorly observed. This lack of observational data is mostly due to two factors. First, AABW originates on the Antarctic continental shelf and slope where in situ measurements are limited and ocean observations by satellites are hampered by persistent sea ice cover and long periods of darkness in winter. Second, north of the Antarctic continental slope, AABW is found below approximately 2 km depth, where in situ observations are also scarce and satellites cannot provide direct measurements. Here, we review progress made during the past decades in observing AABW. We describe 1) long-term monitoring obtained by moorings, by ship-based surveys, and beneath ice shelves through bore holes; 2) the recent development of autonomous observing tools in coastal Antarctic and deep ocean systems; and 3) alternative approaches including data assimilation models and satellite-derived proxies. The variety of approaches is beginning to transform our understanding of AABW, including its formation processes, temporal variability, and contribution to the lower limb of the global ocean meridional overturning circulation. In particular, these observations highlight the key role played by winds, sea ice, and the Antarctic Ice Sheet in AABW-related processes. We conclude by discussing future avenues for observing and understanding AABW, impressing the need for a sustained and coordinated observing system.
|
|
| 8. |
- Artigas Soler, María, et al.
(författare)
-
Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
-
Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
|
|
| 9. |
- Chen, Zhishan, et al.
(författare)
-
Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
-
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.
|
|
| 10. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
-
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
-
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.
|
|
