One of the main biological goals of recent years is to determine the genes in the human genome that cause disease. Recent technological advances have realised genome-wide association studies, which have uncovered numerous genetic regions implicated with human diseases. The current approach to analysing data from these studies is based on testing association at single SNPs but this is widely accepted as underpowered to detect rare and poorly tagged variants. In this thesis we propose several novel approaches to analysing large-scale association data, which aim to improve upon the power offered by traditional approaches. We combine an established imputation framework with a sophisticated disease model that allows for multiple disease causing mutations at a single locus. To evaluate our methods, we have developed a fast and realistic method to simulate association data conditional on population genetic data. The simulation results show that our methods remain powerful even if the causal variant is not well tagged, there are haplotypic effects or there is allelic heterogeneity. Our methods are further validated by the analysis of the recent WTCCC genome-wide association data, where we have detected confirmed disease loci, known regions of allelic heterogeneity and new signals of association. One of our methods also has the facility to identify the high risk haplotype backgrounds that harbour the disease alleles, and therefore can be used for fine-mapping. We believe that the incorporation of our methods into future association studies will help progress the understanding genetic diseases.

Cancer is the leading cause of deaths globally. Although liver cancer ranks only fourth in incidence worldwide among all types of cancer, its survivability rate is the lowest. Liver cancer is often diagnosed at an advanced stage, because in the early stages of the disease patients usually do not have signs or symptoms. After initial diagnosis, therapeutic options are limited and tend to be effective only for small size tumors with limited spread and minimal vascular invasion. As a result, long-term patient survival remains minimal, and has not improved in the past three decades. In order to reduce morbidity and mortality from liver cancer, improvement in early diagnosis and the evaluation of current treatments are essential. This study tested the applicability of the Apriori and FP-Growth association data mining algorithms to liver cancer patient data, obtained from the British Columbia Cancer Agency. The data was used to develop association rules which indicate what combinations of factors are most commonly observed with liver cancer incidence as well as with increased or decreased rates of mortality. Ideally, these association rules will be applied in future studies using liver cancer data extracted from other Electronic Health Record (EHR) systems. The main objective of making these rules available is to facilitate early detection guidelines for liver cancer and to evaluate current treatment options. / Graduate / 0566 / 0984 / fabiola@uvic.ca

Resumo: Neste trabalho, o objetivo foi estudar a associação de marcadores moleculares dos genes do fator do crescimento semelhante à insulina tipo 1 (IGF1), do hormônio do crescimento (GH) e do fator de transcrição da pituitária (PIT1) com pesos ao nascimento (PN), à desmama (PD), aos 12 (P12) e aos 18 (P18) meses de idade, ganho do nascimento a desmama (GND), idade (IPP) e peso (PPP) ao primeiro parto e perímetro escrotal medido aos 12 (PE12) e 18 (PE18) meses de idade em bovinos da raça Canchim. Análises pelo método de máxima verossimilhança restrita, sob modelo animal indicaram que o gene IGF1 foi responsável por 4±3% da variância fenotípica de PN e o gene GH responsável por 7±6% e 26±13% da variação fenotípica de P12 e PPP, respectivamente. Análises de substituição alélica de IGF1, GH e PIT1 sobre o valor genético (VG) direto e materno (PNmaterno e PDmaterno) das características identificaram que os animais com o alelo "229" de IGF1 teriam VG favoráveis para características reprodutivas e de crescimento. Para GH, o alelo "L" apresentou-se relacionado a maiores VG de P12 e IPP e menores VG de