[ES] Durante las últimas décadas, se han realizado importantes avances en el estudio de las causas genéticas de enfermedades raras y comunes, donde un gran número de variantes han sido identificadas y asociadas a múltiples enfermedades. Con las tecnologías de secuenciación de nueva generación, hoy en día somos capaces de investigar, con un alto rendimiento, la contribución de variantes de alta y baja frecuencia a distintos tipos de enfermedades, permitiéndonos así estudiar su importancia en el desarrollo de las mismas. En ésta tesis se ha utilizado la secuenciación del exoma como tecnología para el estudio de variantes raras en una enfermedad compleja, la alergia gastrointestinal inducida por múltiples alimentos. Para ello, se realizó la secuenciación del exoma completo de una cohorte de 31 individuos (ocho afectados y 23 no afectados) provenientes de siete familias diferentes. Se desarrolló un flujo de trabajo para procesar los datos generados a partir de diferentes librerías e instrumentos de secuenciación, así como un control de calidad exhaustivo con el fin de maximizar el número de variantes de alta calidad. Diferentes tipos de mutaciones fueron investigadas, incluyendo polimorfismos de nucleótido único, inserciones/deleciones, variantes del número de copia y haplotipos HLA, y se realizaron diferentes métodos de filtrado para su interpretación. Finalmente, se encontraron una serie de mutaciones que podrían estar asociadas con la enfermedad y se describe su posible papel en la patogénesis de las alergias gastrointestinales. Los resultados de esta tesis suponen importantes avances en el estudio de la compleja arquitectura genética de las alergias gastrointestinales y abren las puertas a futuras líneas de investigación, que serán necesarias para entender completamente las bases genéticas de esta enfermedad. / [CAT] Durant les últimes dècades, s'han realitzat importants avanços en l'estudi de les causes genètiques de malalties rares i comunes, on un gran nombre de variants han sigut identificades i associades a múltiples malalties. Amb les tecnologies de seqüenciació de nova generació, avui en dia som capaços d'investigar, amb un alt rendiment, la contribució de variants d'alta i baixa freqüència a diferents tipus de malalties, permetent-nos així estudiar la seva importància en el desenvolupament de les mateixes. En aquesta tesis s'ha utilitzat la seqüenciació del exoma com a tecnologia per a l'estudi de variants rares en una malaltia complexa, l'al·lèrgia gastrointestinal induïda per múltiples aliments. Per això, es va realitzar la seqüenciació del exoma complet d'una cohort de 31 individus (vuit afectats i 23 no afectats) provinents de set famílies diferents. Es va desenvolupar un flux de treball per a processar les dades generades a partir de diferents llibreries e instruments de seqüenciació, així com un control de qualitat exhaustiu amb la fi de maximitzar el nombre de variants d'alta qualitat. Diferents tipus de mutacions foren investigades, incloïent polimorfismes de nucleòtid únic, insercions/delecions, variants del nombre de còpia i haplotips HLA, i es realitzaren diferent mètodes de filtrat per a la seva interpretació. Finalment, es trobaren una sèrie de mutacions que podrien estar associades amb la malaltia i es descriu el seu possible paper en la patogènesis de les al·lèrgies gastrointestinals. Els resultats d'aquesta tesis suposen importants avanços en l'estudi de la complexa arquitectura genètica de les al·lèrgies gastrointestinals i obrin les portes a futures línies d'investigació, que seran necessàries per entendre completament les bases genètiques d'aquesta malaltia. / [EN] The study of genetics has been making significant progress towards understanding the causes of rare and common disease during the past decades. Across a wide range of disorders, there have been hundreds of associated loci identified and associated with multiple disorders. Now, with the advent of next-generation sequencing technologies, we are able to interrogate the contribution of high and low frequency variation to disease in a high throughput manner. This provides an opportunity to investigate the role of rare variation in complex disease risk, potentially offering insights into disease pathogenesis and biological mechanisms. In this thesis, it has been assessed the use of whole-exome sequencing technology to investigate the role of rare variation in a complex disease, gastrointestinal food allergy induced by multiple food proteins. For that, a cohort of 31 individuals (eight affected and 23 non-affected) from seven different families was whole exome sequenced. Data obtained from multiple sequencing systems and libraries were analysed, and a workflow was developed, focusing on a comprehensive quality control to maximise the number of real positive calls. Different types of genome variations were investigated, including single nucleotide variants, insertions/deletions, copy number variants and HLA haplotypes. By approaching different methods of variant filtering, a set of rare variants that could be associated with the disease was identified. The possible role of these candidate variants in the pathogenesis of gastrointestinal food allergies was also discussed. These results reveal important insights into the genetic architecture of gastrointestinal food allergies and lead to additional lines of investigation that will be required in order to fully understand the genetic basis of this disease. / Sanchis Juan, A. (2019). Exome Sequencing in Gastrointestinal Food Allergy Induced by Multiple Food Protein [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/134361 / TESIS

