Indonesia is experiencing various environmental challenges related to its fast economic growth. Therefore, it is necessary to have measurable and applicable indicators to obtain accurate data and... Show moreIndonesia is experiencing various environmental challenges related to its fast economic growth. Therefore, it is necessary to have measurable and applicable indicators to obtain accurate data and information regarding the costs of adverse environmental impacts arising from economic activities to support more effective and targeted decision-making. Therefore, this thesis aims to answer how we can set up environmental-economic accounts in developing countries such as Indonesia and how such accounts can support both development as environmental policies. So, the overall objective of this PhD thesis can be formulated as follows: how can we set up environmental-economic accounts in developing countries such as Indonesia, and how can such accounts support both development as environmental policies? Show less
Migraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors.... Show moreMigraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors. Unraveling its molecular basis and deciphering pathways leading to migraine attacks will help identifying novel treatment targets. For this thesis different genetic approaches were applied. Families with hemiplegic migraine (FHM), a rare monogenic subtype of migraine, were studied. Three genes were identified, all involved in modulation of ion influxes across neuronal and glial cell membranes. We identified many mutations in these genes and performed assays in cellular models to understand their functional consequences. In addition, we investigated the role of these genes in sporadic hemiplegic migraine (SHM). Importantly, we expanded the clinical spectrum associated with FHM genes, and established the link between migraine and epilepsy. We also performed genetic studies in common migraine families using two different approaches; the first was an outbred linkage approach with MO families, the second a family-based association approach with severe MA patients from a genetic isolate. Our results supported that, most likely, the intrinsic genetic heterogeneity in migraine families seriously hampers the identification of migraine loci and ultimately migraine genes. Show less
Osteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint... Show moreOsteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint specific OA phenotypes. Only a few studies allowed an examination of multiple joint sites in the patients included. In this thesis, we have focused, on the identification and investigation of OA susceptibility of rare and common generalised OA (GOA) in family based studies and common OA in the population. We investigated previously reported relationships between two candidate genes (FRZB and MATN3) with OA in a random sample from the population-based Rotterdam study and in siblings from the Genetics Osteoarthritis and Progression (GARP) study. A functional variant in FRZB indeed associates to OA but this seems not confined to hip only. Associations of MATN3 variants suggest that genetic variation in this gene determines susceptibility to spinal disc degeneration and OA of the first carpometacarpal joint. Different linkage areas were identified for early and late onset GOA. We mapped a major locus for OA at multiple joint sites on 14q32.11 in middle aged siblings from the GARP study and on 2q33.3 in seven early onset families. From our studies so far, DIO2, IDH1 and NRP2 may be new OA loci. Show less
Complex traits are caused by multiple genetic and environmental factors, and are therefore difficult to study compared with simple Mendelian diseases. The modes of inheritance of Mendelian diseases... Show moreComplex traits are caused by multiple genetic and environmental factors, and are therefore difficult to study compared with simple Mendelian diseases. The modes of inheritance of Mendelian diseases are often known. Methods to dissect such diseases are well described in literature. For complex genetic traits, the inheritance pattern is not clear and difficult to understand, and genetic variants contributing to such traits probably have small effect sizes. Hence, searching for genes responsible for complex traits requires different strategies searching for genes responsible for complex traits requires different strategies as well as new methods. A common strategy for mapping complex traits is as follows: (1) perform a genome-wide linkage analysis using dense genetic markers, and identify regions showing evidence of linkage, then (2) perform association analysis to refine these regions. Along these lines we propose several methods for detecting disease genes. Show less