PPP. O alelo "Hinf-" de PIT1 foi associado a menores VG de PN, PDmaterno e IPP e maiores VG de PD e PPP. Concluiu-se que existe um QTL para características de crescimento e reprodutivas segregando junto ao marcador de IGF1. O gene GH foi associado com P12, PPP e IPP, enquanto que o gene PIT1 foi associado ao PD, P12 e PPP. A genotipagem de mais animais, ou a saturação da região desses genes por busca de outros polimorfismos, poderá contribuir para quantificar o exato efeito desses genes sobre as características estudadas / Abstract: Analyses of the association of genetic markers with economic traits in beef cattle have been mainly reported in developed countries. In the Brazilian Canchim breed, studies found association of polymorphism in the insulin-like growth factor 1 (IGF1), growth hormone (GH) and specific pituitary transcriptions (PIT1) genes with growth traits. However, no studies were found that used the variance component approach to estimate the genetic variance due to these genes, or QTLs linked to them, in Canchim cattle.The objective of this study was to evaluate the effects of molecular markers IGF1, GH and PIT1 on the growth and reproductive traits in Canchim cattle. The traits analyzed included: birth weight (BW), weaning weight (WW), average daily gain from birth to weaning (ADG), body weight at 12 (W12) and at 18 months (W18), age at first calving (AFC), body weight at first calving (WFC), scrotal circumference at 12 (SC12) and at 18 months of age (SC18). Proportion of phenotypic variance of these traits that are explained by polymorphisms on the IGF1, GH and PIT1 genes was estimated using the restricted maximum likelihood (REML). In addition the allele substitution effect of these genes on estimated breeding values (EBV) was verified by the least squares method. The polymorphism in the IGF1 explained 4±3% of the BW phenotypic variance, while the polymorphism in GH explained 7±6% e 26±13% of the estimated phenotypic variance for WW and WFC, respectively. There is a QTL for reproductive and growth traits segregating with the marker IGF1. The GH gene was associated with W12, AFC and WFC, while PIT1 was associated with WW, W12 and WFC. Genotyping of more animals or the saturation region of other polymorphisms may help to quantify the exact effect of these genes on these traits / Orientador: Danísio Prado Munari / Coorientador: Claudia Cristina Paro de Paz / Coorientador: Luciana Correia de Almeida Regitano / Banca: Roberto Carvalheiro / Banca: Mônica Corrêa Ledur / Banca: João Ademir de Oliveira / Banca: Sandra Aldair de Queiroz / Doutor

Made available in DSpace on 2014-06-11T19:32:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-01Bitstream added on 2014-06-13T20:23:19Z : No. of bitstreams: 1 grossi_da_dr_jabo.pdf: 310388 bytes, checksum: 2b91ab5f611fab0a39c17b2857959958 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Neste trabalho, o objetivo foi estudar a associação de marcadores moleculares dos genes do fator do crescimento semelhante à insulina tipo 1 (IGF1), do hormônio do crescimento (GH) e do fator de transcrição da pituitária (PIT1) com pesos ao nascimento (PN), à desmama (PD), aos 12 (P12) e aos 18 (P18) meses de idade, ganho do nascimento a desmama (GND), idade (IPP) e peso (PPP) ao primeiro parto e perímetro escrotal medido aos 12 (PE12) e 18 (PE18) meses de idade em bovinos da raça Canchim. Análises pelo método de máxima verossimilhança restrita, sob modelo animal indicaram que o gene IGF1 foi responsável por 4±3% da variância fenotípica de PN e o gene GH responsável por 7±6% e 26±13% da variação fenotípica de P12 e PPP, respectivamente. Análises de substituição alélica de IGF1, GH e PIT1 sobre o valor genético (VG) direto e materno (PNmaterno e PDmaterno) das características identificaram que os animais com o alelo “229” de IGF1 teriam VG favoráveis para características reprodutivas e de crescimento. Para GH, o alelo “L” apresentou-se relacionado a maiores VG de P12 e IPP e menores VG de PPP. O alelo “Hinf-” de PIT1 foi associado a menores VG de PN, PDmaterno e IPP e maiores VG de PD e PPP. Concluiu-se que existe um QTL para características de crescimento e reprodutivas segregando