1. |
- Davies, G., et al.
(author)
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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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2. |
- Paradela, C., et al.
(author)
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High-accuracy determination of the 238U/235U fission cross section ratio up to ~1 GeV at n_TOF at CERN
- 2015
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In: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 91, s. 024602-
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Journal article (peer-reviewed)abstract
- The U238 to U235 fission cross section ratio has been determined at n_TOF up to ≈1 GeV, with two different detection systems, in different geometrical configurations. A total of four datasets has been collected and compared. They are all consistent to each other within the relative systematic uncertainty of 3–4%. The data collected at n_TOF have been suitably combined to yield a unique fission cross section ratio as a function of neutron energy. The result confirms current evaluations up to 200 MeV. Good agreement is also observed with theoretical calculations based on the INCL++/Gemini++ combination up to the highest measured energy. The n_TOF results may help solve a long-standing discrepancy between the two most important experimental datasets available so far above 20 MeV, while extending the neutron energy range for the first time up to ≈1 GeV.
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3. |
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4. |
- Diakaki, M., et al.
(author)
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Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - n_TOF
- 2016
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In: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X.
-
Conference paper (peer-reviewed)abstract
- The U-238 fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The U-238 fission cross section has been measured relative to the U-235 fission cross section at CERN - n_TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards.
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9. |
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10. |
- Leal-Cidoncha, E., et al.
(author)
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High accuracy 234U(n,f) cross section in the resonance energy region
- 2017
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In: ND 2016. - Les Ulis : EDP Sciences. - 9782759890200
-
Conference paper (peer-reviewed)abstract
- New results are presented of the 234U neutron-induced fission cross section, obtained with high accuracy in the resonance region by means of two methods using the 235U(n,f) as reference. The recent evaluation of the 235U(n,f) obtained with SAMMY by L. C. Leal et al. (these Proceedings), based on previous n_TOF data [1], has been used to calculate the 234U(n,f) cross section through the 234U/235U ratio, being here compared with the results obtained by using the n_TOF neutron flux.
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11. |
- Praena, J., et al.
(author)
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Preparation and characterization of 33S samples for 33S(n,alpha)30Si cross-section measurements at the n_TOF facility at CERN
- 2018
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 890, s. 142-147
-
Journal article (peer-reviewed)abstract
- Thin 33S samples for the study of the 33S(n,alpha)30Si cross-section at the n_TOF facility at CERN were made by thermal evaporation of 33S powder onto a dedicated substrate made of kapton covered with thin layers of copper, chromium and titanium. This method has provided for the first time bare sulfur samples a few centimeters in diameter. The samples have shown an excellent adherence with no mass loss after few years and no sublimation in vacuum at room temperature. The determination of the mass thickness of 33S has been performed by means of Rutherford backscattering spectrometry. The samples have been successfully tested under neutron irradiation.
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12. |
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13. |
- Tarrío, Diego, et al.
(author)
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Measurement of the angular distribution of fission fragments using a PPAC assembly at CERN n_TOF
- 2014
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 743, s. 79-85
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Journal article (peer-reviewed)abstract
- A fission reaction chamber based on Parallel Plate Avalanche Counters (PPACs) was built for measuring angular distributions of fragments emitted in neutron-induced fission of actinides at the neutron beam available at the Neutron Time-Of-Flight (n_TOF) facility at CERN. The detectors and the samples were tilted 45 degrees with respect to the neutron beam direction to cover all the possible values of the emission angle of the fission fragments. The main features of this setup are discussed and results on the fission fragment angular distribution are provided for the Th-232(n,f) reaction around the fission threshold. The results are compared with the available data in the literature, demonstrating the good capabilities of this setup.
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14. |
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15. |
- Leal-Cidoncha, E., et al.
(author)
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Fission Fragment Angular Distribution measurements of 235U and 238U at CERN n_TOF facility
- 2016
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In: EPJ Web of Conferences. - : EDP Sciences. - 2100-014X.
-
Conference paper (peer-reviewed)abstract
- Neutron-induced fission cross sections of U-238 and U-235 are used as standards in the fast neutron region up to 200 MeV. A high accuracy of the standards is relevant to experimentally determine other neutron reaction cross sections. Therefore, the detection efficiency should be corrected by using the angular distribution of the fission fragments (FFAD), which are barely known above 20 MeV. In addition, the angular distribution of the fragments produced in the fission of highly excited and deformed nuclei is an important observable to investigate the nuclear fission process. In order to measure the FFAD of neutron-induced reactions, a fission detection setup based on parallel-plate avalanche counters (PPACs) has been developed and successfully used at the CERN-n_TOF facility. In this work, we present the preliminary results on the analysis of new U-235(n,f) and U-238(n,f) data in the extended energy range up to 200 MeV compared to the existing experimental data.