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第21564号 / 理博第4471号 / 新制||理||1642(附属図書館) / 京都大学大学院理学研究科物理学・宇宙物理学専攻 / (主査)准教授 市川 温子, 教授 鶴 剛, 教授 中家 剛 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM

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Many phenotypic traits are heritable, but the exact genetic causes are difficult to determine. A common approach for disentangling the different genetic factors is to conduct a "genome-wide association study" (GWAS), where each single nucleotide variant (SNV) is tested for association with a trait of interest. Many SNVs for complex traits have been found by GWAS, but to date they explain only a fraction of heritability of complex traits. In this dissertation, we propose novel optimization-based and multiple testing procedures for variant set tests. In the second chapter, we propose a novel variant set test, convex-optimized SKAT (cSKAT), that leverages multiple SNV annotations. The test generalizes SKAT to convex combinations of SKAT statistics constructed from functional genomic annotations. We differ from previous approaches by optimizing kernel weights with a multiple kernel learning algorithm. In cSKAT, the contribution of each variant to the overall statistic is a product of annotation values and kernel weights for annotation classes. We demonstrate the utility of our biologically-informed SNV weights in a rare-variant analysis of fasting glucose in the FHS. In the third chapter, we propose a sequential testing procedure for GWAS that joins tests of single SNVs and groups of SNVs (SNV-sets) with common biological function. The proposed procedure differs from previous procedures by testing genes and sliding 4kb intergenic windows rather than chromosomes or the whole genome. We also sharpen an existing tree-based multiple testing correction by incorporating correlation between SNVs, which is present in any SNV-set containing contiguous regions (such as genes). In the fourth chapter, we present a sequential testing procedure for SNV-sets that incorporates correlation between test statistics of the SNV-sets. At each step of the procedure, the multiplicity correction is the number of remaining independent tests, making no assumption about the null distribution of tests. We provide an estimator for the number of remaining independent tests based on previous work in single-SNV GWAS and demonstrate the estimator is valid for sequential procedures. We implement the proposed method for GWAS by sequentially testing chromosomes, genes, 4kb windows, and SNVs.

More resources are being defined as critical, which can be attributed to the linear economy of ‘take, make and dispose’. An alternative is to implement the circular economy (CE) which could reduce several negative effects, among other things resource depletion. The aim of this thesis is to identify what current sustainability indicators are lacking to assess a resource with the CE concept. This is done by developing CE core indicators, which then are compared with sustainability indicators. The life cycle of rare earth elements (REE) is used as a case study to validate the CE core indicators. To achieve this literature studies and comparative analysis will be performed. Existing definitions and indicators of CE were studied to compile a complete set of core indicators. These compiled CE core indicators were then compared with adapted United Nation (UN) sustainability indicators. The UN indicators were chosen after analysing several different sustainability indicator system and their compatibility with the resource perspective. The main differences between the UN indicators and CE core indicators is that the UN indicators does not include economic aspects such as market diversity and social aspects such as consumption behaviour. However, the UN indicator system includes transportation and governance that could be beneficial to include into the CE concept. The economic viability to perform the CE analysis and non-existing CE indicators for companies and countries were identified as two barriers that could hinder development and efficient use of a CE indicator system. A way to increase the economic viability is to use already generated data for the CE indicator analysis, though the economical aspect has to be studied further. The non-existing CE indicators for companies and countries are counted as a barrier due to the risk of sub-optimisation of one resource. Additionally, the CE indicator results could be misinterpreted to blame a few for the problems of the resource instead of using the results to improve all parts of the life cycle. Further research is also needed to investigate how, or even if, social aspects such as culture and society could be indicated within a CE indicator system. In conclusion, the UN indicator system could be a good baseline to develop a CE indicator system for a resource though further research is needed.