junto ao marcador de IGF1. O gene GH foi associado com P12, PPP e IPP, enquanto que o gene PIT1 foi associado ao PD, P12 e PPP. A genotipagem de mais animais, ou a saturação da região desses genes por busca de outros polimorfismos, poderá contribuir para quantificar o exato efeito desses genes sobre as características estudadas / Analyses of the association of genetic markers with economic traits in beef cattle have been mainly reported in developed countries. In the Brazilian Canchim breed, studies found association of polymorphism in the insulin-like growth factor 1 (IGF1), growth hormone (GH) and specific pituitary transcriptions (PIT1) genes with growth traits. However, no studies were found that used the variance component approach to estimate the genetic variance due to these genes, or QTLs linked to them, in Canchim cattle.The objective of this study was to evaluate the effects of molecular markers IGF1, GH and PIT1 on the growth and reproductive traits in Canchim cattle. The traits analyzed included: birth weight (BW), weaning weight (WW), average daily gain from birth to weaning (ADG), body weight at 12 (W12) and at 18 months (W18), age at first calving (AFC), body weight at first calving (WFC), scrotal circumference at 12 (SC12) and at 18 months of age (SC18). Proportion of phenotypic variance of these traits that are explained by polymorphisms on the IGF1, GH and PIT1 genes was estimated using the restricted maximum likelihood (REML). In addition the allele substitution effect of these genes on estimated breeding values (EBV) was verified by the least squares method. The polymorphism in the IGF1 explained 4±3% of the BW phenotypic variance, while the polymorphism in GH explained 7±6% e 26±13% of the estimated phenotypic variance for WW and WFC, respectively. There is a QTL for reproductive and growth traits segregating with the marker IGF1. The GH gene was associated with W12, AFC and WFC, while PIT1 was associated with WW, W12 and WFC. Genotyping of more animals or the saturation region of other polymorphisms may help to quantify the exact effect of these genes on these traits

Background and aims: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify genetic variants associated with carotid plaque and examine the potential shared genetic basis with CAD. Methods: After investigating the reliability of plaque detection, we performed a genome-wide metaassociation study in two independent cohorts (LIFE-Adult, n=4,037 and LIFE-Heart, n=3,152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. Results: We identified two loci with genome-wide significance for PS. One locus is the known CADlocus at chromosome 9p21 (lead SNP rs9644862, p=8.73x10-12). We also describe a novel locus at on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p=1.97x10-8). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. Conclusion: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20278号 / 医博第4237号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森田 智視, 教授 佐藤 俊哉, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Alleles, genotypes and haplotypes (combinations of alleles) have been widely used in gene-disease association studies. More recently, association studies using diplotypes (haplotype pairs on homologous chromosomes) have become increasingly common. This article reviews the rationale of the four types of association analyses and discusses the situations in which diplotype-based analyses are more powerful than the other types of association analyses. Haplotype-based association analyses are more powerful than allele-based association analyses, and diplotype-based association analyses are more powerful than genotype-based analyses. In circumstances where there are no interaction effects between markers and where the criteria for Hardy-Weinberg Equilibrium (HWE) are met, the larger sample size and smaller degrees of freedom of allele-based and haplotype-based association analyses make them more powerful than genotype-based and diplotype-based association analyses, respectively. However, under certain circumstances diplotype-based analyses are more powerful than haplotype-based analysis.

No description available.