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16. |
- Tarrío, Diego, et al.
(author)
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Neutron-induced fission cross sections of Th-232 and U-233 up to 1 GeV using parallel plate avalanche counters at the CERN n_TOF facility
- 2023
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In: Physical Review C. - : American Physical Society. - 2469-9985 .- 2469-9993. ; 107:4
-
Journal article (peer-reviewed)abstract
- The neutron-induced fission cross sections of Th-232 and U-233 were measured relative to U-235 in a wide neutron energy range up to 1 GeV (and from fission threshold in the case of Th-232, and from 0.7 eV in case of U-233), using the white-spectrum neutron source at the CERN Neutron Time-of-Flight (n_TOF) facility. Parallel plate avalanche counters (PPACs) were used, installed at the Experimental Area 1 (EAR1), which is located at 185 m from the neutron spallation target. The anisotropic emission of fission fragments were taken into account in the detection efficiency by using, in the case of U-233, previous results available in EXFOR, whereas in the case of Th-232 these data were obtained from our measurement, using PPACs and targets tilted 45 degrees with respect to the neutron beam direction. Finally, the obtained results are compared with past measurements and major evaluated nuclear data libraries. Calculations using the high-energy reaction models INCL++ and ABLA07 were performed and some of their parameters were modified to reproduce the experimental results. At high energies, where no other neutron data exist, our results are compared with experimental data on proton-induced fission. Moreover, the dependence of the fission cross section at 1 GeV with the fissility parameter of the target nucleus is studied by combining those ( p, f) data with our (n, f) data on Th-232 and U-233 and on other isotopes studied earlier at n_TOF using the same experimental setup.
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17. |
- Tarrío, Diego, et al.
(author)
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Fission Fragment Angular Distribution of Th-232(n,f) at the CERN n_TOF Facility
- 2014
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In: Nuclear Data Sheets. - Univ Santiago de Compostela, Santiago De Compostela, Spain. [Leong, L. S.; Audouin, L.; Tassan-Got, L.; Lederer, C.] IPN, CNRS, IN2P3, Orsay, France. [Altstadt, S.; Langer, C.; Lederer, C.; Reifarth, R.; Schmidt, S.; Weigand, M.] Goethe Univ Frankfurt, D-60054 Frankfurt, Germany. [Andrzejewski, J.; Marganiec, J.; Perkowski, J.] Univ Lodz, PL-90131 Lodz, Poland. [Barbagallo, M.; Colonna, N.; Mastromarco, M.; Meaze, M.; Tagliente, G.; Variale, V.] Ist Nazl Fis Nucl, I-70126 Bari, Italy. [Becares, V.; Cano-Ott, D.; Garcia, A. R.; Gonzalez-Romero, E.; Martinez, T.; Mendoza, E.] CIEMAT, E-28040 Madrid, Spain. [Becvar, F.; Krticka, M.; Kroll, J.; Valenta, S.] Charles Univ Prague, Prague, Czech Republic. [Belloni, F.; Berthoumieux, E.; Bosnar, D.; Chiaveri, E.; Fraval, K.; Gunsing, F.] CEA Saclay, Irfu, F-91191 Gif Sur Yvette, France. [Berthoumieux, E.; Boccone, V.; Bosnar, D.; Brugger, M.; Calviani, M.; Cerutti, F.; Chiaveri, E.; Chin, M.; Ferrari, A.; Guerrero, C.; Kadi, Y.; Losito, R.; Roman, F.; Rubbia, C.; Tsinganis, A.; Versaci, R.; Vlachoudis, V.] CERN, European Org Nucl Res, CH-1211 Geneva, Switzerland. [Billowes, J.; Ware, T.; Wright, T. J.] Univ Manchester, Manchester, Lancs, England. [Zugec, P.] Univ Zagreb, Fac Sci, Dept Phys, Zagreb 41000, Croatia. [Calvino, F.; Cortes, G.; Gomez-Hornillos, M. B.; Riego, A.] Univ Politecn Cataluna, Barcelona, Spain. [Carrapico, C.; Goncalves, I. F.; Sarmento, R.; Vaz, P.] Univ Tecn Lisboa, Inst Super Tecn, Inst Tecnol Nucl, P-1096 Lisbon, Portugal. [Cortes-Giraldo, M. A.; Praena, J.; Quesada, J. M.] Univ Seville, Seville, Spain. [Diakaki, M.; Karadimos, D.; Kokkoris, M.; Vlastou, R.] Natl Tech Univ Athens, GR-10682 Athens, Greece. [Domingo-Pardo, C.; Giubrone, G.; Tain, J. L.] Univ Valencia, CSIC, Inst Fis Corpuscular, E-46003 Valencia, Spain. [Dzysiuk, N.; Mastinu, P. F.] Ist Nazl Fis Nucl, Lab Nazl Legnaro, Milan, Italy. [Eleftheriadis, C.; Manousos, A.] Aristotle Univ Thessaloniki, GR-54006 Thessaloniki, Greece. [Ganesan, S.; Gurusamy, P.] Bhabha Atom Res Ctr, Bombay 400085, Maharashtra, India. [Griesmayer, E.; Jericha, E.; Leeb, H.; Weiss, C.] Vienna Univ Technol, Inst Atom, Vienna, Austria. [Jenkins, D. G.; Vermeulen, M. J.] Univ York, York YO10 5DD, N Yorkshire, England. [Kaeppeler, F.] Karlsruhe Inst Technol, Inst Kernphys, D-76021 Karlsruhe, Germany. [Koehler, P.] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. [Lederer, C.; Pavlik, A.; Wallner, A.] Univ Vienna, Fac Phys, A-1010 Vienna, Austria. [Massimi, C.; Mingrone, F.; Vannini, G.] Univ Bologna, Dipartimento Fis, I-40126 Bologna, Italy. [Massimi, C.; Mingrone, F.; Vannini, G.] Sez INFN Bologna, Bologna, Italy. [Mengoni, A.; Ventura, A.] Agenzia Nazl Nuove Tecnol, Eenergia & Sviluppo Econ Sostenibile ENEA, Bologna, Italy. [Milazzo, P. M.] Ist Nazl Fis Nucl, Trieste, Italy. [Mirea, M.; Roman, F.] Horia Hulubei Natl Inst Phys & Nucl Engn, IFIN HH, Bucharest, Romania. [Mondalaers, W.; Plompen, A.; Schillebeeckx, P.] European Commiss JRC, Inst Reference Mat & Measurements, B-2440 Geel, Belgium. [Rauscher, T.] Univ Basel, Dept Phys & Astron, Basel, Switzerland. [Rubbia, C.] Ist Nazl Fis Nucl, Lab Nazl Gran Sasso, Assergi, AQ, Italy. : Elsevier BV. - 0090-3752 .- 1095-9904. ; 119, s. 35-37
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Journal article (peer-reviewed)abstract
- The angular distribution of fragments emitted in neutron-induced fission of Th-232 was measured in the white spectrum neutron beam at the n_TOF facility at CERN. A reaction chamber based on Parallel Plate Avalanche Counters (PPAC) was used, where the detectors and the targets have been tilted 45 degrees with respect to the neutron beam direction in order to cover the full angular range of the fission fragments. A GEANT4 simulation has been developed to study the setup efficiency. The data analysis and the preliminary results obtained for the Th-232(n,f) between fission threshold and 100 MeV are presented here.
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18. |
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19. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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20. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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21. |
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22. |
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23. |
- Turcot, Valerie, et al.
(author)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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24. |
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25. |
- Kilpelainen, TO, et al.
(author)
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Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
- 2019
-
In: Nature communications. - London : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 376-
-
Journal article (peer-reviewed)abstract
- Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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26. |
- Feitosa, Mary F., et al.
(author)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
-
In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
-
Journal article (peer-reviewed)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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27. |
- Sung, Yun Ju, et al.
(author)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Journal article (peer-reviewed)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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28. |
- de Vries, Paul S., et al.
(author)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
-
Journal article (peer-reviewed)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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29. |
- Plompen, A. J. M., et al.
(author)
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The joint evaluated fission and fusion nuclear data library, JEFF-3.3
- 2020
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In: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 56:7
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Research review (peer-reviewed)abstract
- The joint evaluated fission and fusion nuclear data library 3.3 is described. New evaluations for neutron-induced interactions with the major actinides 235U, 238U and 239Pu, on 241Am and 23Na, 59Ni, Cr, Cu, Zr, Cd, Hf, W, Au, Pb and Bi are presented. It includes new fission yields, prompt fission neutron spectra and average number of neutrons per fission. In addition, new data for radioactive decay, thermal neutron scattering, gamma-ray emission, neutron activation, delayed neutrons and displacement damage are presented. JEFF-3.3 was complemented by files from the TENDL project. The libraries for photon, proton, deuteron, triton, helion and alpha-particle induced reactions are from TENDL-2017. The demands for uncertainty quantification in modeling led to many new covariance data for the evaluations. A comparison between results from model calculations using the JEFF-3.3 library and those from benchmark experiments for criticality, delayed neutron yields, shielding and decay heat, reveals that JEFF-3.3 performes very well for a wide range of nuclear technology applications, in particular nuclear energy.
