京都大学 / マギル大学 / 新制・課程博士 / 博士(ゲノム医学) / 甲第24203号 / 医博JD第1号 / 新制||医||JD1(附属図書館) / 京都大学大学院医学研究科京都大学マギル大学ゲノム医学国際連携専攻 / (主査)教授 稲垣 暢也, 教授 YOUSSEFIAN Shohab, 准教授 Majewski Jacek (マギル大学), 准教授 Gravel Simon (マギル大学), 教授 Gagneur Julien (ミュンヘン工科大学) / 学位規則第4条第1項該当 / Doctor of Philosophy in Human Genetics / Kyoto University / McGill University / DFAM

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Conduct disorder (CD) is a psychiatric syndrome in childhood and adolescence that is one of the most common childhood disorders with continuously increasing prevalence but uncertain pathogenesis. We performed a genome-wide, family-based association study of CD using P2BAT/FBAT software. The data is gathered from Collaborative Study on the Genetics of Alcoholism (COGA) and International Multi-Center ADHD Genetics Project (IMAGE). Using COGA data, we identified 20 markers which showed suggestive associations (p<10-3) with CD. Nine of them are located in known genes. Two genes, ADAM10 and CAMK2A, which had been reported associated with Alzheimer's disease (AD), bipolar disorder, and depression, were of more concern. Using IMAGE sample, our results were well replicated. This study identified several CD associated genetic variants, especially two novel candidate genes. These findings may serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in CD.

Yes / Symptoms and signs (symptoms in brief) are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM). To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. The proposed method gets reliable gene rank list with AUC (area under curve) 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms. / NSFC Project (61105055, 81230086), China 973 Program (2014CB542903), The National Key Technology R&D Program (2013BAI02B01, 2013BAI13B04), the National S&T Major Special Project on Major New Drug Innovation (2012ZX09503-001-003), and the Fundamental Research Funds for the Central Universities.

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10−20), at 17q21.32 (p = 1.51 × 10−9) and at 10p12.1 (p = 2.76 × 10−9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10−9), and at 9q34.12 for IL-10 (p = 4.52 × 10−8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms.

Plant symbiosis with arbuscular mycorrhizal (AM) fungi provides many benefits for plants, including increased nutrient uptake, drought tolerance, and belowground pathogen resistance. In order to have a better understanding of the genetic architecture of mycorrhizal symbiosis, we conducted a genome-wide association study (GWAS) by phenotyping a diversity panel of cultivated sunflower (Helianthus annuus) for root colonization under inoculation with the AM fungus Rhizophagus intraradices. This mapping panel consists of 261 inbred lines that capture approximately 90% of the genetic diversity present in the cultivated sunflower germplasm. Using a mixed linear model approach with a high-density genetic map, we determined regions of the genome that are likely associated with AM colonization in sunflower. Additionally, we used a ‘core 12' set of twelve diverse lines (representing approximately 50% of the genetic diversity in the cultivated germplasm) to assess the effect that inoculation with AM fungi has on dried shoot biomass and macronutrient uptake. Colonization rate among lines in the mapping panel ranged from 0 to 70% and was not correlated with mycorrhizal growth response, shoot P response, or shoot K response among the core 12 lines. Association mapping yielded three SNPs that were significantly associated with AM colonization rate. These SNPs explained 19.0%, 14.4%, and 27.9% of the variance in three different metrics used to measure the degree of root colonization. Three genes of interest identified from the significant regions that contained these SNPs are potentially related to plant defense. Overall, our data suggests that candidate genes involved in plant defense may affect AM colonization rates within cultivated sunflower, and that these genes have a large effect size.

Rice (Oryza sativa) is the staple food for more than 3.5 billion people worldwide. As the population continues to grow, rice yield will need to increase by 1% every year for the next 30 years to keep up with the growth. In the US, Arkansas accounts for more than 50% of rice production. Over the last 68 years, rice production has continued to grow in Mississippi, placing it in fourth place after Arkansas, Louisiana, and California. Due to increasing rice acreage, regionally and worldwide, the need to develop abiotic stress-tolerant rice has increased. Unfortunately, current rice breeding programs lack genetic diversity, and many traits have been lost through the domestication of cultivated rice. Currently, stressors stemming from the continued effects of climate change continue to impact rice. To counteract the impacts of climate change, research has shifted to evaluating wild and weedy relatives of rice to improve breeding techniques. Weedy rice (Oryza sativa ssp.) is a genetically similar, noxious weed in rice with increased competitive ability. Studies have demonstrated that weedy rice has increased genetic variability and inherent tolerance to abiotic stressors. The aims of this study were to 1) screen a weedy rice mini-germplasm for tolerance to cold, heat, and complete submergence-stress, 2) utilize simple sequence repeat (SSR) markers and single nucleotide polymorphisms to evaluate the genetic diversity of the weedy rice population, and 3) use genome-wide association (GWAS) to identify SNPs associated with candidate genes within the population.

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<p>Hypercholesterolemia is the presence of high levels of cholesterol in the blood, and it is one of the major factors for the development of long-term complications in T1D patients.</p> <p>In the thesis, we studied 1303 Caucasians with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT). With the experience of diabetes study, many factors are associated with diabetes complications, they are age, gender, cohort, treatment, diabetes duration, body mass index (BMI), exercise, insulin dose, etc. We mainly focus on which factors are associated with total cholesterol (CHL) analysis in the thesis.</p> <p>Many measures were collected monthly, quarterly or yearly for average 6.5 years from 1983 to 1993. We used annually lipid measures of DCCT because of their values are sufficient and complete, and they belong to longitudinal data.</p> <p>Different methods are discussed in the study, and linear mixed effect models are the appropriate approach to the study. The details of model selection with CHL model analysis are shown, which includes fixed effect selection, random effects selection, and residual correlation structure selection. Then the SNPs were added on three models individually in GWAS. We found locus (rs7412) is not only genome-wide associated with CHL, but also genome-wide associated with LDL.</p> <p>We will assess whether these SNPs are diabetes-specific in the future, and we will add dietary data in the three models to identify locus are associated with the interaction of diet and SNPs.</p> / Master of Science (MSc)