O Departamento de Genética da Escola Superior de Agricultura \"Luiz de Queiroz\" - ESALQ/USP possui um banco de germoplasma de arroz com aproximadamente 460 acessos, oriundos de diferentes instituições de pesquisa do Brasil e do mundo. Desses, cerca de 190 acessos pertenciam ao Japão, 142 são de origem Filipina e os demais são variedades crioulas e cultivares brasileiras. Tais acessos estão passando por uma extensa pesquisa científica afim de obter informações a respeito de sua origem, diversidade e estruturação genética. Este trabalho teve como objetivo estudar a diversidade genética e fazer uma análise de associação genômica ampla (GWAS) de características diversas dos acessos, a fim de conhecer a diversidade e estrutura genética dos mesmos e as regiões genômicas responsáveis pelo controle de características que poderiam ser utilizadas em programas de melhoramento. A genotipagem foi realizada utilizando marcadores SNPs (Single Nucleotide Polimorfism) gerados por meio da tecnologia DArTseq (Diversity Arrays Sequence) de genotipagem por sequenciamento (GBS). A Diversidade genética da população foi analisada por meio do pacote \"hierfstat\", implementado no Software R, onde foram utilizados 269 acessos (os acessos de origem Filipina e Brasileira). Para as análises de associação foram utilizados os 142 acessos filipinos. A instalação dos experimentos de caracterização fenotípica foi realizada em áreas de cultivo de sequeiro, na área experimental do Departamento de Genética da ESALQ/USP em dois anos agrícolas. O delineamento experimental foi de blocos aumentados, sendo realizados os tratos culturais recomendados para a cultura. Os acessos foram caracterizados de acordo com descritores indicados pelo IBPGR - IRRI (Rice Advisory Committee). Os caracteres avaliados foram: Número de dias para a emergência (NDE); Número de dias para o florescimento (NDF); Ciclo total da planta (CTP); Massa de cem sementes (MCS); Produtividade de grãos (PG); Comprimento do colmo (CC); Número de Perfilhos (NP); Comprimento e Largura da folha bandeira (CFB e LFB); Altura de planta na maturidade (APM); Comprimento da Panícula (CP); Comprimento e largura da espigueta (CE e LE); Número de ramificações por panícula (NRP). Os dados coletados foram analisados através do software R (R DEVELOPMENT CORE TEAM, 2018). O Banco de Germoplasma de arroz da ESALQ/USP é uma potencial e importante fonte de acessos que podem ser incorporados aos programas de melhoramento, haja vista, o número de acessos e a diversidade genética existente. Não foram identificadas duplicatas entre os acessos avaliados, sendo assim justificável manter-se todos eles na coleção nuclear do Banco. A Análise Discriminante dos Componentes Principais (DAPC) sugeriu a formação de 5 subgrupos genéticos principais na população de estudo de diversidade genética, já a população estudada para análise de associação pode ser subdividida em 3 grupos em função da análise de componentes principais e foram identificados 33 SNP´s associados a oito caracteres quantitativos avaliados nos acessos. A tecnologia de genotipagem por sequenciamento como a DarT-seq mostrou grande eficiência no estudo de diversidade genética e no estudo de associação genômica ampla nos genótipos de arroz testados. / The Department of Genetics of the \"Luiz de Queiroz\" College of Agriculture - ESALQ / USP has a rice germplasm bank with approximately 460 accessions, coming from different research institutions in Brazil and the world. Of these, about 190 accessions belonged to Japan, 142 are of Filipino origin and the others are Creole varieties and Brazilian cultivars. Such accesses are undergoing extensive scientific research in order to obtain information regarding their origin, diversity and genetic structuring. The objective of this work was to study genetic diversity and to perform an analysis of broad genomic association (GWAS) of different characteristics of the accessions, in order to know the diversity and genetic structure of the same and to know genomic regions responsible for the control of characteristics that could be used in breeding programs. Genotyping was performed using single nucleotide polymorphisms (SNPs) generated by sequencing genotyping (GBS) DArTseq (Diversity Arrays Sequence) technology. The genetic diversity of the population was analyzed through the \"hierfstat\" package, implemented in Software R, where 269 accessions (the accesses of Philippine and Brazilian origin) were used. For the analysis of association, the 142 Filipino accessions were used. The establishment of the phenotypic characterization experiments was carried out in rainfed areas, at the experimental farm of the Department of Genetics of ESALQ / USP, in two agricultural years. The experimental design was of increased blocks, being the cultural treatments recommended for the culture. The accesses were characterized according to descriptors indicated by IBPGR - IRRI (Rice Advisory Committee). The evaluated characters were: Number of days for the emergency (NDE); Number of days for flowering (NDF); Total plant cycle (CTP); One hundred seed mass (MCS); Grain yield (PG); Height of high (CC); Number of Profiles (NP); Length and width of the flag leaf (CFB and LFB); Height of plant at maturity (APM); Panicle Length (CP); Length and width of the spikelet (CE and LE); Number of branches per panicle (NRP). The collected data were analyzed through the software R (R DEVELOPMENT CORE TEAM, 2018). The Rice Germplasm Bank of ESALQ / USP is a potential and important source of access that can be incorporated into breeding programs, presence, number of hits and a possible genetic model. No duplicates were used between the accesses evaluated and thus justified. The Principal Components Discriminant Analysis (DAPC) suggested the formation of 5 major genetic subgroups in its genetic study series, already the population studied for analysis of association can be subdivided into 3 groups as a function of the analysis of main components and 33 SNP\'s associated to eight quantitative traits evaluated in the accessions were identified. Sequencing genotyping technology such as DarT-seq showed great efficiency in the study of genetic diversity and in the study of broad genomic association in the tested rice genotypes.