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30. |
- Joshi, Peter K, et al.
(author)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Journal article (peer-reviewed)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.
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31. |
- de las Fuentes, Lisa, et al.
(author)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Journal article (peer-reviewed)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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- Sikkema, Lisa, et al.
(author)
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An integrated cell atlas of the lung in health and disease
- 2023
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In: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Journal article (peer-reviewed)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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36. |
- Smith, Jennifer A, et al.
(author)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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In: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Journal article (peer-reviewed)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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37. |
- Whiffin, N, et al.
(author)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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In: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Journal article (peer-reviewed)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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- Haljas, Kadri, et al.
(author)
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Bivariate genome-wide association study of depressive symptoms with type 2 diabetes and quantitative glycemic traits
- 2018
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In: Psychosomatic Medicine. - 0033-3174. ; 80:3, s. 242-251
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Journal article (peer-reviewed)abstract
- Objective: Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits. Methods: We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of β-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 10−8). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases. Results: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes). Conclusions: We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.
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44. |
- Maddali, Manoj V., et al.
(author)
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Validation and utility of ARDS subphenotypes identified by machine-learning models using clinical data : an observational, multicohort, retrospective analysis
- 2022
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In: The Lancet Respiratory Medicine. - 2213-2600. ; 10:4, s. 367-377
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Journal article (peer-reviewed)abstract
- Background: Two acute respiratory distress syndrome (ARDS) subphenotypes (hyperinflammatory and hypoinflammatory) with distinct clinical and biological features and differential treatment responses have been identified using latent class analysis (LCA) in seven individual cohorts. To facilitate bedside identification of subphenotypes, clinical classifier models using readily available clinical variables have been described in four randomised controlled trials. We aimed to assess the performance of these models in observational cohorts of ARDS. Methods: In this observational, multicohort, retrospective study, we validated two machine-learning clinical classifier models for assigning ARDS subphenotypes in two observational cohorts of patients with ARDS: Early Assessment of Renal and Lung Injury (EARLI; n=335) and Validating Acute Lung Injury Markers for Diagnosis (VALID; n=452), with LCA-derived subphenotypes as the gold standard. The primary model comprised only vital signs and laboratory variables, and the secondary model comprised all predictors in the primary model, with the addition of ventilatory variables and demographics. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC) and calibration plots, and assigning subphenotypes using a probability cutoff value of 0·5 to determine sensitivity, specificity, and accuracy of the assignments. We also assessed the performance of the primary model in EARLI using data automatically extracted from an electronic health record (EHR; EHR-derived EARLI cohort). In Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE; n=2813), a multinational, observational ARDS cohort, we applied a custom classifier model (with fewer variables than the primary model) to determine the prognostic value of the subphenotypes and tested their interaction with the positive end-expiratory pressure (PEEP) strategy, with 90-day mortality as the dependent variable. Findings: The primary clinical classifier model had an area under receiver operating characteristic curve (AUC) of 0·92 (95% CI 0·90–0·95) in EARLI and 0·88 (0·84–0·91) in VALID. Performance of the primary model was similar when using exclusively EHR-derived predictors compared with manually curated predictors (AUC=0·88 [95% CI 0·81–0·94] vs 0·92 [0·88–0·97]). In LUNG SAFE, 90-day mortality was higher in patients assigned the hyperinflammatory subphenotype than in those with the hypoinflammatory phenotype (414 [57%] of 725 vs 694 [33%] of 2088; p<0·0001). There was a significant treatment interaction with PEEP strategy and ARDS subphenotype (p=0·041), with lower 90-day mortality in the high PEEP group of patients with the hyperinflammatory subphenotype (hyperinflammatory subphenotype: 169 [54%] of 313 patients in the high PEEP group vs 127 [62%] of 205 patients in the low PEEP group; hypoinflammatory subphenotype: 231 [34%] of 675 patients in the high PEEP group vs 233 [32%] of 734 patients in the low PEEP group). Interpretation: Classifier models using clinical variables alone can accurately assign ARDS subphenotypes in observational cohorts. Application of these models can provide valuable prognostic information and could inform management strategies for personalised treatment, including application of PEEP, once prospectively validated. Funding: US National Institutes of Health and European Society of Intensive Care Medicine.
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45. |
- Walsh, Roddy, et al.
(author)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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In: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Journal article (peer-reviewed)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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