The rare earth polysulfides and polyselenides of Tm, Yb, and Lu are unknown. The ionic radius of the rare earth has become too small to allow the structure common to the known members of the series, and with the polysulfides the stable temperature zone is too low to give the high sulfur pressure necessary for synthesis of RS_2. It was felt that high pressure, high temperature techniques could be used to overcome both problems and to allow synthesis of compounds not possible by ordinary methods. Synthesis studies were carried out on mixtures of the rare earth element plus sulfur in the 1:2 mole ratio for Nd, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Y. The known polysulfide series was extended three members, TmS_2, YbS_2, and LuS_2. A high pressure pseudo-cubic polymorph was found for nine members, GdS_2, TbS_2, DyS_2, HoS_2, ErS_2, TmS_2, YbS_2, LuS_2, and YS_2. The minimum pressure of formation for the cubic polymorphs was found to be a smooth function of the ionic radius of the rare earth elements except for Y. YS_2 required a higher pressure to form the cubic polymorph than expected from the usual value of the ionic radius of Y, but the compressibility of Y is somewhat higher than Dy, which Y otherwise closely resembles. The reaction product diagrams of the rare earth polysulfides were all very similar. Regions were found where Ho_2S_3 and Yb_2S_3 were found on their respective diagrams. These compounds had the recently reported cubic Th_3P_4 type structure. Synthesis studies were carried out on 1:2 molar mixtures of rare earth element plus selenium for Er, Tm, Yb, and Lu. The known polyselenide series was extended three members to include TmSe_2, YbSe_2, and LuSe_2. Cubic Er_2Se_3 with the Th_3P_4 type structure was found at the highest pressure and temperature tried for the Er + 2 Se system. Prior to this work Er_2Se_3 was known only with the orthorhombic Sc_2S_3 type structure. The results of this investigation suggest that high pressure, high temperature techniques can be used to extend other series of rare earth compounds and several possibilities are suggested.

This thesis examines the way in which China's share of the rare earths global industry is constructed as a threat. The central argument of the research is that the US discourse presented a new form of danger through the lens of classical geopolitical thinking, thus, creating a new type of prospective conflict derived from resources that are perceived to be scarce and yet relatively abundant. It argues that the construction of this 'threat' that the US faces is a constant articulation of perceived vulnerabilities in shaping geopolitical identities and reinforcing ideologies through which are carried out by different actors. Rare earths are crucial for modern conditions and their applications include commercial, military and green technology but mining and production are neither economical nor environmentally friendly. The People's Republic of China is the principal exporter of these rare metals, but because of a territorial dispute in the South China Sea in 2010 it has been labelled as a monopoly power. This study seeks to examine the constructed threat that China poses to the US. China, here, is not only constructed to be a resource hungry giant but also a malicious state that would utilise its 'monopoly' status as geopolitical leverage. The thesis will employ discourse analysis and wisdoms of...

Genetic association analyses have successfully identified thousands of genetic variants contributing to complex disease susceptibility. However, these discoveries do not explain the full heritability of many diseases, due to the limited statistical power to detect loci with small effects, especially in regions with rare variants. The development of new and powerful methods is necessary to fully characterize the underlying genetic basis of complex diseases. Family history (FH) contains information on the disease status of un-genotyped relatives, which is related to the genotypes of probands at disease loci. Exploiting available FH in relatives could potentially enhance the ability to identify associations by increasing sample size. Many studies have very low power for genetic research in late-onset diseases because younger participants do not contribute a sufficient number of cases and older patients are more likely deceased without genotypes. Genetic association studies relying on cases and controls need to progress by incorporating additional information from FH to expand genetic research. This dissertation overcomes these challenges and opens up a new paradigm in genetic research. The first chapter summarizes relevant methods used in this dissertation. In the second chapter, we develop novel methods to exploit the availability of FH in aggregation unit-based test, which have greater power than other existing methods that do not incorporate FH, while maintaining a correct type I error. In the third chapter, we develop methods to exploit FH while adjusting for relatedness using the generalized linear mixed effect models. Such adjustment allows the methods to have well-controlled type I error and maintain the highest sample size because there is no need to restrict the analysis to an unrelated subset in family studies. We demonstrate the flexibility and validity of the methods to incorporate FH from various relatives. The methods presented in the fourth chapter overcome the issue of inflated type I error caused by extremely unbalanced case-control ratio. We propose robust versions of the methods developed in the second and third chapters, which can provide more accurate results for unbalanced study designs. Availability of these novel methods will facilitate the identification of rare variants associated with complex traits.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes.

We comprehensively examined the rare variants in the IPO11-HTR1A region to explore their roles in neuropsychiatric disorders. Five hundred seventy-three to 1,181 rare SNPs in subjects of European descent and 1,234-2,529 SNPs in subjects of African descent (0