The objective of this Bachelor thesis is to analyze moving patterns in Norrköping’s municipality. The main aim is to analyze the migration to, from, and within the municipality of Norrköping, not only for the population as a whole but also for groups of special interest. Another aim is to compare migration patterns in Norrköping with those of other municipalities in Sweden.Several data sets have been used, each of them extracted from population statistics carried out by Statistics Sweden (SCB).Data mining using association analysis is used for finding the migration pattern within Norrköping’s municipality and several questions are examined using descriptive statistics. Mann-Kendall tests are used to determine interesting trends in the population changes.The results show that pre-school children do not remain longer in the city centre than they did previously; people moving to Norrköping from within Sweden move mostly to the city centre, though immigrants from abroad mainly favour Hageby and Åby tätort. Furthermore, the results show that people generally move to areas that are geographically similar to where they were or have been before. There is a decrease in migration of people with a Humanities or Arts background, as there is for those with a pedagogy and teacher training background. Areas with a decrease in migration are the suburbs as well as built-up areas at the fringe of the municipality. Norrköping has both lower immigration and emigration than other comparable Swedish municipalities. / Syftet med denna kandidatuppsats är att analysera flyttmönster i Norrköpings kommun. Målet är att analysera både flyttningar till, från, och inom Norrköpings kommun för dels hela populationen och dels speciellt intressanta grupper. Ett annat mål är att jämföra flyttmönster i Norrköping med några andra kommuner i Sverige.För att kunna genomföra dessa analyser har flera datamaterial använts. Gemensamt för datamaterialen är att de allihop baseras på Statistiska Centralbyråns (SCB:s) befolkningsstatistik.För att hitta mönster för hur människor flyttar inom Norrköpings kommun används associationsanalys. Med hjälp av deskriptiv analys undersöks olika särskilt intressanta områden av omflyttningarna i kommunen. Vidare används Mann-Kendalltester för att se om det finns några särskilt intressanta trender i befolkningsutvecklingen.Resultatet visar att ingen förändring har skett när det gäller ifall barn i förskoleåldern bor kvar i stadskärnan i större utsträckning än tidigare. Inflyttare från Sverige flyttar i stor utsträckning till stadskärnan, medan Hageby och Åby tätort är vanliga att flytta till om man flyttar från utlandet. Vidare visar resultatet att människor oftast flyttar till geografiskt nära områden samt områden som har ungefär samma bostadsform som det man tidigare bott i. Flyttningsnettot är negativt för de med utbildning inom Humaniora och konst samt Pedagogik och lärarutbildning. De områden som har negativ befolkningsutveckling ligger i utkanten av centralorten eller är tätorter i utkanten av kommunen. Norrköpings kommun har lägre inflyttning och utflyttning än de flesta andra jämförbara kommuner.